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This study investigated if cadmium chloride (CdCl 2 )-induced hepatic steatosis and fibrosis and the protective effect of quercetin (QUR) are mediated modulating the activity of miR-21, a known hepatic lipogenic and fibrotic miRNA. Male rats (n = 8/group) were divided as control, control + QUR (50 mg/kg; orally), CdCl 2 (10 moml/L; drinking water), CdCl 2  + miR-21 antagomir (inhibitor) (16 mg/kg/first 3 days), and CdCl 2  + QUR (50 mg/kg). Treatments were conducted for 20 weeks, daily. All treatments showed no effect on fasting glucose and insulin levels. Administration of either miR-21 or QUR prevented CdCl 2 -induced hepatic damage, as well as lipid droplets and collagen deposition. They also reduced serum levels of ALT and AST and decreased serum and hepatic levels of total cholesterol, triglycerides, and low-density lipoproteins in CdCl 2 -treated rats. Concomitantly, they reduced hepatic levels of reactive oxygen species, malondialdehyde, interleukin-6, and tumor necrosis factor-α, suppressed the activation of NF-kb P65, and increased hepatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), and superoxide dismutase (SOD). These effects were associated with reduced expression of SREBP1, TGF-β1, Smad3, and collagen1 A and increased expression of PPARα, CPT1, and smad7. Interestingly, QUR significantly lowered levels of miR-21 and increased the protein levels and activity of Nrf2, as well as levels of GSH and SOD in the livers of both the control and CdCl 2 -treated rats. Of note, levels of Nrf2 were negatively correlated with the transcription of miR-21. In conclusion: QUR prevents CdCl 2 -induced hepatic steatosis and fibrosis mainly through attenuating its ability to upregulate miR-21, at least, by upregulation of Nrf2., (© 2021 International Union of Biochemistry and Molecular Biology.)

Aim: The aim of this study is to investigate the sex-specific association between the ZJU index and risk of fatty liver disease in a large Chinese cohort., Methods: A total of 28 729 adults without fatty liver disease at baseline and who completed at least one follow-up of annual examinations between 2009 and 2016 were included in this study. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for fatty liver disease risk associated with the ZJU index., Results: During a median follow-up of 3.01 years, 7373 developed fatty liver disease. There were significant associations between the ZJU index and fatty liver disease for women and men with increasing HRs as the quartiles increase across Q2-Q4, corresponding HRs (95% CIs) in M3 were 2.28 (1.98-2.64), 3.52 (3.07-4.04), and 4.87 (4.24-5.59) for women and 2.44 (2.17-2.75), 4.18 (3.73-4.68), and 6.23 (5.56-6.98) for men. The association between the ZJU index and fatty liver disease risk remained significant in all the subgroups except that of T2DM and abdominal obesity subgroups for men. However, the association became nonsignificant when comparing Q3 and Q2 of the ZJU index with reference in the subgroups of T2DM for men, and nonsignificant when comparing Q3 of the ZJU index with reference in the subgroups of participants with T2DM and abdominal obesity for women., Conclusion: The ZJU index was significantly associated with the risk of fatty liver disease in Chinese population. It will be better to keep body mass index, alanine aminotransferase, aspartate aminotransferase, triglyceride, and fasting plasma glucose at a normal level for preventing fatty liver disease., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: Protein deficiency is known to cause ectopic fat accumulation in the liver. The aim of this study was to analyse the mechanism of suppression of hepatic fat accumulation by testosterone and to clarify the mechanism behind the gender difference in fatty liver formation due to protein deficiency., Methods: Hepatic fat accumulation due to protein deficiency was evaluated in male and female rats before and after sexual maturation. Then, the effects of testosterone on liver lipid, muscle protein metabolism and energy expenditure in adipose tissue were investigated in castrated or testosterone-injected male rats fed control or protein-restricted diet., Results: Hepatic triglyceride accumulation diminished with sex maturation in male but not in female protein-restricted rats. Protein restriction resulted in a significant increase in hepatic triglyceride content in castrated rats but not in sham-operated rats demonstrating that endogenous testosterone reduces hepatic lipid accumulation in male rats. Protein restriction reduced plasma IGF-I and muscle protein synthesis measured using the SUnSET method. Castration increased the plasma corticosterone level and muscle autophagic activity. Muscle weight was reduced and energy expenditure in adipose tissue was increased only when both factors were combined., Conclusions: Muscle protein synthesis downregulation owing to protein restriction and activation of autophagy following castration reduced muscle mass thereby releasing surplus energy and promoting steatosis in protein-restricted castrated rats despite increased energy expenditure in adipose tissue. We hypothesize that endogenous testosterone reduces hepatic lipid accumulation in protein-deficient male rats and provide novel findings on the gender-specific differences in hepatic steatosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the effect of the dietary supplementation of an alpha- and gamma-tocopherol mixture (1:5 ratio) in the adipose tissue expansion, hepatic steatosis, and expression of inflammatory markers induced by consumption of a high-fat diet (HFD) in mice., Methods: Male C57BL/6 J mice were fed for 12 wk and divided into the following: 1) control diet (CD; 10% fat, 20% protein, 70% carbohydrates); 2) CD + TF (CD plus alpha-tocopherol: 0.7 mg/kg/d, gamma-tocopherol: 3.5 mg/kg/d); 3) HFD (60% fat, 20% protein, 20% carbohydrates); and 4) HFD + TF (HFD plus alpha-tocopherol: 0.7 mg/kg/d, gamma-tocopherol: 3.5 mg/kg/d). General parameters, adipocyte size, liver steatosis, adipose and hepatic tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) expression, hepatic nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor α (PPAR-α) levels were evaluated., Results: Tocopherol supplementation in HFD-fed mice showed a significant decrease in the body weight (19%) and adipose tissue weight (52%), adipose tissue/body weight ratio (36%), and serum triacylglycerols (56%); a 42% decrease (P < 0.05) of adipocyte size compared to HFD; attenuation of liver steatosis by decreasing (P < 0.05) lipid vesicles presence (90%) and total lipid content (75%); and downregulation of inflammatory markers (TNF-α and IL-1β), along with an upregulation of hepatic PPAR-α expression and its downstream-regulated genes (ACOX and CAT-1), and an inhibition of hepatic NF-κB activation., Conclusion: The present study suggests that alpha- and gamma-tocopherol (1:5 ratio) supplementation attenuates the adipocyte enlargement, hepatic steatosis, and metabolic inflammation induced by HFD in association with PPAR-α/NF-κB modulation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The links between fatty acids (FAs) and cardiometabolic outcomes are topics of debate., Objective: Our aim was to investigate the associations between serum standardized FA percentages and cardiometabolic outcomes., Methods: We used cross-sectional (n = 2187-2200 subjects, age 24-39 y, women 54%) and 10-year prospective data (n = 975-1414 subjects) from the Young Finns Study. Outcomes included prevalent and incident obesity, insulin resistance (HOMA-IR index in the upper quintile), elevated blood pressure (BP; taking medication, or diastolic or systolic BP in the upper quintile), and incident nonalcoholic fatty liver. Logistic regression models were used to calculate ORs per SD increase in fatty acids (FAs). The models were adjusted for age and sex, and additionally for other potential confounders., Results: Several cross-sectional findings were also statistically significant in prospective models (Bonferroni corrected P < 0.003). In fully-adjusted models for obesity, these consisted of SFAs (OR: 1.28) and MUFAs (OR: 1.38), including palmitoleic (OR: 1.39) and oleic acids (OR: 1.37). Furthermore, PUFAs (OR: 0.70), including linoleic (OR: 0.67) and docosahexaenoic acids (OR: 0.75), were inversely related with obesity, whereas γ-linolenic acid (OR: 1.32) was positively associated with obesity. In age- and sex-adjusted models for insulin resistance, MUFAs (OR: 1.26) and oleic acid (OR: 1.25) were positively, and PUFAs (OR: 0.81), particularly linoleic acid (OR: 0.78), were inversely associated with HOMA-IR. Similarly with elevated BP, palmitic acid (OR: 1.22), MUFAs (OR: 1.28), and oleic acid (OR: 1.28) were positively associated with elevated BP, whereas PUFAs (OR: 0.77), n-6 (omega-6) PUFAs (OR: 0.79), and linoleic acid (OR: 0.77) were inversely associated. In fully-adjusted models for incident fatty liver, the most consistent predictors were high palmitic (OR: 1.61) and low linoleic acid (OR: 0.63) percentages. The n-6/n-3 (omega-3) PUFA ratio was not linked with any adverse outcomes., Conclusions: High serum percentages of total SFAs and MUFAs and low PUFAs, but also several specific FAs, predict future unfavorable cardiometabolic outcomes in Finnish adults., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: The benefit of ischemic postconditioning (IPostC) might be the throttled inflow following cold ischemia. The current study investigated advantage and mechanisms of IPostC in healthy and fatty rat livers., Methods: Male SD rats received a high-fat diet to induce fatty livers. Isolated liver perfusion was performed after 24 h ischemia at 4 °C as well as in vivo experiments after 90 min warm ischemia. The so-called follow-up perfusions served to investigate the hypothesis that medium from IPostC experiments is less harmful. Lactate dehydrogenase (LDH), transaminases, different cytokines, and gene expressions, respectively, were measured., Results: Fatty livers showed histologically mild inflammation and moderate to severe fat storage. IPostC reduced LDH and TXB 2 in healthy and fatty livers and increased bile flow. LDH, TNF-α, and IL-6 levels in serum decreased after warm ischemia + IPostC. The gene expressions of Tnf, IL-6, Ccl2, and Ripk3 were downregulated in vivo after IPostC., Conclusions: IPostC showed protective effects after ischemia in situ and in vivo in healthy and fatty livers. Restricted cyclic inflow was an important mechanism and further suggested involvement of necroptosis. IPostC represents a promising and easy intervention to improve outcomes after transplantation.

