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Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Previous studies have reported that fucoidan can relieve obesity and hepatic steatosis in vivo, although the molecular mechanism remains unclear. This study aimed to explore the effect and potential molecular mechanism of fucoidan in NAFLD using the free fatty acid (FFA)-induced NAFLD spheroid model., Materials and Methods: The spheroids were constructed by fusing the HepG2 and LX-2 cells. Spheroids and HepG2 cells were stimulated with FFAs and fucoidan, then the intracellular lipid contents and the oxidative stress levels (ROS/MDA/GSH/GR/GPx/NQO1/GCLC/HO-1) were detected. Furthermore, the regulation of PI3K/AKT/Nrf2 pathway and the expression of inflammatory factors (TNF-α and IL-6) were measured., Results: Fucoidan markedly reduced FFA-induced intracellular lipid accumulation in spheroids and HepG2 cells. Notably, fucoidan relieved FFA-induced oxidative stress by reducing the levels of ROS and MDA, and elevating the levels of GSH, GR, and GPx. Furthermore, fucoidan reduced FFA-induced oxidative stress by activating the PI3K/AKT/Nrf2 signaling pathway and by inhibiting ROS-induced P65 NF-κB activation and inflammatory responses via Nrf2 pathway activation., Conclusions: Our results demonstrated that fucoidan ameliorated FFA-induced lipid accumulation, oxidative stress, and NF-κB-mediated inflammation through the PI3K/AKT/Nrf2 signaling pathway in the spheroid and HepG2 cells model of NAFLD. These results provided new evidence for the clinical use of fucoidan in the treatment of NAFLD and its potential molecular mechanism of action., Competing Interests: Declarations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background/aims: : Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China., Methods: : A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators., Results: : Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders., Conclusions: : In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease associated with type 2 diabetes mellitus (T2D). NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and even cancer, all of which have a very poor prognosis. Semaglutide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist, has been recognized as a specific drug for the treatment of diabetes. In this study, we used a gene mutation mouse model (db/db mice) to investigate the potential liver-improving effects of semaglutide. The results showed that semaglutide improved lipid levels and glucose metabolism in db/db mice. HE staining and oil red staining showed alleviation of liver damage and reduction of hepatic lipid deposition after injection of semaglutide. In addition, semaglutide also improved the integrity of gut barrier and altered gut microbiota, especially Alloprevotella, Alistpes, Ligilactobacillus and Lactobacillus. In summary, our findings validate that semaglutide induces modifications in the composition of the gut microbiota and ameliorates NAFLD, positioning it as a promising therapeutic candidate for addressing hepatic steatosis and associated inflammation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TUOHUA MAO reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To investigate the neural static and dynamic intrinsic activity of intra-/inter-network topology among patients with type 2 diabetes (T2D) with non-alcoholic fatty liver disease (NAFLD) and those without NAFLD (T2NAFLD group and T2noNAFLD group, respectively) and to assess the relationship with metabolism., Methods: Fifty-six patients with T2NAFLD, 78 with T2noNAFLD, and 55 healthy controls (HCs) were recruited to the study. Participants had normal cognition and underwent functional magnetic resonance imaging scans, clinical measurements, and global cognition evaluation. Independent component analysis was used to identify frequency spectrum parameters, static functional network connectivity, and temporal properties of dynamic functional network connectivity (P < 0.05, false discovery rate-corrected). Statistical analysis involved one-way analysis of covariance with post hoc, partial correlation and canonical correlation analyses., Results: Our findings showed that: (i) T2NAFLD patients had more disordered glucose and lipid metabolism, had more severe insulin resistance, and were more obese than T2noNAFLD patients; (ii) T2D patients exhibited disrupted brain function, as evidenced by alterations in intra-/inter-network topology, even without clinically measurable cognitive impairment; (iii) T2NAFLD patients had more significant reductions in the frequency spectrum parameters of cognitive executive and visual networks than those with T2noNAFLD; and (iv) altered brain function in T2D patients was correlated with postprandial glucose, high-density lipoprotein cholesterol, and waist-hip ratio., Conclusion: This study may provide novel insights into neuroimaging correlates for underlying pathophysiological processes inducing brain damage in T2NAFLD. Thus, controlling blood glucose levels, lipid levels and abdominal obesity may reduce brain damage risk in such patients., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background and Aims: The American Heart Association (AHA) updated the construct and algorithm of cardiovascular health (CVH) recently. We aimed to explore the relationship between the new CVH score and the development of non-alcoholic fatty liver disease (NAFLD)., Methods and Results: 3266 adults free of NAFLD identified via ultrasound were recruited in this prospective study. A modified AHA "Life's Essential 8" (mLE8, i.e., physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) were collected to evaluate the CVH score. Then participants were categorized into low, moderate, and high CVH subgroups based on overall mLE8 CVH score. According to modified Life's Simple 7 (mLS7) CVH construct, participants were also subdivided into poor, intermediate, and ideal CVH subgroups. During a median 4.3 years follow-up, 623 incident cases of NAFLD were recorded. Compared to those with high CVH, participants with low CVH (adjusted OR = 2.56, 95% CI 1.55-4.24) and moderate CVH (adjusted OR = 1.83, 95% CI 1.17-2.85) had a significantly increased risk of incident NAFLD. Participants with poor CVH (mLS7) but without low CVH (mLE8) did not show a significant elevated risk of incident NAFLD (P = 0.1053). A significant trend was found between increased changes in mLE8 score and a lower risk of NAFLD occurrence., Conclusion: Our findings suggested high mLE8 CVH score was associated with a lower risk of NAFLD incidence. The new CVH construct showed a more reasonable classification of CVH status and was more robust in association with NAFLD risks compared with the original one., Competing Interests: Declaration of competing interest We declare that we have no conflict of interest., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Diabesity is a term used to emphasize the dual epidemic and the combined detrimental effects of diabetes and obesity. We aimed to investigate the associations of diabesity with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD)., Methods: This prospective cohort study included 5549 participants with a median follow-up of 4.3 years (2010-2015). Diabesity was defined as six categories by the combinations of glucose tolerance status (normal glucose tolerance [NGT], prediabetes, and diabetes) diagnosed by fasting and oral glucose tolerance test 2-h glucose and hemoglobin A1c and general or abdominal obesity status. We examined the odds ratios (ORs) for the incidence and resolution of NAFLD associated with diabesity categories, respectively., Results: For NAFLD incidence, compared with the diabesity category of NGT with nonobesity, the categories of either glucose intolerance or general obesity were associated with higher risks of NAFLD, of which the categories with obesity, regardless of glucose intolerance status, exhibited greater risks (ORs ranged from 3.19 to 4.49) than the categories of nonobesity. For NAFLD resolution, the categories of prediabetes or diabetes with obesity were associated with decreased likelihoods of a resolution of NAFLD (ORs ranged from 0.40 to 0.58). These association patterns were consistent across various definitions of diabesity by glucose tolerance status diagnosed by different combinations of glycemic parameters and general or abdominal obesity., Conclusions: The diabesity association pattern with NAFLD incidence was mainly determined by obesity, while that with NAFLD resolution was driven by the combined phenotype of glucose intolerance and obesity., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Cells and tissues, such as macrophages, express inducible nitric oxide synthase (INOS) after stimulation by certain factors. INOS helps mediate the macrophage inflammatory reaction, but few studies have explored how INOS affects macrophage function in nonalcoholic fatty liver disease (NAFLD)., Objective: This study investigated the role of INOS-mediated macrophage activity in NAFLD., Methods: A high-fat diet was used to establish an NAFLD mouse model. After 12 weeks, blood was collected for immune cell and lipid analyses, and liver tissues were collected for pathological analyses with hematoxylin and eosin and Oil Red O staining. Peritoneal macrophages were extracted in situ, cultured in Dulbecco's modified Eagle's medium, and stimulated with palmitic acid to mimic in vivo conditions for further assays. Real-time polymerase chain reaction, western blot analysis, and immunofluorescence were used to verify the expression of target genes or proteins., Results: In the NAFLD model, INOS expression in macrophages increased, and INOS knockdown significantly decreased the number of macrophages. Pathological examinations confirmed that INOS knockdown slowed NAFLD progression and macrophage infiltration during inflammation. INOS knockdown also enhanced phagocytosis and lipid transport by macrophages, and increased the expression of autophagy-related molecules in macrophages, which improved the autophagy level, promoted apoptotic cell degradation, and maintained intracellular environment homeostasis., Conclusions: These results indicate a correlation between INOS expression and macrophage function in NAFLD., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Context: Although cognitive impairment in nonalcoholic fatty liver disease (NAFLD) has received attention in recent years, little is known about detailed cognitive functions in histologically diagnosed individuals., Objective: This study aimed to investigate the association of liver pathological changes with cognitive features and further explore the underlying brain manifestations., Methods and Patients: We performed a cross-sectional study in 320 subjects who underwent liver biopsy. Among the enrolled participants, 225 underwent assessments of global cognition and cognitive subdomains. Furthermore, 70 individuals received functional magnetic resonance imaging scans for neuroimaging evaluations. The associations among liver histological features, brain alterations, and cognitive functions were evaluated using structural equation model., Results: Compared with controls, patients with NAFLD had poorer immediate memory and delayed memory. Severe liver steatosis (odds ratio, 2.189; 95% CI, 1.020-4.699) and ballooning (OR, 3.655; 95% CI, 1.419-9.414) were related to a higher proportion of memory impairment. Structural magnetic resonance imaging showed that patients with nonalcoholic steatohepatitis exhibited volume loss in left hippocampus and its subregions of subiculum and presubiculum. Task-based magnetic resonance imaging showed that patients with nonalcoholic steatohepatitis had decreased left hippocampal activation. Path analysis demonstrated that higher NAFLD activity scores were associated with lower subiculum volume and reduced hippocampal activation, and such hippocampal damage contributed to lower delayed memory scores., Conclusions: We are the first to report the presence and severity of NAFLD to be associated with an increased risk of memory impairment and hippocampal structural and functional abnormalities. These findings stress the significance of early cognitive evaluation in patients with NAFLD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways., Methods: We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association., Results: Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%)., Conclusions: Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10-1.32] for ALM to 2.30 [1.14-4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08-1.64] for ALM to 2.30 [1.02-5.18] for grip strength), hypertension (1.12 [1.05-1.20] for ALM to 4.43 [2.68-7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13-1.27] for ALM to 2.73 [1.84-4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11-1.25] for ALM to 2.47 [1.63-3.73] for walking pace), small vessel stroke (1.25 [1.15-1.37] for ALM to 1.29 [1.10-1.52] for WBLM), and Alzheimer's disease (1.10 [1.05-1.15] for ALM to 1.28 [1.19-1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%-34% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Hypertriglyceridemic hyperapoB is an adverse lipoprotein phenotype characterized by low high density lipoprotein (HDL) cholesterol, high triglycerides, high apolipoprotein B (ApoB), and low low density lipoprotein (LDL) cholesterol to ApoB ratio. We investigated whether and to what extent hypertriglyceridemic hyperapoB associates with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD). This prospective cohort study included 9,019 Chinese participants 40 years or older, from 2010 to 2015. Logistic regression models were used to examine the odds ratios (ORs) for the incidence and resolution of NAFLD associated with the hypertriglyceridemic hyperapoB lipoprotein phenotype and individual lipid and lipoprotein parameters. During a median 4.3 years of follow-up, compared with participants with optimal phenotype, the fully adjusted ORs (95% CIs) for participants with hypertriglyceridemic hyperapoB were 2.75 (1.91, 3.95) and 0.57 (0.33, 1.00) for incidence and resolution of NAFLD, respectively. These associations were consistent across subgroup participants with varied demographic, lifestyle, and metabolic status. Individually, each unit increase in HDL cholesterol (OR: 0.98; 95% CI: 0.97, 0.99), natural logarithm-transformed triglycerides (1.89; 1.52, 2.36), and ApoB (1.006; 1.002, 1.011) was independently associated with NAFLD incidence, and only triglycerides (0.77; 0.60, 0.99) was independently associated with NAFLD resolution. Our findings suggest that Chinese adults with hypertriglyceridemic hyperapoB have a higher risk of NAFLD incidence and a lower likelihood of NAFLD resolution. These associations were stable among adults with different demographic, lifestyle, and metabolic status, supporting hypertriglyceridemic hyperapoB as a valuable clinical marker for the prevention and control of NAFLD., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Single-nucleotide polymorphisms in G protein-coupled receptor 180 (GPR180) are associated with hypertriglyceridemia. The aim of this study was to determine whether hepatic GPR180 impacts lipid metabolism. Hepatic GPR180 was knocked down using two approaches: Gpr180 -specific short hairpin (sh)RNA carried by adeno-associated virus 9 (AAV9) and alb-Gpr180 -/- transgene established by crossbreeding albumin-Cre mice with Gpr180 flox/flox animals, in which Gpr180 was specifically knocked down in hepatocytes. Adiposity, hepatic lipid contents, and proteins related to lipid metabolism were analyzed. The effects of GPR180 on triglyceride and cholesterol synthesis were further verified by knocking down or overexpressing Gpr180 in Hepa1-6 cells. Gpr180 mRNA was upregulated in the liver of HFD-induced obese mice. Deficiency of Gpr180 decreased triglyceride and cholesterol contents in the liver and plasma, ameliorated hepatic lipid deposition in HFD-induced obese mice, increased energy metabolism, and reduced adiposity. These alterations were associated with downregulation of transcription factors SREBP1 and SREBP2, and their target acetyl-CoA carboxylase. In Hepa1-6 cells, Gpr180 knockdown decreased intracellular triglyceride and cholesterol contents, whereas its overexpression increased their levels. Overexpression of Gpr180 significantly reduced the PKA-mediated phosphorylation of substrates and consequent CREB activity. Hence, GPR180 might represent a novel drug target for intervention of adiposity and liver steatosis.

Background & Aims: The causal association of lower birthweight with non-alcoholic fatty liver disease (NAFLD) and the mediating pathways remain unclear. We aimed to investigate the causal, independent association of lower birthweight with NAFLD and identify potential metabolic mediators and their mediation effects in this association., Methods: We performed two-step, two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics for birthweight from the Early Growth Genetics Consortium of 298 142 Europeans, NAFLD from a GWAS meta-analysis of 8434 NAFLD cases and 770 180 controls of Europeans, and 25 candidate mediators from corresponding reliable GWASs., Results: Genetically determined each 1-SD lower birthweight was associated with a 45% (95% CI: 1.25-1.69) increased risk of NAFLD, and this causal association persisted after adjusting for childhood obesity or adult adiposity traits in multivariable MR. Two-step MR identified 6 of 25 candidate mediators partially mediate the effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.05%), leucine (17.29%), isoleucine (13.55%), valine (11.37%), alanine (10.01%) and monounsaturated fatty acids (MUFA; 7.23%). Bidirectional MR suggested a unidirectional effect of insulin resistance on isoleucine, leucine and valine and a unidirectional effect of alanine on insulin resistance., Conclusions: This MR study elucidated the causal impact of lower birthweight on subsequent risk of NAFLD, independently of later-life adiposity and identified mediators including insulin resistance, branched-chain amino acids, alanine and MUFA in this association pathway. Our findings shed light on the pathogenesis of NAFLD and imply additional targets for prevention and intervention of NAFLD attributed to low birthweight., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: The association of bone turnover with the incidence and progression of nonalcoholic fatty liver disease (NAFLD) is unclear. We aimed to evaluate serum levels of bone turnover markers in relation to NAFLD and nonalcoholic hepatic steatohepatitis (NASH)., Methods: Two cohorts were involved in our study. For the first cohort, 370 participants without NAFLD were retrospectively recruited and followed up for incident NAFLD according to ultrasound. For the second cohort, 562 subjects who underwent liver biopsy were included and grouped into non-NAFLD, non-NASH or NASH according to the NASH Clinical Research Network system. The bone turnover markers osteocalcin, C-terminal telopeptide (CTX) and N-terminal propeptide of type-1 procollagen (P1NP) were measured., Results: Baseline osteocalcin was significantly lower in subjects who developed NAFLD (13.93 [11.03;16.39] versus 18.24 [15.45;22.47] ng/ml, P < 0.001), with a median of 26.4 months of follow-up. Low levels of osteocalcin, but not CTX or P1NP, was an independent predictor of incident NAFLD (OR 0.755 [95%CI 0.668; 0.855] P < 0.001). Moreover, the osteocalcin level was negatively associated with the degree of liver steatosis. Furthermore, subjects with NASH had significantly lower osteocalcin than non-NASH and non-NAFLD group (13.28 [10.49;16.59] versus 14.91 [12.45;18.09] versus 18.21 [15.04;22.05] ng/ml, all P < 0.001). A low osteocalcin level was an independent risk factor for NASH (OR for highest versus lowest quartile: 0.282 [0.147;0.543] P < 0.001)., Conclusion: Low level of osteocalcin, but not CTX or P1NP, was associated with NAFLD and NASH, indicating its potential role as an important endocrine regulator of hepatic energy metabolism., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the association between visceral adipocyte hypertrophy and the onset and development of non-alcoholic fatty liver disease (NAFLD) in subjects with different degrees of adiposity., Methods: Omental adipose tissue and liver biopsies were collected from obese subjects. NAFLD was defined according to the NASH Clinical Research Network scoring system. Adipocyte size was measured using pathological section analysis. Adipose tissue insulin resistance (Adipo-IR) was calculated as fasting insulin (pmol/L) × fasting free fatty acid concentration (mmol/L)., Results: In total, 275 obese patients were enrolled, including 158 females and 58 males with NAFLD. In females, adipocyte size was significantly larger in NAFLD participants as compared to the controls (99.37 ± 14.18 vs. 84.14 ± 12.65 [Formula: see text]m, p < 0.001). Moreover, adipocyte size was larger in females with non-alcoholic steatohepatitis (NASH) as compared to those with non-alcoholic fatty liver (NAFL) (101.45 ± 12.77 vs. 95.79 ± 15.80 [Formula: see text]m, p = 0.015). Mediation analysis showed that adipocyte size impacted the NAFLD activity score through Adipo-IR (b = 0.007 [95% bootstrap CI 0.002, 0.013]). Furthermore, the females were divided into: Q1 (BMI < 32.5 kg/m 2 ), Q2 (BMI 32.5-35.5 kg/m 2 ), Q3 (BMI 35.5-38.8 kg/m 2 ) and Q4 (BMI ≥ 38.8 kg/m 2 ) according to BMI quartiles. Omental adipocyte size was larger in NAFLD subjects in Q1-Q3, but not in Q4. No similar results were observed in males., Conclusion: For the first time, we reported that visceral adipocyte hypertrophy was associated with the onset and progression of NAFLD in mild to moderate adiposity but not in severe obesity, which may be mediated by adipose tissue insulin resistance., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background: Non-alcoholic fatty liver disease (NAFLD) has become an epidemic worldwide and has been linked to a series of metabolic co-morbidities. Prolactin (PRL) has recently been found to have a negative effect on NAFLD, but a causal relationship is not well-understood. Here we investigated the causative relationship between PRL and NAFLD occurrence., Methods: In this retrospective cohort study, we enrolled patients without NAFLD who were diagnosed by abdominal ultrasonography undergone serum PRL testing at 8.00 a.m. at baseline, and followed up for a median of 32 (19, 46) months., Results: This study enrolled 355 persons [215 men and 140 women; media age 56 (49, 64) years], in which 72 (20.28%) patients who eventually developed NAFLD. Compared with those in the non-NAFLD group, basal serum PRL levels of patients were lower in the NAFLD group [male: 7.35 (5.48, 10.60) vs. 9.13 (6.92, 12.50) ug/L, P = 0.002; female: 5.66 (4.67, 9.03) vs. 9.01 (6.31, 11.60) ug/L, P = 0.009]. The prevalence of NAFLD was significantly decreased along with the increased quartile of basal serum PRL levels in both genders (P < 0.05). Serum PRL concentration was independently associated with NAFLD development [male: OR, 0.881 (0.777, 0.998), P = 0.047; female: OR, 0.725 (0.554, 0.949), P = 0.019]., Conclusion: Our study is the first to find that basal serum PRL level can predict the occurrence of NAFLD and it may be a potential biomarker to prevent and treat NAFLD., (© 2022. The Author(s).)