Approximately 400 metric tons of egg chalazae, a byproduct in the liquid-egg processing plant, are produced yearly but always regarded as a waste in Taiwan. Our team successfully developed a crude egg chalaza hydrolysate by protease-A digestion (CCH-A). Free branched-chain amino acids, 3-aminoisobutyric acid, and β-alanine, and anserine were assayed in the CCH-A used in this study. Besides, the in vitro bile-acid binding ability and inhibitory lipase activity of CCH-As were demonstrated. Then, high-fat diet feeding for 10 wk caused hyperlipidemia, insulin resistance, and hepatosteatosis in hamsters (P < 0.05). However, CCH-A co-treatment decreased serum/liver triglyceride levels and lipid accumulation in livers by increasing daily fecal lipid/bile-acid outputs, upregulating fatty-acid β oxidation, and downregulating fatty-acid biosynthesis in livers (P < 0.05). CCH-A co-treatment also amended insulin resistance, augmented hepatic antioxidant capacity, and decreased liver damages and inflammatory responses (P < 0.05). Taken together, our results do not only demonstrate the hepatoprotective effects of CCH-As against a chronic high-fat dietary habit, achieving effects similar to Simvastatin, but also decrease the environmental burden of handling chalazae in the liquid-egg industry., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Fibrates, including fenofibrate, are a class of hypolipidemic drugs that activate peroxisome proliferator-activated receptor α (PPARα), which in-turn regulates the expression of lipid and lipoprotein metabolism genes. We investigated whether fenofibrate can reduce visceral obesity and nonalcoholic fatty liver disease via adipose tissue PPARα activation in female ovariectomized (OVX) C57BL/6J mice fed a high-fat diet (HFD), a mouse model of obese postmenopausal women. Fenofibrate reduced body weight gain (-38%, p < 0.05), visceral adipose tissue mass (-46%, p < 0.05), and visceral adipocyte size (-20%, p < 0.05) in HFD-fed obese OVX mice. In addition, plasma levels of alanine aminotransferase and aspartate aminotransferase, as well as free fatty acids, triglycerides, and total cholesterol, were decreased. Fenofibrate also inhibited hepatic lipid accumulation (-69%, p < 0.05) and infiltration of macrophages (-72%, p < 0.05), while concomitantly upregulating the expression of fatty acid β-oxidation genes targeted by PPARα and decreasing macrophage infiltration and mRNA expression of inflammatory factors in visceral adipose tissue. These results suggest that fenofibrate inhibits visceral obesity, as well as hepatic steatosis and inflammation, in part through visceral adipose tissue PPARα activation in obese female OVX mice.

A prime concern of young patients with Polycystic Ovary Syndrome (PCOS) is the control of body adiposity, given their tendency to gain weight and/or their difficulty to lose weight. Circulating growth-and-differentiation factor-15 (GDF15) facilitates the control of body weight via receptors in the brainstem. C-reactive protein (CRP) and insulin are endogenous GDF15 secretagogues. We hypothesised that PCOS in non-obese adolescents is characterised by low concentrations of circulating GDF15, when judged by the degree of CRP and insulin drive. GDF15 was added as a post-hoc endpoint of two previously reported, randomised studies in non-obese adolescent girls with PCOS (N = 58; 60% normal weight; 40% overweight) who received either an oral oestroprogestogen contraceptive (OC), or a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) for 1 year; subsequently, all girls remained untreated for 1 year. Adolescent girls with regular menses (N = 20) served as healthy controls. Circulating GDF15, CRP and fasting insulin were assessed prior to treatment, and halfway the on- and post-treatment years. Pre-treatment, the absolute GDF15 concentrations were normal in PCOS girls, but their relative levels were markedly low, in view of the augmented CRP and insulin drives. OC treatment was accompanied by a near-doubling of circulating GDF15 (on average, from 296 to 507 pg/mL) and CRP, so that the relative GDF15 levels remained low. SPIOMET treatment was accompanied by a 3.4-fold rise of circulating GDF15 (on average, from 308 to 1045 pg/mL) and by a concomitant lowering of CRP and insulin concentrations towards normal, so that the relative GDF15 levels became markedly abundant. Post-OC, the relatively low GDF15 levels persisted; post-SPIOMET, the circulating concentrations of GDF15, CRP and insulin were all normal. BMI remained stable in both treatment groups. Only SPIOMET was accompanied by a reduction of hepato-visceral fat (by MRI) towards normal. In conclusion, early PCOS was found to be characterised by a relative GDF15 deficit that may partly explain the difficulties that young patients experience to control their body adiposity. This relative GDF15 deficit persisted during and after OC treatment. In contrast, SPIOMET treatment was accompanied by an absolute and a relative abundance of GDF15, and followed by normal GDF15, CRP and insulin concentrations. The present findings strengthen the rationale to raise the concentrations of circulating GDF15 in early PCOS, for example with a SPIOMET-like intervention that attenuates low-grade inflammation, insulin resistance and ectopic adiposity, without necessarily lowering body weight.Clinical trial registries: ISRCTN29234515 and ISRCTN11062950.