Objective: To investigate the association between serum sex hormone-binding globulin (SHBG) and non-alcoholic steatohepatitis (NASH). Methods: In this cross-sectional study, a total of 371 middle-aged and young obese patients who were hospitalized and underwent liver puncture in Nanjing Drum Tower Hospital from January 2016 to April 2021 were included. The population was divided into control group ( n =43) and non-alcoholic fatty liver disease (NAFLD) group ( n =328) based on the non-alcoholic fatty liver disease activity score. Subjects in NAFLD group were further divided into non-alcoholic fatty liver (NAFL) ( n =60), uncertain-NASH ( n =172), and NASH ( n =96). Serum SHBG was tested in patients with NAFLD who were divided into three subgroups according to tertiles. The liver pathological characteristics in different SHBG level subgroups were compared. The risk factors of NASH were analyzed by logistic regression. The prediction model of NASH noninvasive diagnosis was established by forward stepwise regression, and the diagnostic value of non-invasive model for NASH was evaluated by receiver operating characteristic (ROC) curve. Results: The median age in patients were (32±10) years old with a body mass index of (39.16±6.58) kg/m², including 236 females (63.6%). Serum SHBG level [ M ( Q 1 , Q 3 )] in NAFLD group was significantly lower than that in control group [16.90 (11.43, 23.00) vs. (23.45 (15.40, 31.22) mmol/L, P <0.05], and progressively diminished in NAFL, uncertain-NASH and NASH subgroups [(22.24±10.47), (20.57±19.58), (15.80±8.74) mmol; P for trend<0.05]. Compared with the high-leveled SHBG subgroup, the steatosis score (2.09±0.80 vs. 1.51±0.72, P <0.01) and lobular inflammation score (1.10±0.68 vs. 0.85±0.68, P <0.05) were significantly higher in the low-leveled SHBG group. Multivariate logistic regression analysis indicated that lower serum SHBG level was an independent risk factor for NASH ( OR =2.527, 95% CI : 1.296 to 4.928, P <0.05). The area under ROC curve of SHBG combined with aspartate aminotransferase in predicting NASH in NAFLD patients was 0.752 (95% CI : 0.696 to 0.809). Conclusion: Low serum SHBG level is associated with NASH.

A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has recently been proposed. We aim to examine the associations of MAFLD, particularly its discordance from non-alcoholic fatty liver disease (NAFLD), with the progression of elevated brachial-ankle pulse wave velocity (baPWV) and albuminuria in a community-based study sample in Shanghai, China. After 4.3 years of follow-up, 778 participants developed elevated baPWV and 499 developed albuminuria. In comparison with the non-MAFLD group, the multivariable adjusted odds ratio (OR) of MAFLD group for new-onset elevated baPWV was 1.25 (95% confidence interval (CI) 1.01-1.55) and 1.35 (95% CI 1.07-1.70) for albuminuria. Participants without NAFLD but diagnosed according to MAFLD definition were associated with higher risk of incident albuminuria (OR 1.77; 95% CI 1.07-2.94). Patients with MAFLD with high value of hepamet fibrosis score or poor-controlled diabetes had higher risk of elevated baPWV or albuminuria. In conclusion, MAFLD was associated with new-onset elevated baPWV and albuminuria independently of body mass index, waist circumference, and hip circumference. Individuals without NAFLD but diagnosed as MAFLD had high risk of albuminuria, supporting that MAFLD criteria would be practical for the evaluation of long-term risk of subclinical atherosclerosis among fatty liver patients., (© 2022. Higher Education Press.)

Background: The study aimed to explore the associations of nonalcoholic fatty liver disease (NAFLD) with the remission and progression along the glycemic continuum., Methods: This prospective cohort study was performed among the general population in 2010-2015. NAFLD was defined as ultrasound-detected hepatic steatosis with absence of excessive alcohol consumption and other hepatic diseases. Remission of type 2 diabetes referred to glycated hemoglobin <6.5% without hypoglycemic agents for ≥3 months. Prediabetes remission referred to normalization of blood glucose. Multivariable logistic analysis was applied to identify the risk of glycemic metabolic transition., Results: During a median follow-up of 4.3 years, participants with NAFLD had a significantly higher risk of progressing from normal glucose tolerance to diabetes (3.36 [1.60-7.07]) and lower likelihood of diabetes remission (0.48 [0.30-0.78]). Associations in participants with overweight or obesity and higher probability of hepatic fibrosis remained consistent. Results related to the effect of NAFLD on the specific glucose parameters were generally in line with the changes of glycemic status. NAFLD improvement decreased the risk of prediabetes progressing to diabetes (0.50 [0.32-0.80]) and increased the probability of prediabetes remission (2.67 [1.49-4.79]). NAFLD tended to show the most significant association with glycemic progression and decreased the likelihood in remission of prediabetes and diabetes., Conclusions: Presence of NAFLD increased risk of glycemic progression and decreased likelihood of remission. NAFLD improvement mitigated glycemic deterioration, whereas NAFLD progression impeded the chance of remission. The results emphasized joint management of NAFLD and diabetes and further focused on liver-specific subgroups of diabetes to tailor early intervention., (© 2022 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background and Purpose: The association between the severity of obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in patients with obesity remains unclear. We conducted this study to determine the effects of OSA on the severity of NAFLD in individuals with obesity and its link to the development of non-alcoholic steatohepatitis (NASH)., Methods: Patients were subjected to standard polysomnography up to 1 week before undergoing bariatric surgery, during which liver biopsy specimens were obtained. The apnea-hypopnea index (AHI) obtained by polysomnography was used to determine the severity of OSA., Results: In total, 183 patients with obesity and biopsy-confirmed NAFLD were included; 49 (27%) had NASH. Patients with NASH had higher AHIs (p = 0.014) and oxygen desaturation indices (p = 0.031), more frequent OSA (p = 0.001), and lower minimum oxygen saturation (p = 0.035). The severity of OSA was directly correlated with the NAFLD activity score (p < 0.001), NASH activity grade (p < 0.001), semi-quantitative indices of lobular inflammation (p = 0.001), and hepatocyte ballooning (p = 0.006). The odds ratios (95% confidence intervals) for NASH and severe NASH (activity grade ≥ 3) associated with moderate-to-severe OSA were 3.85 (1.35-10.94; p < 0.05) and 5.02 (1.66-15.18; p < 0.01), respectively, after adjusting for sex, age, body mass index, waist circumference, insulin resistance values, and metabolic syndrome., Conclusions: Chronic intermittent hypoxia caused by OSA may aggravate NAFLD and lead to a higher risk of NASH in patients with obesity., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background and Aim: Body composition was associated with nonalcoholic steatohepatitis (NASH), but results were controversial probably due to gender differences. Hence, we aim to explore the association of body composition and NASH in males and females., Methods: We conducted a cross-sectional analysis of obese subjects undergone liver biopsy. According to NASH Clinical Research Network system, subjects were categorized as Normal Control (NC), non-NASH or NASH. Body composition was accessed by dual-energy X-ray absorptiometry., Results: This study enrolled 336 subjects (mean age 32.0 years, mean BMI 39.15 kg/m 2 , female, 64.0%). Males have lower relative muscle mass (RMM 55.21 ± 4.07%) and females have higher android to gynoid ratio (AGR, 0.82 ± 0.21) in NASH when compared with non-NASH (RMM 57.49 ± 4.75%; AGR 0.7 ± 0.15) and NC (RMM 58.69 ± 4.09%; AGR 0.66 ± 0.19, p < 0.05 for each). After adjusting for confounding factors, low RMM was the independent risk factor for NASH in males (odds ratio [OR] 0.550; 95% confidence interval [CI] 0.312-0.970), high AGR was the independent risk factor for NASH in females (OR 1.694; 95% CI 1.073-2.674). Further, RMM in males and AGR in females, respectively, was associated with liver steatosis and activity, but not with fibrosis. ROC curve revealed that the optimal cutoff value of RMM was 58.09% in males and AGR was 0.92 in females for predicting NASH., Conclusions: We firstly revealed that low RMM and high AGR were the independent risk factors for NASH in males and females, respectively, indicating that sex-specific interventions for improving body composition may reduce the risk of NASH in obese subjects., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background: Accumulated studies have pointed out the striking association between variants in or near APOC3 , GCKR , PNPLA3 , and nonalcoholic fatty liver disease (NAFLD) at various ages from multiple ethnic groups. This association remained unclear in the Chinese Han elderly population, and whether this relationship correlated to any clinical parameters was also unclear., Objectives: This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis., Methods: Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within APOC3 , GCKR, and PNPLA3 were genotyped using the MassARRAY® platform in a large Chinese Han sample comprising of 733 elderly NAFLD patients and 824 age- and ethnic-matched controls. Association and mediation analysis were employed by R., Results: The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: P =0.004, P corr =0.020, OR [95%CI]= 0.69 [0.54-0.89]; rs780094: P =0.005, P corr =0.025, OR [95%CI]= 0.70 [0.55-0.90]). Particularly, an increased triglyceride level was observed in carriers of rs1260326 T allele (1.94±1.19 mmol/L) compared with non-carriers (1.73±1.05 mmol/L).no significant results were observed in rs780094. Notably, triglyceride levels had considerably indirect impacts on association between NAFLD and rs1260326 (β =0.01, 95% CI: 0.01-0.02), indicating that 12.7% of the association of NAFLD with rs1260326 was mediated by triglyceride levels., Conclusions: Our results identified a prominent relationship between GCKR rs1260326 and NAFLD, and highlighted the mediated effect of triglyceride levels on the that association in the Chinese Han elderly.

Background: Diabetes mellitus, especially type 2 diabetes mellitus (T2DM), is regarded as highly heterogeneous. Novel diabetes phenotypes by cluster analysis have been proposed in Europeans but may show different cluster features in Asians. The applicability of cluster analysis in middle-aged and elderly Chinese community T2DM patients needs further investigation., Methods: Participants were recruited from Jiading community in Shanghai, China. We adopted k-means cluster analysis in 1130 patients (aged ≥ 40 years) with newly-diagnosed T2DM at baseline. Cluster analysis was performed based on seven variables, including fasting plasma glucose, 2 hours postprandial blood glucose, age at diagnosis, body mass index, hemoglobin A1c, homoeostatic model assessment estimates of β-cell function and insulin resistance. All subjects were re-examined at 4.4 years later. Metabolic associated fatty liver disease was diagnosed using B-ultrasound, hepatic fibrosis by non-invasive scores, renal and cardiovascular status by subclinical biomarkers. Multivariable logistic regression models were used to compare the risks of complications between clusters., Results: Patients were classified into 4 clusters. 381 (33.7%), 456 (40.4%), 87 (7.7%), and 206 (18.2%) patients were separately assigned to mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), severe insulin-deficient and insulin-resistant diabetes (SIDRD), or severe obesity-related and insulin-resistant diabetes (SOIRD), respectively. Participants in MARD, SOIRD, and SIDRD clusters were associated with significantly increased risks of different complications. SOIRD and SIDRD showed novel features in Chinese T2DM patients that were different from those in Europeans., Conclusions: The refined diabetes phenotypic approach was applicable to Chinese middle-aged and elderly T2DM patients. Patients in different clusters presented significantly different characteristics, progression of metabolic features, and risks of diabetic complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zheng, Li, Xu, Lu, Zhao, Li, Wang, Wang, Bi, Xu, Ning and Cai.)

Background: Non-alcoholic fatty liver disease (NAFLD) has become a global epidemic disease. Its incidence is associated with type 2 diabetes mellitus (T2DM). Presently, there is no approved pharmacological agents specially developed for NAFLD. One promising disease-modifying strategy is the transplantation of stem cells to promote metabolic regulation and repair of injury., Method: In this study, a T2DM model was established through 28-week high-fat diet (HFD) feeding resulting in T2DM-associated NAFLD, followed by the injection of bone marrow mesenchymal stem cells (BMSCs). The morphology, function, and transfer of hepatocyte mitochondria were evaluated in both vivo and in vitro., Results: BMSC implantation resulted in the considerable recovery of increasing weight, HFD-induced steatosis, liver function, and disordered glucose and lipid metabolism. The treatment with BMSC transplantation was accompanied by reduced fat accumulation. Moreover, mitochondrial transfer was observed in both vivo and vitro studies. And the mitochondria-recipient steatotic cells exhibited significantly enhanced OXPHOS activity, ATP production, and mitochondrial membrane potential, and reduced reactive oxygen species levels, which were not achieved by the blocking of mitochondrial transfer., Conclusion: Mitochondrial transfer from BMSCs is a feasible process to combat NAFLD via rescuing dysfunction mitochondria, and has a promising therapeutic effect on metabolism-related diseases., (© 2021. The Author(s).)

Aims/hypothesis: We aimed to evaluate the effect of NAFLD on the risk of incident cardiovascular disease (CVD) and estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD), and further test the joint effects and interactions between NAFLD status and individual metabolic element, as well as the total 'ABCs' metabolic goal achievement, on the CVD and CKD risk among 101,296 patients with prediabetes or diabetes from a prospective cohort study., Methods: We conducted the study based on the China Cardiometabolic Disease and Cancer Cohort (4C) study, a large-scale, population-based prospective cohort. After excluding alcohol abuse and other cause of hepatic diseases, we used fatty liver index (FLI) ≥ 60 as a proxy of NAFLD and stratified the probability of fibrosis by aspartate transaminase/alanine transaminase ratio (AAR) with cut-offs of 0.8 and 1.4. 'ABCs' metabolic goal was defined as subjects who had HbA1c < 6.5% (A), SBP/DBP < 130/80 mmHg (B), and LDL-C < 100 mg/dL (C). During 3.8 years follow-up, we validated 2340 CVD events based on medical records and identified 1943 participants developed CKD based on centrally tested eGFR., Results: The multivariable adjusted hazard ratios (HRs) were 1.15 (95% confidence interval (CI), 1.05-1.27) for CVD events and 1.33 (95% CI, 1.20-1.48) for CKD among NAFLD patients, compared with participants without NAFLD. Of NAFLD patients, relative to individuals with low AAR (<0.8), those with high AAR (≥1.4) were more likely to experience CVD events [1.62 (1.21-2.18)] and CKD [1.63 (1.17-2.28)]. Participants with NAFLD and comorbid poorly controlled metabolic risk factors had higher risk of CVD events or CKD than having either alone, with a significant interaction between poor glycemic control and NAFLD on the risk of vascular complications., Conclusions: NAFLD was associated with incident CVD and CKD among patients with prediabetes or diabetes. Such associations were substantially modified by the comprehensive achievement of metabolic goal., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Context: Little is known about the link between nonalcoholic fatty liver disease (NAFLD) evolution and incident chronic kidney disease (CKD)., Objective: We aim to assess the associations of NALFD status changes and NAFLD fibrosis progression with the risk of incident CKD., Methods: We conducted a community-based prospective study that included participants aged 40 years or older and free of CKD at baseline in 2010, with follow-up evaluations after a mean of 4.4 years. NAFLD was diagnosed by ultrasonography and NAFLD fibrosis score (NFS) was used to evaluate fibrosis stage and progression. CKD was defined by estimated glomerular filtration rate or urine albumin-to-creatinine ratio. All the measurements were performed at baseline and follow-up examination., Results: Among 4042 participants with 4 NAFLD status change groups, incident NAFLD was associated with an increased risk of incident CKD (odds ratio [OR] = 1.44; 95% CI, 1.003-2.06; P = 0.048) compared with non-NAFLD after adjustments for the confounders, including evolution of diabetes, hypertension, and obesity, in addition to the baseline levels. However, the risk of incident CKD was not significantly different between NAFLD resolution and persistent NAFLD. Among 534 participants in the persistent NAFLD group, fibrosis progression from low NFS to intermediate or high NFS was associated with a significantly increased risk of incident CKD compared with stable fibrosis in low NFS (OR = 2.82; 95% CI, 1.22-6.56; P = 0.016)., Conclusion: NAFLD development and fibrosis progression are associated with increased risk of incident CKD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed and diagnosed based on modified criteria. However, evidence for the risks of developing subclinical atherosclerosis with MAFLD transitions according to its new definition has never been reported., Methods: Using data from a community-based cohort, 6232 participants aged 40 years or older were included and were followed up for a median of 4.3 years during 2010-2015. Participants were categorized into four groups (stable non-MAFLD, MAFLD regressed to non-MAFLD, non-MAFLD progressed to MAFLD, and stable MAFLD). Subclinical atherosclerosis was defined as elevated carotid intima-media thickness (CIMT), elevated brachial-ankle pulse wave velocity (ba-PWV), or microalbuminuria., Results: Compared with the stable non-MAFLD category, participants who progressed to MAFLD at follow-up visit had a 1.356-fold increased risk of developing elevated CIMT [odds ratio (OR) = 1.356; 95% confidence interval (CI) = 1.134-1.620], and a 1.458-fold increased risk of incident microalbuminuria (OR = 1.458; 95% CI = 1.034-2.056) after adjustment for confounders, respectively. In addition, participants with stable MAFLD showed 17.6%, 32.4%, and 35.4% increased risks of developing elevated CIMT, elevated ba-PWV and microalbuminuria, respectively. Compared with the stable MAFLD category, participants with MAFLD and low probability of fibrosis at baseline who regressed to non-MAFLD at follow-up visit had a 29.4% decreased risk of developing elevated CIMT (OR = 0.706; 95% CI = 0.507-0.984), a 43.1% decreased risk of developing elevated ba-PWV (OR = 0.569; 95% CI = 0.340-0.950), but was not significantly associated with incident microalbuminuria (OR = 0.709; 95% CI = 0.386-1.301). The decreased risks attributed to MAFLD regression were more evident in participants without diabetes or dyslipidemia, as well as in those with 0-1 metabolic risk abnormalities, respectively., Conclusions: MAFLD was significantly associated with higher risks of developing subclinical atherosclerosis. Moreover, the regression of MAFLD might modify the risks of developing subclinical atherosclerosis, especially among those with low probability of fibrosis or less metabolic risk abnormalities. Since 40% of baseline