Ethnopharmacological relevanceQuercetin is the active component of the higher content in PCP, which exerts various biological activities such as anti-obesity effect, anti-inflammatory and anti-oxidant activities in alcoholic liver disease (ALD)., Aim of the Study: P2X7 receptor (P2X7R) plays an important role in health and disease, which can be activated by extracellular ATP to induce a variety of downstream events, including lipid metabolism, inflammatory molecule release, oxidative stress. However, whether the mechanism of quercetin on ethanol-induced hepatic steatosis via P2X7R-mediated haven't been elucidated., Material and Methods: Zebrafish transgenic (fabp10: EGFP) larvae were treated with 100 μM, 50 μM, 25 μM quercetin for 48 h at 3 days post fertilization (dpf), then soaked in 350 mmol/L ethanol for 32 h, treated with 1 mM ATP (P2X7R activator) for 30min. Serum lipids, liver steatosis, oxidative stress factors were respectively detected. The mRNA levels in the related pathways were measured by quantitative Real-Time PCR (RT-qPCR) to investigate the mechanisms., Results: Quercetin improved the liver function via decreasing ALT, AST and γ-GT level of zebrafish with acute ethanol-induced hepatic steatosis and attenuated hepatic TG, TC accumulation. Additionally, quercetin significantly reduced the MDA content and suppressed the ethanol-induced reduction of hepatic oxidative stress biomarkers GSH, CAT and SOD and significantly down-regulated the expression of P2X7R, and up-regulated the expression of phosphatidylinositol 3-kinase (PI3K), Kelch like ECH associated protein1 (Keap1), Nuclear Factor E2 related factor 2 (Nrf2). Moreover, ATP stimulation activated P2X7R, which further mediated the mRNA expressions of PI3K, Keap1 and Nrf2., Conclusion: Quercetin exhibited hepatoprotective capacity in zebrafish model, via regulating P2X7R-mediated PI3K/Keap1/Nrf2 oxidative stress signaling pathway., (Copyright © 2020. Published by Elsevier B.V.)

Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

Fatty liver is an abnormal metabolic condition of excess intrahepatic fat. This condition, referred to as hepatic steatosis, is tightly associated with chronic liver disease and systemic metabolic morbidity. The most prevalent form in humans, i.e. non-alcoholic fatty liver, generally develops due to overnutrition and sedentary lifestyle, and has as yet no approved drug therapy. Previously, we have developed a relevant large-animal model in which overnourished sheep raised on a high-calorie carbohydrate-rich diet develop hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. Here, we tested the hypothesis that treatment with thiamine (vitamin B1) can counter the development of hepatic steatosis driven by overnutrition. Remarkably, the thiamine-treated animals presented with completely normal levels of intrahepatic fat, despite consuming the same amount of liver-fattening diet. Thiamine treatment also decreased hyperglycemia and increased the glycogen content of the liver, but it did not improve insulin sensitivity, suggesting that steatosis can be addressed independently of targeting insulin resistance. Thiamine increased the catalytic capacity for hepatic oxidation of carbohydrates and fatty acids. However, at gene-expression levels, more-pronounced effects were observed on lipid-droplet formation and lipidation of very-low-density lipoprotein, suggesting that thiamine affects lipid metabolism not only through its known classic coenzyme roles. This discovery of the potent anti-steatotic effect of thiamine may prove clinically useful in managing fatty liver-related disorders.This article has an associated First Person interview with the joint first authors of the paper., Competing Interests: Competing interestsAn institutional patent application regarding the potential use of thiamine for the management of fatty liver-related disorders has been filed by H.D. and S.B. All other authors declare no competing interests., (© 2021. Published by The Company of Biologists Ltd.)

Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified, despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here, we identified in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increased to concentrations similar to those of steroidal bile acids. The biliary docosahexaenoic acid-containing (DHA-containing) NAT C22:6 NAT was increased in human and mouse plasma after dietary omega-3 fatty acid supplementation and potently inhibited intestinal triacylglycerol hydrolysis and lipid absorption. Supporting this observation, genetic elevation of endogenous NAT levels in mice impaired lipid absorption, whereas selective augmentation of C22:6 NAT levels protected against hypertriglyceridemia and fatty liver. When administered pharmacologically, C22:6 NAT accumulated in bile and reduced high-fat diet-induced, but not sucrose-induced, hepatic lipid accumulation in mice, suggesting that C22:6 NAT is a negative feedback mediator that limits excess intestinal lipid absorption. Thus, biliary omega-3 NATs may contribute to the hypotriglyceridemic mechanism of action of fish oil and could influence the design of more potent omega-3 fatty acid-based therapeutics.

The AHNAK nucleoprotein has been determined to exert an anti-obesity effect in adipose tissue and further inhibit adipogenic differentiation. In this study, we examined the role of AHNAK in regulating hepatic lipid metabolism to prevent diet-induced fatty liver. Ahnak KO mice have reportedly exhibited reduced fat accumulation in the liver and decreased serum triglyceride (TG) levels when provided with either a normal chow diet or a high-fat diet (HFD). Gene expression profiling was used to identify novel factors that could be modulated by genetic manipulation of the Ahnak gene. The results revealed that fibroblast growth factor 21 (FGF21) was markedly increased in the livers of Ahnak KO mice compared with WT mice fed a HFD. Ahnak knockdown in hepatocytes reportedly prevented excessive lipid accumulation induced by palmitate treatment and was associated with increased secretion of FGF21 and the expression of genes involved in fatty acid oxidation, which are primarily downstream of PPARα. These results indicate that pronounced obesity and hepatic steatosis are attenuated in HFD-fed Ahnak KO mice. This may be attributed, in part, to the induction of FGF21 and regulation of lipid metabolism, which are considered to be involved in increased fatty acid oxidation and reduced lipogenesis in the liver. These findings suggest that targeting AHNAK may have beneficial implications in preventing or treating hepatic steatosis.

Branched-chain amino acids (BCAA) reverse malnutrition and l-carnitine leads to the reduction of hyperammonemia and muscle cramps in cirrhotic patients. BCAA and l-carnitine are involved in glucose and fatty acid metabolism, however their mechanistic activity in cirrhotic liver is not fully understood. We aim to define the molecular mechanism(s) and combined effects of BCAA and l-carnitine using a cirrhotic rat model. Rats were administered carbon tetrachloride for 10 weeks to induce cirrhosis. During the last 6 weeks of administration, cirrhotic rats received BCAA, l-carnitine or a combination of BCAA and l-carnitine daily via gavage. We found that BCAA and l-carnitine treatments significantly improved hepatocellular function associated with reduced triglyceride level, lipid deposition and adipophilin expression, in cirrhotic liver. Lipidomic analysis revealed dynamic changes in hepatic lipid composition by BCAA and l-carnitine administrations. BCAA and l-carnitine globally increased molecular species of phosphatidylcholine. Liver triacylglycerol and phosphatidylcholine hydroperoxides were significantly decreased by BCAA and l-carnitine. Furthermore, serum and liver ATP levels were significantly increased in all treatments, which were attributed to the elevation of mature cardiolipins and mitochondrial component gene expressions. Finally, BCAA and l-carnitine dramatically reduced hepatocellular death. In conclusion, BCAA and l-carnitine treatments attenuate hepatocellular damage through the reduction of lipid peroxides and the overall maintenance of mitochondrial integrity within the cirrhotic liver. These effectiveness of BCAA and l-carnitine support the therapeutic strategies in human chronic liver diseases., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The purpose of this study is to assess the effects of an alternative approach to type 2 diabetes prevention. Ninety-six patients with prediabetes (age 52 (10) years; 80% female; BMI 39.2 (7.1) kg/m 2 ) received a continuous remote care intervention focused on reducing hyperglycemia through carbohydrate restricted nutrition therapy for two years in a single arm, prospective, longitudinal pilot study. Two-year retention was 75% (72 of 96 participants). Fifty-one percent of participants (49 of 96) met carbohydrate restriction goals as assessed by blood beta-hydroxybutyrate concentrations for more than one-third of reported measurements. Estimated cumulative incidence of normoglycemia (HbA1c <5.7% without medication) and type 2 diabetes (HbA1c ≥6.5% or <6.5% with medication other than metformin) at two years were 52.3% and 3%, respectively. Prevalence of metabolic syndrome, class II or greater obesity, and suspected hepatic steatosis significantly decreased at two years. These results demonstrate the potential utility of an alternate approach to type 2 diabetes prevention, carbohydrate restricted nutrition therapy delivered through a continuous remote care model, for normalization of glycemia and improvement in related comorbidities.

Weight control based on dietary restriction (DR) alone can cause lipid metabolic failure and progression to fatty liver. This study aimed to investigate the effect of exercise on preventing DR-induced hepatic fat accumulation in Zucker fatty (ZF) rats by focusing on the relationship between adipose tissue lipolysis and hepatic fat uptake. Six-week-old male ZF rats were randomly assigned to obese, DR, or DR with exercise (DR + Ex) groups. The DR and DR + Ex groups were fed a restricted diet, with the latter also undergoing voluntary exercise. After 6 weeks, hepatic fat accumulation was observed in the DR group, whereas intrahepatic fat was markedly reduced in the DR + Ex group. Compared with the obese (Ob) group, the DR group exhibited 2.09-fold expression of hepatic fatty acid translocase (FAT)/CD36 proteins ( p < 0.01) and 0.14-fold expression of hepatic fatty acid-binding protein (FABP)1 ( p < 0.01). There were no significant differences between the DR + Ex group and the Ob group. FAT/CD36 and hepatic triglyceride (TG) expression levels were strongly positively correlated ( r = 0.81, p < 0.001), whereas there was a strong negative correlation between FABP1 and hepatic TG expression levels ( r = -0.65, p < 0.001). Our results suggest that hepatic fat accumulation induced by DR in ZF rats might be prevented through exercise-induced modifications in FAT/CD36 and FABP1 expression.

Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer ( nfkb1 -/- mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD + , this leading to increased hepatic NAD + and elevated activity of the NAD + -dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease., (Copyright © 2021 The Authors.)

The aim of this study was to investigate the effects of osteocalcin (OCN) on fatty liver hemorrhagic syndrome (FLHS) in aged laying hens. Thirty 68-week-old White Plymouth laying hens were randomly assigned into conventional single-bird cages, and the cages were randomly allocated into one of 3 treatments (n = 10): normal diet (ND + vehicle, ND + V), high-fat diet (HFD + vehicle, HFD + V), and HFD + OCN (3 μg/bird, 1 time/2 d, i.m.) for 40 d. At day 30, oral glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) were performed. At the end of experiment, the hens were euthanized followed by blood collection. The plasma aspartate transaminase (AST), alkaline phosphatase (ALP), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured using an automatic biochemistry analyzer. Pathological changes in the liver were examined under both light and transmission electron microscopes. The plasma inflammatory factors including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α) were analyzed by ELISA, and the gene expressions of these inflammatory factors in the liver were analyzed by real-time PCR. The level of oxidative stress was evaluated using malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) assay kits, respectively. The results showed that HFD + V hens had more severe liver hemorrhage and fibrosis than ND + V hens (P < 0.05). The ultramicrostructural examination showed that hepatocytes of HFD + V hens exhibited necrotic pyknosis showing great intracellular electron, mitochondrial swelling, shrunk nucleus, and absence of autolysosomes. Osteocalcin mitigated HFD + V-induced pathological changes in aged laying hens. High-fat diet + OCN hens had higher insulin sensitivity; lower liver concentrations of MDA (P = 0.12) but higher GSH-Px (P < 0.05); and lower blood TNF-α concentrations (P < 0.05) and mRNA expressions (P < 0.05) than HFD + V hens. These results suggest OCN functions in preventing the FLHS process in old laying hens through inhibiting excessive energy diet-induced metabolic disorder, oxidative stress, and related pathological damage., (Copyright © 2020. Published by Elsevier Inc.)

Bile acids (BAs) play important roles in lipid homeostasis, and BA signaling pathways serve as therapeutic targets for nonalcoholic fatty liver disease (NAFLD). Recently, we generated cytochrome P450, family 2, subfamily C, polypeptide 70 (Cyp2c70 -/- ) mice with a human-like BA composition lacking mouse-/rat-specific muricholic acids to accelerate translation from mice to humans. We employed this model to assess the consequences of a human-like BA pool on diet-induced obesity and NAFLD development. Male and female Cyp2c70 -/- mice and WT littermates were challenged with a 12-week high-fat Western-type diet (WTD) supplemented with 0.25% cholesterol. Cyp2c70 deficiency induced a hydrophobic BA pool with high abundances of chenodeoxycholic acid, particularly in females, because of sex-dependent suppression of sterol 12α-hydroxylase (Cyp8b1). Plasma transaminases were elevated, and hepatic fibrosis was present in Cyp2c70 -/- mice, especially in females. Surprisingly, female Cyp2c70 -/- mice were resistant to WTD-induced obesity and hepatic steatosis, whereas male Cyp2c70 -/- mice showed similar adiposity and moderately reduced steatosis compared with WT controls. Both intestinal cholesterol and FA absorption were reduced in Cyp2c70 -/- mice, the latter more strongly in females, despite unaffected biliary BA secretion rates. Intriguingly, the biliary ratio 12α-/non-12α-hydroxylated BAs significantly correlated with FA absorption and hepatic triglyceride content as well as with specific changes in gut microbiome composition. The hydrophobic human-like BA pool in Cyp2c70 -/- mice prevents WTD-induced obesity in female mice and NAFLD development in both genders, primarily because of impaired intestinal fat absorption. Our data point to a key role for 12α-hydroxylated BAs in control of intestinal fat absorption and modulation of gut microbiome composition., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Hyperlipidaemia is one of the major risk factors for atherosclerosis, coronary heart disease, stroke and diabetes. In the present study, we synthesized a new anthraquinone compound, 1,8-dihydroxy-3-succinic acid monoethyl ester-6-methylanthraquinone, and named it Kanglexin (KLX). The aim of this study was to evaluate whether KLX has a lipid-lowering effect and to explore the potential molecular mechanism. In this study, Sprague-Dawley rats were fed a high fat diet (HFD) for 5 weeks to establish a hyperlipidaemia model; then, the rats were orally administered KLX (20, 40, and 80 mg kg -1 ·d -1 ) or atorvastatin calcium (AT, 10 mg kg -1 ·d -1 ) once a day for 2 weeks. KLX had prominent effects on reducing blood lipids, hepatic lipid accumulation, body weight and the ratio of liver weight/body weight. Furthermore, KLXdramatically reduced the total cholesterol (TC) and triglyceride (TG) levels and lipid accumulation in a HepG2 cell model of dyslipidaemia induced by 1 mmol/L oleic acid (OA). KLX may decrease lipid levels by phosphorylating adenosine monophosphate-activated protein kinase (AMPK) and the downstream sterol regulatory element binding protein 2 (SREBP-2)/proprotein convertase subtilisin/kexin type 9 (PCSK9)/low-density lipoprotein receptor (LDLR) signalling pathway in the HFD rats and OA-treated HepG2 cells. The effects of KLX on the AMPK/SREBP-2/PCSK9/LDLR signalling pathway were abolished when AMPK was inhibited by compound C (a specific AMPK inhibitor) in HepG2 cells. In summary, KLX has an efficient lipid-lowering effect mediated by activation of the AMPK/SREBP-2/PCSK9/LDLR signalling pathway. Our findings may provide new insight into and evidence for the discovery of a new lipid-lowering drug for the prevention and treatment of hyperlipidaemia, fatty liver, and cardiovascular disease in the clinic., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Time-restricted feeding (TRF) initiated early during the dark phase prevents the metabolic consequences of a high-fat diet in rodent models. However, the metabolic consequences of delaying the initiation of TRF, akin to breakfast skipping in humans, is unclear. We assigned 8-week-old male C57BL/6J mice (n = 192) to chow or high-fat diet ad libitum (AL) for 4 weeks, before randomization to continue AL or 10 h of TRF, initiated at lights off (TRFe) or 4-h after lights off (TRFd) for a further 8 weeks. Oral glucose tolerance tests (1 g/kg), metabolic monitoring and body composition by echoMRI were performed, and tissues were collected at six time points. TRF reduced weight and fat mass vs AL, with a greater reduction in TRFe vs TRFd. TRF improved glucose tolerance and protected mice from high-fat diet-induced hepatosteatosis vs AL, with no difference between TRFe and TRFd. TRF increased the amplitude of Bmal1, Cry1, Per2, Nampt, and Nocturnin mRNA levels in liver. A phase delay in Bmal1, Cry1, Per2, Reverbα, Nampt, NAD, Sirt1, and Nocturnin was observed in TRFd. Thus, delaying TRF limited the weight benefit and induced a phase delay in the hepatic clock, but improved metabolic health. Allowing more flexibility in when TRF is initiated may increase the translational potential of this dietary approach in humans.