participants with missing data on MAFLD measurement at follow-up were excluded, the conclusions should be speculated with caution., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To investigate the impact of diabetes on subclinical atherosclerosis and cardiovascular disease (CVD) in individuals with and without non-alcoholic fatty liver disease (NAFLD)., Methods: The prospective cohort study included 8451 Chinese adults free of baseline CVD in 2010. NAFLD was diagnosed based on hepatic ultrasonography. Fibrosis-4 index as a non-invasive marker was used to evaluate the degree of fibrosis. Subclinical atherosclerosis was evaluated by carotid intima-media thickness, brachial-ankle pulse wave velocity, ankle-brachial index, and carotid plaque. At follow-up during 2014-2016, the composite of incident fatal or nonfatal CVD were ascertained., Results: Of the 8451 participants, 2557 (30.3%) had NAFLD at baseline. Diabetes was associated with arterial stiffness and carotid plaque in participants with NAFLD (P < 0.001). Similar associations were observed in participants without NAFLD. During a mean 4.6 years of follow-up, 432 incident CVD events occurred. The multivariable-adjusted hazard ratio (HR) for CVD events associated with diabetes was 1.27 (95% CI 0.90-1.81) in participants with NAFLD and 1.73 (95% CI 1.32-2.26) in those without NAFLD (P for interaction = 0.21). Among participants with NAFLD who had pre-existing diabetes, those with ≥5 years of diabetes duration had an adjusted HR of 2.02 (95% CI 1.12-3.62) for CVD as compared to those with <2 years of duration. When categorizing participants with NAFLD by fibrosis severity, diabetes conferred an increased risk of CVD in those with potential advanced fibrosis., Conclusions: Among participants with NAFLD, diabetes was associated with prevalent atherosclerosis, and a long duration of diabetes was associated with an increased risk of developing CVD. The effects of diabetes on cardiovascular outcomes did not appreciably differ by NAFLD status., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: and purpose: Acupoint therapy is suggested as a potential intervention for treating nonalcoholic fatty liver disease (NAFLD). This review assessed current evidence for the effect of acupoint therapy on NAFLD., Methods: Eight electronic databases were searched to identify randomized controlled trials (RCTs) of patients with NAFLD treated by acupoint therapy from their inception to August 2020. A meta-analysis of outcomes was conducted by RevMan 5.3., Results: Sixteen RCTs with 1320 patients were included. Acupoint therapy was significantly associated with improvements in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Additionally, acupoint therapy significantly reduced triglyceride (TG), total cholesterol (TC) and low-density lipoprotein (LDL) levels. High-density lipoprotein (HDL) levels were also increased in NAFLD patients., Conclusion: Compared with other treatments, acupoint therapy may improve liver function and lipid metabolism, making it an available treatment for NAFLD. However, these findings need to be confirmed in large-scale, rigorously designed RCTs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Non-alcoholic fatty liver disease (NAFLD) is an aberrant lipid metabolism disease. Hypoxia inducible factor-1 (HIF-1α) is a transcription factor which plays an important part in adapting lower oxygen condition. Here, we aimed to clarify the relationship between HIF-1α and NAFLD., Methods: HepG2 cells was stimulated by oleic acid (OA) and palmitic acid (PA) to establish in vitro model of NAFLD. The expression of lipid metabolism-related genes, the binding of PPARα to HIF-1α promoter, the lipid deposition, and oxidative stress were detected by qRT-PCR, western blot, Chip assay, Oil Red O staining and ELISA assays, respectively., Results: HIF-1α silence promoted lipid accumulation in NAFLD cells, accompanying by the significantly increased contents of TG (triglyceride) and ApoB (apolipoprotein B). In HepG2 cells treated with OA/PA, the expression of lipid metabolism-related genes and proteins, including APOE, A2m, TNFRSF11B, LDLr, and SREBP2, and the intracellular lipid deposition were up-regulated and further aggravated after silencing HIF-1α. In addition, the loss of HIF-1α could remarkably elevate MDA contents while inhibit the activities of beneficial antioxidant enzymes SOD and GSH-Px to activate oxidative stress, and promote the secretion of pro-inflammatory IL-6 and TNF-α to aggravate inflammation in NDFLD cells. PPARα positively bound to HIF-1α promoter. The silence of PPARα aggravated lipid deposition under normal or hypoxic environment in NAFLD cells. In addition, PPAR-α silence could decrease the expression of HIF-1α and ANGPTL4 in NAFLD cell model; moreover, the expression of APOE, A2m and TNFRSF11B and the production of TG and MDA were increased by PPAR-α suppression., Conclusion: HIF-1α plays a crucial role in the regulation of lipid metabolism through activating PPAR-α/ANGPTL4 signaling pathway in NAFLD., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

Background: Interventions involving both exercise and dietary modification are effective in reducing steatosis in nonalcoholic fatty liver disease (NAFLD). However, exercise alone may reduce liver fat and is known to have other positive effects on health. The primary aim of this study was to systematically review the effect of exercise alone without dietary intervention on NAFLD and to examine correlations across changes in liver fat and metabolic markers during exercise., Methods: Relevant online databases were searched from earliest records to May 2020 by two researchers. Studies were included where the trial was a randomized controlled trial, participants were adults, exercise intervention was longer than 4 weeks, no dietary intervention occurred, and the effect of the intervention on liver fat was quantified via magnetic resonance imaging/proton magnetic resonance spectroscopy., Results: Of 21 597 studies retrieved, 16 were included involving 706 participants. Exercise was found to have a beneficial effect on liver fat without dietary modification (-2.4%, -3.13 to -1.66) (mean, 95% CI). Pearson correlation showed significant relationships between change in liver fat and change in weight (r = 0.67, P = .007), liver enzymes aspartate aminotransferase (r = 0.76, P = .002) and alanine aminotransferase (r = 0.91, P < .001), and cardiorespiratory fitness VO 2 peak (peak volume oxygen consumption) (r = -0.88, P = .004). By multivariate regression, change in weight and change in VO 2 peak significantly contributed to change in liver fat (R 2 = 0.84, P = .01)., Conclusions: This systematic review found that exercise without dietary intervention improves liver fat and that clinical markers may be useful proxies for quantifying liver fat changes., (© 2020 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background & Aim: Low-grade albuminuria, as an early marker of endothelial dysfunction and kidney damage, has been recognized as a risk factor for metabolic disorders. Epidemiological studies manifesting the association of low-grade albuminuria with the risk of incident NAFLD and fibrosis were not available. We aimed to investigate the association of low-grade albuminuria with incident NAFLD and fibrosis by glycaemia status., Methods: A prospective population-based study was performed in 3308 participants without NAFLD at recruitment. Baseline urinary albumin excretion was obtained by a first-voided early morning spot urine sample. At follow-up visit, incident NAFLD was diagnosed by hepatic ultrasound after excluding alcohol abuse and other cause of hepatic diseases. Fatty liver index (FLI) was employed to reflect liver fat content. Liver fibrosis was evaluated by NAFLD fibrosis score (NFS), fibrosis-4 score (FIB-4) and Hepamet fibrosis score (HFS) respectively., Results: After 4.3 years of follow-up, 622 (18.8%) were detected as incident NAFLD. Participants with low-grade albuminuria imposed a 40.4% [1.404 (1.112-1.772)] greater risk on incident NAFLD, and 52.0% [1.520 (1.141-2.026)], 87.4% [1.874 (1.291-2.720)] and 40.4% [1.404 (1.038-1.898)] higher risks on newly onset higher values of FLI, NFS and FIB-4 respectively. The effect of low-grade albuminuria was stronger in the subgroup of non-diabetic population., Conclusions: Low-grade albuminuria was independently associated with incident NAFLD and a higher probability of fibrosis, especially among non-diabetic individuals., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Early life exposure to famine and adulthood obesity increased the risk of nonalcoholic fatty liver disease (NAFLD) in adulthood. However, the joint effects on adulthood NAFLD risk are not clear., Aim: This study aimed to explore the joint effects of famine exposure and adulthood obesity on NAFLD risk in later life., Methods: We included 7632 subjects aged ≥40 years from a community-dwelling population. Participants were divided into 4 famine exposure groups according to the birth year, including nonexposed (1963-1974), fetal-exposed (1959-1962), childhood-exposed (1949-1958) and adolescent-exposed (1941-1948). General obesity was assessed by body mass index (BMI: overweight ≥24.0 kg/m 2 , obesity ≥28.0 kg/m 2 ) and abdominal obesity assessed by waist-to-hip ratio (WHR, men/women: moderate ≥0.90/0.85, high ≥0.95/0.90)., Results: Compared with nonexposed, fetal- and childhood-exposed participants show an increased