Rationale: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of regulators in these processes remain largely elusive. Evidence has suggested that the glutamate/N-methyl-D-aspartic acid receptor (NMDAR) axis contributes to acute lung injury, pulmonary arterial hypertension, and diabetes, but the specific metabolic contribution of the glutamate/NMDAR axis is not clear. Here we provide data at the animal, cellular, and molecular levels to support the role of the glutamate/NMDAR axis as a therapeutic target for metabolic syndrome in obesity. Methods: We examined the glutamate level in the obese mouse induced by a high-fat diet (HFD) for 12 weeks. To assess the role of NMDAR in insulin sensitivity and lipid metabolism, we tested the effects of Memantine (an NMDAR antagonist) and NMDA (an NMDAR agonist) on mice fed with HFD or standard chow diet. The in vitro s NMDAR roles were analyzed in hepatocytes and potential mechanisms involved in regulating lipid metabolism were investigated. Results: Glutamate was increased in the serum of HFD-treated mice. The NMDAR blockade by Memantine decreased the susceptibility to insulin resistance and hepatic steatosis in obese mice. NMDA treatment for 6 months induced obesity in mice, characterized by hyperglycemia, hyperlipidemia, insulin resistance, and pathological changes in the liver. We provided in vitro evidence demonstrating that NMDAR activation facilitated metabolic syndrome in obesity through promoting lipid accumulation. NMDAR inhibition attenuated lipid accumulation induced by palmitic acid. Mechanistically, NMDAR activation impaired fatty acid oxidation by reducing PPARα phosphorylation and activity. The PPARα activity reduction induced by NMDAR activation was reversibly mediated by ERK1/2 signaling. Conclusion: These findings revealed that targeting NMDAR might be a promising therapeutic strategy for metabolic syndrome in obesity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Parental lifestyle has been related to alterations in the phenotype of their offspring. Obese sires can induce offspring insulin resistance as well as increase susceptibility to obesity. On the other hand, obese sires submitted to voluntary exercise ameliorate the deleterious metabolic effects on their offspring. However, there are no studies reporting the effect of programmed exercise training of lean sires on offspring metabolism., Aims: This study aimed to investigate the role of swimming training of sires for 6 weeks on the offspring metabolic phenotype., Main Methods: Male C57BL/6 mice fed a control diet were divided into sedentary and swimming groups. After the exercise, they were mated with sedentary females, and body weight and molecular parameters of the offspring were subsequently monitored., Key Findings: Swimming decreased the gene expression of Fasn and Acaca in the testes and increased the AMPK protein content in the testes and epididymis of the sires. The progeny presented a low weight at P1, which reached a normal level at P60 and at P90 the animals were challenged with HFD for 16 weeks. The male offspring of trained sires presented less body weight gain than the control group. The level of steatosis decreased in the male offspring from trained sires. The gene expression of Prkaa2, Ppar-1α and Cpt-1 was also increased in the liver of male offspring from trained sires., Significance: Taken together, these findings suggest that paternal exercise training can improve the metabolic profile in the liver of the progeny, thereby ameliorating the effects of obesity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The generation of large metabolomic data sets has created a high demand for software that can fit statistical models to one-metabolite-at-a-time on hundreds of metabolites. We provide the %polynova&#95;2way macro in SAS to identify metabolites differentially expressed in study designs with a two-way factorial treatment and hierarchical design structure. For each metabolite, the macro calculates the least squares means using a linear mixed model with fixed and random effects, runs a 2-way ANOVA, corrects the P-values for the number of metabolites using the false discovery rate or Bonferroni procedure, and calculate the P-value for the least squares mean differences for each metabolite. Finally, the %polynova&#95;2way macro outputs a table in excel format that combines all the results to facilitate the identification of significant metabolites for each factor. The macro code is freely available in the Supporting Information., Competing Interests: The authors have declared that no competing interests exist.

Background: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking., Objectives: We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms., Methods: Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%-15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0-9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched low-fat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed., Results: In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes., Conclusions: These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Background/objectives: Visceral adiposity is associated with increased diabetes risk, while expansion of subcutaneous adipose tissue may be protective. However, the visceral compartment contains different fat depots. Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot. Here, we aimed to define PAT functionality in lean and high-fat-diet (HFD)-induced obese mice., Subjects/methods: Four adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic adipose tissue) from chow- and HFD-fed male mice were compared with respect to adipocyte size (n = 4-5/group), cellular composition (FACS analysis, n = 5-6/group), lipogenesis and lipolysis (n = 3/group), and gene expression (n = 6-10/group). Radioactive tracers were used to compare lipid and glucose metabolism between these four fat depots in vivo (n = 5-11/group). To determine the role of PAT in obesity-associated metabolic disturbances, PAT was surgically removed prior to challenging the mice with HFD. PAT-ectomized mice were compared to sham controls with respect to glucose tolerance, basal and glucose-stimulated insulin levels, hepatic and pancreatic steatosis, and gene expression (n = 8-10/group)., Results: We found that PAT is a tiny fat depot (~0.2% of the total fat mass) containing relatively small adipocytes and many "non-adipocytes" such as leukocytes and fibroblasts. PAT was distinguished from the other fat depots by increased glucose uptake and increased fatty acid oxidation in both lean and obese mice. Moreover, PAT was the only fat depot where the tissue weight correlated positively with liver weight in obese mice (R = 0.65; p = 0.009). Surgical removal of PAT followed by 16-week HFD feeding was associated with aggravated hepatic steatosis (p = 0.008) and higher basal (p < 0.05) and glucose-stimulated insulin levels (p < 0.01). PAT removal also led to enlarged pancreatic islets and increased pancreatic expression of markers of glucose-stimulated insulin secretion and islet development (p < 0.05)., Conclusions: PAT is a small metabolically highly active fat depot that plays a previously unrecognized role in the pathogenesis of hepatic steatosis and insulin resistance in advanced obesity.

Background and Aim: Non-alcoholic fatty liver disease is a rapidly growing public health problem. In this study, we explored the association between dietary patterns (DPs) and fatty liver and liver function tests., Methods: This was a cross-sectional study using data from the US community-based National Health and Nutrition Examination Survey. Participants with data on dietary intake, blood pressure, and status for diabetes mellitus were analyzed. DPs were determined by principal components analysis. Analysis of covariance and logistic regression models accounted for the survey design and sample weights., Results: Of the 20 643 eligible participants, 45.7% had prevalent fatty liver. Three DPs collectively explained 50.8% of variance in dietary nutrients consumption. The first DP was representative of a diet containing high levels of saturated and mono-unsaturated fatty acids, total fat and carbohydrate; the second DP comprised vitamins, minerals and dietary fibre; and the third DP was mainly representative of polyunsaturated fatty acids. In adjusted multivariable regression models, participants in the top quarter of the second DP had 34% lower odds of prevalent fatty liver (odds ratio 0.66 [95% confidence interval [CI]: 0.43-0.71]), while those in the top quarter of the first DP had 86% higher odds (1.86 [95% CI: 1.42-2.95]) of prevalent fatty liver, relative to participants in the bottom quarter of each of the DPs., Conclusion: Our findings suggest that a diet with high load of vitamins, minerals, and fiber content is associated with a lower prevalence of non-alcoholic fatty liver disease., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Some drugs may induce hepatotoxic lesions, such as steatosis or steatohepatitis found in Non-Alcoholic Fatty Liver Disease (NAFLD). Among these drugs there are some anti-tumoral molecules, such as methotrexate, 5-fluorouracil, irinotecan, tamoxifen and l-asparaginase. The hepatotoxic phenotype developed from treatment with such drugs is known as "CASH" for "Chemotherapy-induced Acute Steatohepatitis". The mechanism of toxicity is essentially based on mitochondrial toxicity. These lesions are chronic and often reversible when the treatment is stopped. Contributing factors related to the patient, the disease or the treatment play a major role in the emergence of CASH. It is important to identify chemotherapies with steatosis or steatohepatitis as risk factors in order to improve control of the metabolic risk factors associated with the patient and to reinforce monitoring during treatment. In the particular context of neo-adjuvant chemotherapy for metastatic colorectal cancer, a short duration of chemotherapy and a few-weeks delay between chemotherapy and surgery could reduce postoperative morbidity and mortality., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Ethnopharmacological Relevance: Cecropia peltata L. (CP) leaves have been used in Latin American traditional medicine by its purported hypoglycemic, anti-inflammatory and antioxidant properties., Purpose: The aim of this study was to evaluate the metabolic effects of an ethanolic extract of CP leaves in rats fed a high-fat diet and 10% of sugar in water (HFD)., Methods: Male Wistar rats were randomly divided into four groups: group 1 was fed a control diet; groups 2, 3 and 4 were fed a HFD. In addition, group 3 was co-administered with 10 mg/kg/day of CP extract (HFD + CP) and group 4 with a solution of 5 mg/kg/day metformin (HFD + M) for 90 days., Results: Body weight gain and serum triglycerides were significantly decreased in the HFD + CP group compared with the HFD and HFD + M groups. Glucose tolerance increased in the HFD + CP compared with the HFD group. Administration with CP extract reduced adipose tissue lipolysis and lipid accumulation in liver of HFD + CP rats with respect to HFD and HFD + M groups. Histological examinations showed that the area of the adipocytes in WAT and the area of lipid vesicles in BAT were significantly smaller in the HFD + CP group than in the HFD and HFD + M groups., Conclusion: Administration of a CP extract prevented glucose intolerance and hepatic lipid accumulation in rats fed a HFD in association with reduced adipocyte hypertrophy, demonstrating potential antidiabetic properties., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative bacteria alter intestinal permeability and cause bacterial translocation. This study evaluated the effects of gut microbiota modulation by a purified PPAR-alpha agonist (WY14643), a DPP-4 inhibitor (linagliptin), or their association on intestinal barrier integrity, endotoxemia, and hepatic energy metabolism in high-fructose-fed C57BL/6 mice. Fifty mice were divided to receive the control diet (C group) or the high-fructose diet (HFRU) for 12 weeks. Subsequently, the HFRU group was divided to initiate the treatment with PPAR-alpha agonist (3.5 mg/kg/BM) and DPP-4 inhibitor (15 mg/kg/BM). The HFRU group had glucose intolerance, endotoxemia, and dysbiosis (with increased Proteobacteria) without changes in body mass in comparison with the C group. HFRU group showed damaged intestinal ultrastructure, which led to liver inflammation and marked hepatic steatosis in the HFRU group when compared to the C group. PPAR-alpha activation and DPP-4 inhibition countered glucose intolerance, endotoxemia, and dysbiosis, ameliorating the ultrastructure of the intestinal barrier and reducing Tlr4 expression in the liver of treated animals. These beneficial effects suppressed lipogenesis and mitigated hepatic steatosis. In conclusion, the results herein propose a role for PPAR-alpha activation, DPP-4 inhibition, and their association in attenuating hepatic steatosis by gut-liver axis modulation in high-fructose mice model. These observations suggest these treatments as potential targets to treat hepatic steatosis and avoid its progression.

Background and Aims: Coffee is known to have a beneficial effect on various liver diseases. The aim of this retrospective longitudinal study was to investigate an association between the amount of coffee consumption and the incidence of fatty liver disease in Korean adults., Methods and Results: Data from a total of 91,436 male and female subjects with the mean follow-up period of 2.8 years were analyzed. The incidence of fatty liver was not associated with the amount of coffee consumption at baseline, but it was associated with the change in the amount of coffee consumption at the follow-up period. Multiple linear regression analyses showed that hazard ratios for incidence of fatty liver disease were significantly low in "increase" group comparing with "no change" group in fully adjusted model. When a subgroup analysis by gender was conducted, similar significant results were observed in male subjects, but not in females., Conclusions: The increment in the amount of coffee consumption is associated with the lower incidence of fatty liver in Korean men and suggests that increasing the coffee consumption may have a protective effect on fatty liver., Competing Interests: Declaration of Competing Interest There is no potential conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Drug-induced phospholipidosis (DIPL) is characterized by phospholipid storage in the lysosomes of affected tissues. Many severe effects and toxicities have been linked to DIPL. The aim of this study was to determine whether the endogenous opioid system is involved in chloroquine-induced phospholipidosis. The effect of naltrexone as an antagonist of opioid receptors in chloroquine-induced phospholipidosis in rat liver was investigated by morphological, biochemical, and molecular modelling studies. Transmission electron microscopy (TEM) showed that morphological characteristic changes of rat liver, including the number of lamellar bodies, grade of vacuolization and cell steatosis, were markedly attenuated in rats treated with naltrexone alone or in combination with chloroquine, in comparison with chloroquine-treated rats. The results of liquid chromatography mass spectrometry (LC/MS) showed that the concentrations of phenylacetylglycine (PAG) and hippuric acid (HA) were significantly decreased and increased, respectively, in target groups. Besides, the concentration ratio of PAG/HA was significantly decreased. Spectrophotometry resulted in a notable decrease in alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities in target groups. The results from the molecular docking and molecular dynamic simulation studies demonstrated clear chloroquine interaction with the active site cavity of the µ opioid receptor. These data suggest that administration of naltrexone alone, or in combination with chloroquine, notably attenuates the side effects of chloroquine-induced phospholipidosis, as well as demonstrating an increased probability of the endogenous opioid system involvement in chloroquine-induced phospholipidosis in rat liver., (© 2020 John Wiley & Sons Australia, Ltd.)