risk of NAFLD with multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) of 1.28 (1.02-1.61) and 1.40 (1.04-1.88) respectively. After further adjusting BMI and WHR, the increased risk was observed only in childhood-exposed participants (OR = 1.46, 95% CI = 1.04-2.05). Significant interaction between famine exposure and general obesity on the risk of NAFLD was observed in women (P for interaction = .02). No significant interactions were detected between famine exposure and abdominal obesity (all P for interaction >.05). Compared with normal-BMI and -WHR participants, those with both general and abdominal obesity in adulthood had 20.74 (95% CI: 12.00-35.96), 14.45 (8.76-23.86), 23.02 (16.28-32.57) and 13.04 (8.30-20.48)-fold higher risk in nonexposed, fetal-, childhood- and adolescent-exposed groups respectively., Conclusion: Coexistence of early life famine exposure and adulthood obesity was associated with a higher risk of NAFLD., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Emerging evidence indicated that sleep characteristics may play important roles in the development of metabolic disorders. However, little is known as to the association between bedtime and the risk of non-alcoholic fatty liver disease (NAFLD) in individuals with pre-diabetes and diabetes., Methods: In a prospective cohort of 10 375 adults aged ≥40 years, 1960 of 3484 eligible pre-diabetic and diabetic individuals were identified for the current study. NAFLD was diagnosed using liver ultrasonography at baseline and at follow-up. Information on bedtime was obtained at baseline using a standard questionnaire., Results: We documented 433 incident cases of NAFLD among this study population. In multivariable-adjusted logistic regression model, later bedtime was associated with increased risk of NAFLD (29% increased risk per hour of later bedtime). Compared to individuals with bedtime ≤20:00, the odds ratios (95% confidence intervals) of NAFLD for bedtime of 20:00-22:00 and ≥22:00 were 1.56 (1.04-2.34) and 2.05 (1.31-3.20), respectively. In the subgroup analysis, significant associations were observed among those who were overweight or physically inactive, or those with metabolic syndrome or elevated 10-year risks for atherosclerotic cardiovascular disease. When estimating the joint effect of bedtime and other sleep characteristics, higher risk of incident NAFLD was observed in groups of late bed/early rise, late bed/napping (yes), late bed/bad sleeper, or late bed/shorter sleep durations., Conclusions: Later bedtime was significantly associated with an increased risk of incident NAFLD in adults with pre-diabetes and diabetes, underscoring the importance of sleep behaviour management in the prevention of NAFLD., (© 2020 John Wiley & Sons Ltd.)

Background: As fat and obesity play a vital role in the pathophysiology of metabolic dysfunction-associated fatty liver disease (MAFLD), this study aims to investigate the association between the fat mass and obesity-associated gene ( FTO ) and MAFLD., Methods: Six SNPs (rs6499640, rs1421085, rs8050136, rs3751812, rs9939609 and rs9930506) within FTO were genotyped for 741 MAFLD patients (median age, 69.98; interquartile range, 66.55-75.93) and 825 healthy people (median age, 69.94; interquartile range, 66.39-75.64). Allele and genotype frequencies, pairwise linkage disequilibrium (LD) and haplotype analysis were calculated., Results: BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, triglyceride, alanine transaminase, glutamyl transpeptidase and the prevalence of diabetes were found to be higher in the MAFLD individuals comparing to the control ones ( P < 0.05). For rs1421085, the C allele frequency was remarkably higher in MAFLD after Bonferroni correction (OR [95% CI] =1.353 [1.095-1.671]; P corr =0.030), and a significantly different genotype result was observed in log-additive model (OR [95% CI] =1.369 [1.108-1.691]; P corr =0.024). For rs8050136, significantly increased A allele frequency was observed in MAFLD (OR [95% CI] =1.371 [1.109-1.695]; P corr =0.024), and A-allele carriers showed increased MAFLD risk (OR [95% CI] =1.393 [1.103-1.759]; P corr =0.030). For rs3751812, the T allele frequency was remarkably higher in MAFLD (OR [95% CI] =1.369 [1.108-1.691]; P corr =0.024), and T-allele carriers demonstrated high MAFLD risk (OR [95% CI] =1.392 [1.103-1.756]; P corr =0.030). For rs9939609, A allele frequency was also remarkably high in MAFLD (OR [95% CI] =1.369 [1.108-1.691]; P corr =0.024), and A-allele carriers were more susceptible to MAFLD (OR [95% CI] =[1.103-1.756]; P corr =0.030). A strong LD was found among rs1421085, rs8050136, rs3751812 and rs9939609 (r 2 >0.8), and individuals with C-A-T-A haplotype had an elevated MAFLD risk (P =0.005)., Conclusion: The case-control study indicated that C variant of rs1421085, A variant of rs8050136, T variant of rs3751812 and A variant of rs9939609 are associated with elevated MAFLD risk in the older Chinese Han population., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Gu et al.)

Non-alcoholic fatty liver disease (NAFLD) is difficult to manage due to the lack of effective treatments. Increased oxygen consumption caused by overnutrition, along with reduced oxygen delivery to liver cells induces hepatic steatosis. Here, we investigated the efficacy of oxygen therapy (OT) to alleviate hepatic steatosis. The effect of OT on hepatic steatosis was evaluated in high-fat-diet (HFD)-fed mice and palmitic acid (PA)-treated primary hepatocytes. Liver biopsy tissue samples were used to determine the relationship between the expression of hypoxia-inducible factor-2α (HIF-2α) and the progression of NAFLD. The role of HIF-2α in the OT group was determined based on the overexpression of HIF-2α in vitro. OT safely alleviated hepatic hypoxia and improved hepatic steatosis by inhibiting hepatic de novo lipogenesis in HFD-fed mice and PA-treated primary hepatocytes, and this was accompanied by reduced expression of HIF-2α and hepatic de novo lipogenesis. The analysis of liver tissues from individuals with or without NAFLD revealed a positive correlation between hepatic HIF-2α expression and NAFLD progression. Overexpression of HIF-2α in vitro inhibited the beneficial effect of OT against hepatic lipogenesis and steatosis. OT might be a viable treatment option for NAFLD and functions by alleviating hypoxia and inhibiting the liver HIF-2α signaling pathway.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a global health problem with high geographic heterogeneity. We aimed to investigate regional-specific concomitant rate of NAFLD and quantitative relationship between liver fat content (LFC) and glucose metabolism parameters in representative clinical populations from six provinces/municipalities of China., Research Design and Methods: A total of 2420 eligible Han Chinese were enrolled consecutively from 10 clinics of obesity, diabetes and metabolic diseases located at six provinces/municipalities of China, and divided into North (Tianjin, Shandong and Heilongjiang) and South (Shanghai, Jiangsu and Henan) groups according to their geographical latitude and proximity of NAFLD concomitant rate. LFC was assessed by a quantitative ultrasound method. Multivariate regression models and analysis of covariance were used to assess the regional difference in the risk of NAFLD., Results: The concomitant rate of NAFLD was 23.3%, 44.0% and 55.3% in individuals with normal glucose tolerance (NGT), pre-diabetes and diabetes, respectively. A higher concomitant rate of NAFLD was found in the participants from the North comparing with the South group, regardless of glucose metabolism status (34.7% vs 16.2% in NGT, 61.5% vs 34.7% in pre-diabetes and 67.1% vs 48.1% in diabetes). This regional difference remained significant after adjustment for age, gender, alcohol drinking, cigarette smoking, confounding metabolic parameters and liver enzymes. For any given blood glucose, participants from the North had higher LFC than those from the South group., Conclusions: Half of Han Chinese with pre-diabetes/type 2 diabetes had NAFLD, and the individuals from the North cities were more susceptible to NAFLD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Type 2 diabetes (T2D) is closely associated with nonalcoholic fatty liver disease (NAFLD); however, evidence regarding the link between blood glucose, especially below the threshold for T2D, and NAFLD is scarce., Objective: The objective of this work is to examine the associations of fasting glucose, oral glucose tolerance test (OGTT) 2-hour glucose, and hemoglobin A1c (HbA1c), and changes in these measures with development and resolution of NAFLD in nondiabetic individuals., Methods: This longitudinal cohort study comprised 4273 Chinese adults age 40 years or older and free of baseline T2D from 2010 to 2015. Blood sampling was performed during the OGTT test. NAFLD was ascertained by hepatic ultrasonography. Risk ratios (RRs) were calculated using modified Poisson regression models., Results: During a mean 4.4 years of follow-up, NAFLD occurred in 573 (17.9%) of the 3209 participants without baseline NAFLD and resolved in 304 (28.6%) of the 1064 participants with baseline NAFLD. OGTT 2-h glucose was positively associated with NAFLD incidence (RR per 1-SD increase: 1.16, 95% CI: 1.08-1.25), whereas fasting (RR: 0.86, 95% CI: 0.78-0.94) and 2-hour glucose (RR: 0.85, 95% CI: 0.77-0.93) were inversely associated with resolution of NAFLD. Glycemic deterioration