Obesity is a worldwide epidemic characterized by excessive fat accumulation, associated with multiple comorbidities and complications. Emerging evidence points to gut microbiome as a driving force in the pathogenesis of obesity. Vinegar intake, a traditional remedy source of exogenous acetate, has been shown to improve glycemic control and to have anti-obesity effects. New functional foods may be developed by supplementing traditional food with probiotics. B. coagulans is a suitable choice because of its resistance to high temperatures. To analyze the possible synergic effect of Vinegar and B. coagulans against the metabolic alterations induced by a high fat diet (HFD), we fed twelve-week-old C57BL/6 mice with HFD for 5 weeks after 2 weeks of acclimation on a normal diet. Then, food intake, body weight, blood biochemical parameters, histology and liver inflammatory markers were analyzed. Although vinegar drink, either alone or supplemented with B. coagulans , reduced food intake, attenuated body weight gain and enhanced glucose tolerance, only the supplemented drink improved the lipid serum profile and prevented hepatic HFD-induced overexpression of CD36, IL-1β, IL-6, LXR and SREBP, thus reducing lipid deposition in the liver. The beneficial properties of the B. coagulans -supplemented vinegar appear to be mediated by a reduction in insulin and leptin circulating levels.

Maternal nutritional programming by a high-fat (HF) diet is related to hepatic lipid accumulation and steatosis in offspring. Conjugated linoleic acid (CLA) might ameliorate impaired hepatic lipid homoeostasis; therefore, the aim was to investigate the potential preventive effect of maternal CLA consumption on TAG metabolism alterations induced by HF diets in adult male rat offspring receiving or not receiving CLA. Female Wistar rats were fed a control (C) diet, HF diet or HF diet supplemented with CLA (HF+CLA) for 4 weeks before mating and throughout pregnancy and lactation. After weaning, for 9 weeks, male offspring of C or HF rats continued with the same diets as their mothers (C/C or HF/HF groups, respectively) and male offspring of HF+CLA rats were fed HF or HF+CLA diets (HF+CLA/HF or HF+CLA/HF+CLA groups, respectively). Nutritional parameters, serum and liver TAG levels, the TAG secretion rate (TAG-SR) and the activities as well as gene expression of key hepatic enzymes involved in TAG regulation were assessed. The most interesting results were that maternal CLA decreased epididymal white adipose tissue weight and prevented serum and liver TAG accumulation induced by a HF diet in adult male offspring receiving or not receiving CLA. The prevention of liver steatosis in HF+CLA/HF+CLA and HF+CLA/HF offspring was associated with an increased hepatic TAG-SR. Overall, this study provides evidence that maternal CLA consumption programmes TAG regulation and in this way contributes to lowering lipid levels in tissues and preventing liver steatosis in particular.

Goat's milk is a rich source of bioactive compounds (peptides, conjugated linoleic acid, short chain fatty acids, monounsaturated and polyunsaturated fatty acids, polyphenols such as phytoestrogens and minerals among others) that exert important health benefits. However, goat's milk composition depends on the type of food provided to the animal and thus, the abundance of bioactive compounds in milk depends on the dietary sources of the goat feed. The metabolic impact of goat milk rich in bioactive compounds during metabolic challenges such as a high-fat (HF) diet has not been explored. Thus, we evaluated the effect of milk from goats fed a conventional diet, a conventional diet supplemented with 30% Acacia farnesiana (AF) pods or grazing on metabolic alterations in mice fed a HF diet. Interestingly, the incorporation of goat's milk in the diet decreased body weight and body fat mass, improved glucose tolerance, prevented adipose tissue hypertrophy and hepatic steatosis in mice fed a HF diet. These effects were associated with an increase in energy expenditure, augmented oxidative fibers in skeletal muscle, and reduced inflammatory markers. Consequently, goat's milk can be considered a non-pharmacologic strategy to improve the metabolic alterations induced by a HF diet. Using the body surface area normalization method gave a conversion equivalent daily human intake dose of 1.4 to 2.8 glasses (250 mL per glass/day) of fresh goat milk for an adult of 60 kg, which can be used as reference for future clinical studies.

Aims: Rg1 is the most active component of traditional Chinese medicine ginseng, having anti-aging and anti-oxidative stress features in multiple organs. Cellular senescence of hepatocytes is involved in the progression of a wide spectrum of chronic liver diseases. In this study, we investigated the potential benefits and mechanism of action of Rg1 on aging-driven chronic liver diseases., Materials and Methods: A total of 40 male C57BL/6 mice were randomly divided into four groups: control group; Rg1 group; Rg1+d-gal group; and d-gal group. Blood and liver tissue samples were collected for determination of liver function, biochemical and molecular markers, as well as histopathological investigation., Key Findings: Rg1 played an anti-aging role in reversing d-galactose induced increase in senescence-associated SA-β-gal staining and p53, p21 protein in hepatocytes of mice and sustained mitochondria homeostasis. Meanwhile, Rg1 protected livers from d-galactose caused abnormal elevation of ALT and AST in serum, hepatic steatosis, reduction in hepatic glucose production, hydrogenic degeneration, inflammatory phenomena including senescence-associated secretory phenotype (SASP) IL-1β, IL-6, MCP-1 elevation and lymphocyte infiltration. Furthermore, Rg1 suppressed drastic elevation in FOXO1 phosphorylation resulting in maintaining FOXO1 protein level in the liver after d-galactose treatment, followed by FOXO1 targeted antioxidase SOD and CAT significant up-regulation concurrent with marked decrease in lipid peroxidation marker MDA., Significance: Rg1 exerts pharmaceutic effects of maintaining FOXO1 activity in liver, which enhances anti-oxidation potential of Rg1 to ameliorate SASP and to inhibit inflammation, also promotes metabolic homeostasis, and thus protects livers from senescence induced fatty liver disease. The study provides a potential therapeutic strategy for alleviating chronic liver pathology., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Excess dietary sugar is associated with deleterious metabolic effects, liver injury, and coenzyme-Q10 (CoQ10) deficiency. This study investigates the ability of CoQ10 to protect against fructose-induced hepatic damage., Methods: Rats were fed tap water or 30% fructose for 12 weeks with or without CoQ10 (10 mg/kg, po). An additional group of rats were allowed to feed on either water or 30% fructose for 12 weeks, followed by four weeks of treatment with either the vehicle or CoQ10., Results: Fructose-fed rats showed lower CoQ10 levels, increased systolic pressure, increased body weight, higher liquid consumption, decreased food intake and hyperglycemia. Fructose-fed rats also showed deteriorated serum and liver lipid profiles, impaired liver function tests and oxidative status, and lower expression of adiponectin receptor 1 and 2 along with higher GLUT-2 levels. Furthermore, following fructose treatment, tyrosine kinase-PI3K pathway was inhibited. Additionally, there was an increase in the levels of apoptotic markers and serum visfatin and a decrease in the levels of adiponectin and soluble receptor of the advanced glycated end product. Consequently, several histopathological changes were detected in the liver. Concurrent or three months post-exposure administration of CoQ10 in fructose rats significantly reversed or attenuated all the measured parameters and hepato-cytoarchitecture alterations., Conclusion: This study suggests CoQ10 supplement as a possible prophylaxis or treatment candidate for fructose-induced liver injury.