conferred increased risk of developing NAFLD and decreased likelihood of resolution of NAFLD than maintaining normal glycemic regulation (NGR). The strongest associations were observed for individuals who developed T2D. Meanwhile, baseline or incident NAFLD significantly increased the risk of deterioration in glucose metabolism., Conclusions: Increased glycemic levels within the nondiabetic range, as well as progression from NGR to T2D or prediabetes, were adversely associated with development and improvement of NAFLD., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) has been considered as a risk factor of adverse cardiovascular prognosis, but the relationship between subclinical atherosclerosis and NAFLD remains controversial. We aimed to investigate the impact of subclinical atherosclerosis on incident NAFLD and liver fibrosis., Methods: We included 3433 subjects aged ≥40 years and free of NAFLD. Brachial-ankle pulse wave velocity (ba-PWV) and carotid intima-media thickness (CIMT) were measured at baseline to assess subclinical atherosclerosis status. At follow-up visit, NAFLD was diagnosed by hepatic ultrasound and fibrosis was assessed by NAFLD fibrosis score (NFS), fibrosis-4 score (FIB-4) and aspartate aminotransferase to platelet ratio index (APRI)., Results: A total of 654 (19.1%) subjects developed NAFLD during the follow-up period of 4.3 years. In the multivariate logistic regression models, each standard deviation (SD) increment of ba-PWV was associated with 20% (95% confidence interval [CI] 1.07-1.33), 22% (95% CI 1.08-1.39), 17% (95% CI 1.04-1.32) and 37% (95% CI 1.07-1.75) higher risk of incident NAFLD, higher NFS, FIB-4 and APRI respectively. Compared with the lowest quartile of ba-PWV, the highest quartile ba-PWV had 63% (95% CI 1.20-2.22), 112% (95% CI 1.42-3.17), 86% (95% CI 1.28-2.69) and 201% (95% CI 1.29-7.04) higher risk of incident NAFLD, higher NFS, FIB-4 and APRI respectively. Besides, per SD increase of CIMT was associated with a 12% (95% CI 1.01-1.24) higher risk of incident NAFLD., Conclusions: Increased ba-PWV was independently associated with incident NAFLD and higher probability of fibrosis, whereas CIMT was associated with incident NAFLD but not with fibrosis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study aimed to determine whether modulation of the gut microbiota structure by liraglutide helps improve nonalcoholic fatty liver disease (NAFLD) in rats on a high-fat diet (HFD). Rats were administered an HFD for 12 weeks to induce NAFLD and then administered liraglutide for 4 additional weeks. Next-generation sequencing and multivariate analysis were performed to assess structural changes in the gut microbiota. Liraglutide attenuated excessive hepatic ectopic fat deposition, maintained intestinal barrier integrity, and alleviated metabolic endotoxemia in HFD rats. Liraglutide significantly altered the overall structure of the HFD-disrupted gut microbiota and gut microbial composition in HFD rats in comparison to those on a normal diet. An abundance of 100 operational taxonomic units (OTUs) were altered upon liraglutide administration, with 78 OTUs associated with weight gain or inflammation. Twenty-three OTUs positively correlated with hepatic steatosis-related parameters were decreased upon liraglutide intervention, while 5 OTUs negatively correlated with hepatic steatosis-related parameters were increased. These results suggest that liraglutide-mediated attenuation of NAFLD partly results from structural changes in gut microbiota associated with hepatic steatosis., Competing Interests: The authors have no actual or potential conflicts of interest to declare., (Copyright © 2020 Ningjing Zhang et al.)

Backgrounds: To investigate the value of prolactin (PRL) in diagnosing non-alcoholic fatty liver disease (NAFLD)., Methods: Metabolic parameters and serum PRL levels were measured in 452 males and 421 females, who were randomized to the estimation or the validation group as a 1:1 ratio. Hepatic steatosis was diagnosed via abdominal ultrasound. Variables that significantly associated with NAFLD in univariate analysis were included in multiple logistic regression. We used the receiver operator characteristic (ROC) curves to test the model performance. Besides, 147 patients underwent metabolic and liver biopsy were analyzed to validate the diagnostic value of this model., Results: Body mass index, alanine aminotransferase, prolactin, high density lipoprotein cholesterol and HbA1c were included into models. In males, the area under ROC curve (AUC) was 0.86 (95%CI: 0.82-0.91) for the validation group. With two cut-off points (- 0.79 and 1.71), the sensitivity and specificity for predicting NALFD was 95.2 and 91.1% in the validation group, respectively. In females, the AUC was 0.82 (95%CI: 0.76-0.88) for the validation group. With two cut-off points (- 0.68 and 2.16), the sensitivity and specificity for predicting NALFD was 97.1 and 91.4% in the validation group, respectively. In subjects with liver pathology, the AUC was higher than that of fatty liver index. A positive correlation between the scores of the model and the severities of NAFLD was observed. Importantly, we demonstrated a potential value of this model in predicting nonalcoholic steatohepatitis., Conclusion: We established a mathematic model that can conveniently and effectively diagnose the existence and severities of NAFLD.

Aims/introduction: To compare the effects of gliclazide, liraglutide and metformin on body composition in patients with type 2 diabetes mellitus with non-alcoholic fatty liver disease., Materials and Methods: A total of 85 patients were randomly allocated to receive gliclazide (n = 27), liraglutide (n = 29) or metformin (n = 29) monotherapy for 24 weeks. Body composition was measured using dual-energy X-ray absorptiometry., Results: Liraglutide and metformin reduced total, trunk, limb, android and gynoid fat mass; this also led to weight reduction. However, gliclazide treatment produced no significant changes in weight or fat mass, likely because reductions in fat mass were concomitant with increases in lean tissue mass. Blood glucose concentrations and glycated hemoglobin levels improved in all treatment arms; levels of the latter were lower in patients treated with liraglutide and metformin. Serum alanine aminotransferase concentrations decreased in all treatment arms, whereas serum aspartate aminotransferase concentrations were reduced only by liraglutide and metformin. In all patients, weight loss and total, trunk, limb, and android fat mass reductions were positively correlated with decreases in serum alanine aminotransferase and aspartate aminotransferase levels, whereas reductions in waist circumference were positively correlated with lower serum alanine aminotransferase levels., Conclusions: Compared with gliclazide, liraglutide and metformin monotherapies result in greater weight loss, reductions in body fat mass, and better blood glucose control among type 2 diabetes mellitus patients with non-alcoholic fatty liver disease. Reductions in weight, fat mass and waist circumference favorably affect hepatic function., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Cardiovascular health has been proven to be associated with major cardiometabolic diseases. However, little is known of associations between cardiovascular health and nonalcoholic fatty liver disease., Methods: This study included 3424 adults aged ≥40 years who were free of nonalcoholic fatty liver disease at baseline from a community cohort followed for up to 5 years. Liver ultrasonography was conducted at baseline and at follow-up to diagnose incident nonalcoholic fatty liver disease. Six metrics including smoking, physical activity, body mass index, total cholesterol, blood pressure, and fasting glucose were used to define cardiovascular health status. Associations of individual cardiovascular health metrics, number of cardiovascular health metrics, and overall cardiovascular health status at baseline, as well as changes in cardiovascular health during follow-up with risks of developing nonalcoholic fatty liver disease, were examined., Results: A total of 649 participants developed nonalcoholic fatty liver disease during follow-up. Risks of nonalcoholic fatty liver disease reduced in a dose-response manner in participants with 3-4 ideal cardiovascular health metrics (odds ratio 0.50; 95% confidence interval, 0.41-0.61) and in participants with 5-6 ideal metrics (odds ratio 0.34; 95% confidence interval 0.22-0.51) compared with participants with 0-2 ideal metrics. An overall ideal or intermediate cardiovascular health was associated with 37% reduction in developing nonalcoholic fatty liver disease compared with poor cardiovascular health. In addition, improving cardiovascular health during follow-up reduced the risk by 71% compared with deteriorating cardiovascular health. Furthermore, an overall ideal or intermediate cardiovascular health was significantly associated with a lower fibrosis score in nonalcoholic fatty liver disease patients compared with an overall poor cardiovascular health., Conclusions: Ideal cardiovascular health was inversely associated with risks of nonalcoholic fatty liver disease. Although treatment of nonalcoholic fatty liver disease and subsequent inflammation and fibrosis remains a challenge, cardiovascular health goals should be advocated for nonalcoholic fatty liver disease prevention., (Copyright © 2018. Published by Elsevier Inc.)

In this study, treatment of high-fat diet-induced obesity (DIO) C57BL/6J mice with spermidine decreased body weight and subcutaneous and visceral fat content, reversed the apparent hepatosteatosis, and reduced hepatic intracellular and serum triglyceride and total cholesterol concentrations. Moreover, spermidine treatment improved glucose tolerance and insulin sensitivity in DIO mice. The mechanism studies indicated that spermidine indeed increased the phosphorylation of hepatic AMP-activated protein kinase (AMPK), and inhibited the expression of lipogenic genes in vivo and in vitro. Moreover, these spermidine-mediated molecular effects were also abolished by compound C, an inhibitor of AMPK, in primary hepatocytes. In summary, spermidine protected against DIO-induced hepatosteatosis by decreasing lipogenic genes expression through an AMPK-mediated mechanism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: This study is to investigate the association between the hepatic expression of Yin Yang 1 (YY1) and the progression of non-alcoholic fatty liver disease (NAFLD) in patients undergoing bariatric surgery., Methods: Obese patients undergoing bariatric surgery were included. Liver tissues were subjected to the quantitative real-time PCR, Western blot analysis, and immunohistochemical assay, to determine the expression levels of YY1., Results: Totally 88 patients were included. According to the NAFLD activity score (NAS), these patients were divided into the control (n = 12), steatosis (n = 20), non-defining NASH (n = 38), and NASH (n = 18) groups. Significant differences in the serum glucose, insulin, ALT, AST, and HOMA-IR levels were observed among these different NAFLD groups. Hepatic YY1 expression had correlation with serum glucose, insulin, HOMA-IR, ALT, AST, triglycerides, HDL, and GGT. Immunohistochemical analysis showed that, compared with the control group, the expression levels of YY1 were significantly higher in the non-defining NASH and NASH groups. In addition, multivariate regression model showed that the serum ALT and YY1 levels were strongly associated with the NAFLD activity., Conclusions: Several factors are associated with NAFLD progression, including the expression of YY1. Our findings contribute to understanding of the pathogenesis of NAFLD., Trial Registration: NCT03296605 , registered on September 28, 2017.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid deposition and oxidative stress. It has been demonstrated that general control nonderepressible 2 (GCN2) is required to maintain hepatic fatty acid homeostasis under conditions of amino acid deprivation. However, the impact of GCN2 on the development of NAFLD has not been investigated. In this study, we used Gcn2 -/- mice to investigate the effect of GCN2 on high fat diet (HFD)-induced hepatic steatosis. After HFD feeding for 12 weeks, Gcn2 -/- mice were less obese than wild-type (WT) mice, and Gcn2 -/- significantly attenuated HFD-induced liver dysfunction, hepatic steatosis and insulin resistance. In the livers of the HFD-fed mice, GCN2 deficiency resulted in higher levels of lipolysis genes, lower expression of genes related to FA synthesis, transport and lipogenesis, and less induction of oxidative stress. Furthermore, we found that knockdown of GCN2 attenuated, whereas overexpression of GCN2 exacerbated, palmitic acid-induced steatosis, oxidative & ER stress, and changes of peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS) and metallothionein (MT) expression in HepG2 cells. Collectively, our data provide evidences that GCN2 deficiency protects against HFD-induced hepatic steatosis by inhibiting lipogenesis and reducing oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in the liver may provide a novel approach to attenuate NAFLD development., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background & Aims: Prolactin (PRL) is a multifunctional polypeptide with effects on metabolism, however, little is known about its effect on hepatic steatosis and lipid metabolism. Herein, we aimed to assess the role of PRL in the development of non-alcoholic fatty liver disease (NAFLD)., Methods: The serum PRL levels of 456 patients with NAFLD, 403 controls without NAFLD diagnosed by ultrasound, and 85 individuals with liver histology obtained during metabolic surgery (44 female and 30 male patients with NAFLD and 11 age-matched non-NAFLD female individuals) were evaluated. The expression of the gene encoding the prolactin receptor (PRLR) and signalling molecules involved in hepatic lipid metabolism were evaluated in human liver and HepG2 cells. The effects of overexpression of PRLR or fatty acid translocase (FAT)/CD36 or knockdown of PRLR on hepatic lipid metabolism were tested in free fatty acid (FFA)-treated HepG2 cells., Results: Circulating PRL levels were lower in individuals with ultrasound-diagnosed NAFLD (men: 7.9 [range, 5.9-10.3] µg/L; women: 8.7 [range, 6.1-12.4] µg/L) than those with non-NAFLD (men: 9.1 [range, 6.8-13.0] µg/L, p = 0.002; women: 11.6 [range, 8.2-16.1] µg/L, p <0.001). PRL levels in patients with biopsy-proven severe hepatic steatosis were lower compared with those with mild-to-moderate hepatic steatosis in both men (8.3 [range, 5.4-9.5] µg/L vs. 9.7 [range, 7.1-12.3] µg/L, p = 0.031) and women (8.5 [range, 4.2-10.6] µg/L vs. 9.8 [range, 8.2-15.7] µg/L, p = 0.027). Furthermore, hepatic PRLR gene expression was significantly reduced in patients with NAFLD and negatively correlated with CD36 gene expression. In FFA-induced HepG2 cells, PRL treatment or PRLR overexpression significantly reduced the expression of CD36 and lipid content, effects that were abrogated after silencing of PRLR. Furthermore, overexpression of CD36 significantly reduced the PRL-mediated improvement in lipid content., Conclusions: Our results reveal a novel association between the central nervous system and the liver, whereby PRL/PRLR improved hepatic lipid accumulation via the CD36 pathway., Lay Summary: Our clinical study suggests a negative association between prolactin (PRL)/prolactin receptor (PRLR) and the presence of non-alcoholic fatty liver disease (NAFLD). Using cell experiments, we found that PRL ameliorates hepatic steatosis via the hepatic PRLR and fatty acid translocase (FAT)/CD36, a key transporter of free fatty acid uptake in liver. Our findings suggest a novel approach to improving NAFLD using PRL and PRLR. Clinical trial number: NCT03296605., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Epidemiologic studies have reported conflicting results on the relationship between short sleep duration and non-alcoholic fatty liver disease (NAFLD). There are no previous studies investigating the effect of daytime napping on NAFLD. In the present study we examined the associations between NAFLD and both nightly sleep duration and daytime napping in a middle-aged and elderly Chinese population., Methods: This cross-sectional community-based population study was performed on 8559 individuals aged ≥40 years. Sleep duration and the duration of daytime napping were self-reported using a standardized questionnaire; NAFLD was diagnosed by ultrasonography., Results: In this study sample, the overall prevalence of NAFLD was 30.4%. There was an inverse association between sleep duration and the risk of prevalent NAFLD. In multivariate analysis, the odds ratios (ORs) and 95% confidence intervals (CIs) of prevalent NAFLD for decreasing sleep duration categories (≥9, 8.1-9, 7.1-8, 6.1-7, and ≤6.1 h) were 1.00 (reference), 1.38 (1.13-1.70), 1.32 (1.08-1.61), 1.29 (1.04-1.60), and 1.66 (1.28-2.15), respectively (P trend  = 0.0073). Compared with participants without a daytime napping habit, nap takers with a longer nap duration (>0.5 h) had an increased risk of prevalent NAFLD (OR 1.22; 95% CI 1.06-1.41). The associations of sleep duration and daytime napping duration with NAFLD were generally consistent across different categories of age and obesity, metabolic syndrome, and insulin resistance status., Conclusions: Short sleep duration and longer daytime napping were associated with an increased risk of prevalent NAFLD in a middle-aged and elderly Chinese population., (© 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: The aim of the present study was to compare the effects of gliclazide, liraglutide, and metformin in type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD)., Methods: Eighty-seven subjects were randomized to receive liraglutide, metformin, or gliclazide for 24 weeks. Primary outcomes included HbA1c levels, intrahepatic fat (IHF) content, and liver function., Results: Both HbA1c levels and IHF content were reduced after treatment in all three groups. However, HbA1c levels were lower in the liraglutide- and metformin-treated groups than in the gliclazide-treated group, and reductions in IHF content were greater with liraglutide than with gliclazide. Liraglutide and metformin treatments reduced weight and improved liver function. Changes in IHF content were positively correlated with reductions in serum alanine aminotransferase and triglyceride levels, as well as weight. At 24 weeks, reductions in IHF content were greater in subjects with weight loss ≥5%, changes in waistline ≤0 cm (including decreases in waistline), HbA1c reductions ≥2.5%, and HbA1c levels <6.5%., Conclusions: In T2DM patients with NAFLD, compared with liraglutide and metformin, gliclazide resulted in less improvement in liver function, reductions in IHF content and HbA1c levels, and less weight loss; in addition, slightly better improvements were achieved with liraglutide than with metformin., (© 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)