Short bowel syndrome (SBS) is associated with changes in the intestinal microbiome and marked local and systemic inflammation. There is also a late complication of SBS, intestinal failure associated liver disease (IFALD) in which hepatic steatosis progresses to cirrhosis. Most patients with SBS arrive at massive intestinal resection after a contaminating intraabdominal catastrophe and have a history of exposure to broad-spectrum antibiotics. We therefore investigated whether the administration of broad-spectrum antibiotics in conjunction with SBS in zebrafish (ZF) would replicate these systemic effects observed in humans to identify potentially druggable targets to aid in the management of SBS and resulting IFALD. In zebrafish with SBS, broad-spectrum antibiotics altered the microbiome, decreased inflammation, and reduced the development of hepatic steatosis. After two weeks of broad-spectrum antibiotics, these fish exhibited decreased alpha diversity, with less variation in microbial community composition between SBS and sham fish. Additionally, administration of broad-spectrum antibiotics was associated with decreased expression of intestinal toll-like receptor 4 ( tlr 4), increased expression of the intestinal gene encoding the Farnesoid X receptor ( fxr), decreased expression of downstream hepatic cyp7a1 , and decreased development of hepatic steatosis. SBS in zebrafish reproducibly results in increased epithelial surface area as occurs in human patients who demonstrate intestinal adaptation, but antibiotic administration in zebrafish with SBS reduced these gains with increased cell death in the intervillus pocket that contains stem/progenitor cells. These alternate states in SBS zebrafish might direct the development of future human therapies. NEW & NOTEWORTHY In a zebrafish model that replicates a common clinical scenario, systemic effects of the administration of broad-spectrum antibiotics in a zebrafish model of SBS identified two alternate states that led to the establishment of fat accumulation in the liver or its absence. Broad-spectrum antibiotics given to zebrafish with SBS over 2 wk altered the intestinal microbiome, decreased intestinal and hepatic inflammation, and decreased hepatic steatosis.

Browning of white adipose tissue (WAT) has been shown to reduce obesity and obesity-related complications, suggesting that factors that promote WAT browning may have applications in the development of therapeutic strategies for treating obesity. Here, we show that ablation of spinophilin (SPL), a ubiquitously expressed, multidomain scaffolding protein, increases metabolism and improves energy balance. Male and female SPL knockout (KO) and wild-type (WT) littermate controls were fed a chow diet or a high-fat diet (HFD). Body weight, hepatic steatosis, glucose and insulin tolerance, physical activity, and expression of browning genes in adipose tissues were measured and compared. Male SPL knockout (KO) mice fed a chow diet were significantly leaner, had lower body weights, and exhibited better glucose tolerance and insulin sensitivity than wild-type (WT) littermate controls. When fed an HFD, SPL KO mice were protected from increased body fat, weight gain, hepatic steatosis, hyperinsulinemia, and insulin resistance. Physical activity of SPL KO mice was markedly increased compared with WT controls. Furthermore, expression of the brown adipocyte marker, uncoupling protein-1 (UCP-1), and the mitochondrial activity markers, cd137 and c-idea, were significantly increased in visceral WAT (vWAT) of SPL KO mice, suggesting that SPL knockout protected the mice from HFD-induced obesity and its metabolic complications, at least in part, by promoting the browning of white adipocytes in vWAT. Our data identify a critical role of SPL in regulating glucose homeostasis, obesity, and adipocyte browning. These results suggest SPL may serve as a drug target for obesity and diabetes.

Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes in vitro. Here, we used platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR's role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahrfl/fl) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahrfl/fl mice (control mice). The Pdgfrα-Cre Ahrfl/fl knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahrfl/fl mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of Ahr mediated by Pdgfrα-Cre is protective against diet-induced obesity and suggest a mechanism by which enhanced UCP1 activity within BAT might confer these effects., Competing Interests: The authors have declared that no competing interests exist.

Elafin is an antimicrobial and anti-inflammatory protein. We hypothesize that elafin expression correlates with diabetes. Among non-diabetic and prediabetic groups, men have significantly higher serum elafin levels than women. Men with type 2 diabetes mellitus (T2DM) have significantly lower serum elafin levels than men without T2DM. Serum elafin levels are inversely correlated with fasting blood glucose and hemoglobin A1c levels in men with T2DM, but not women with T2DM. Lentiviral elafin overexpression inhibited obesity, hyperglycemia, and liver steatosis in high-fat diet (HFD)-treated male mice. Elafin-overexpressing HFD-treated male mice had increased serum leptin levels, and serum exosomal miR181b-5p and miR219-5p expression. Transplantation of splenocytes and serum exosomes from elafin-overexpressing HFD-treated donor mice reduced food consumption and fat mass, and increased adipose tissue leptin mRNA expression in HFD-treated recipient mice. Elafin improved leptin sensitivity via reduced interferon-gamma expression and induced adipose leptin expression via increased miR181b-5p and miR219-5p expression. Subcutaneous and oral administration of modified elafin inhibited obesity, hyperglycemia, and liver steatosis in the HFD-treated mice. Circulating elafin levels are associated with hyperglycemia in men with T2DM. Elafin, via immune-derived miRNAs and cytokine, activates leptin sensitivity and expression that subsequently inhibit food consumption, obesity, hyperglycemia, and liver steatosis in HFD-treated male mice.

Metabolic associated fatty liver disease (MAFLD) due to excess weight and obesity threatens public health worldwide. Gut microbiota dysbiosis contributes to obesity and related diseases. The cholesterol-lowering, anti-inflammatory, and antioxidant effects of wild rice have been reported in several studies; however, whether it has beneficial effects on the gut microbiota is unknown. Here, we show that wild rice reduces body weight, liver steatosis, and low-grade inflammation, and improves insulin resistance in high-fat diet (HFD)-fed mice. High-throughput 16S rRNA pyrosequencing demonstrated that wild rice treatment significantly changed the gut microbiota composition in mice fed an HFD. The richness and diversity of the gut microbiota were notably decreased upon wild rice consumption. Compared with a normal chow diet (NCD), HFD feeding altered 117 operational taxonomic units (OTUs), and wild rice supplementation reversed 90 OTUs to the configuration in the NCD group. Overall, our results suggest that wild rice may be used as a probiotic agent to reverse HFD-induced MAFLD through the modulation of the gut microbiota.

Impaired vascularization of adipose tissue leads to local hypoxia and results in chronic inflammation and obesity-related metabolic disorders. We have recently constructed an engineered protein named tPep-VEGF-B by bridging vascular endothelial growth factor (VEGF-B) with an adipose-targeted peptide. Here, we reported tPep-VEGF-B diminishes obesity and alleviates metabolic syndrome. High fat diet (HFD) treated mice had reduced adipose vascular density and showed adipose hypoxia and metabolic complications. In contrast, the treatment of tPep-VEGF-B repressed HFD-induced body weight gain, which led to increased adipose vasculature and reduced hypoxia. This treatment also alleviated obesity associated hyperlipidemia and fatty liver disease. This study provided a leading molecule for the treatment of type 2 diabetes and other metabolic diseases. It also provided experimental support for the theory that modulation of angiogenesis plays a key role in the treatment of metabolic diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-related metabolic syndrome., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is a key regulator of energy metabolism in the liver. In nonruminants, the hepatic abundance of SIRT3 is decreased in individuals with nonalcoholic fatty liver diseases, and recovery of SIRT3 alleviates hepatic triacylglycerol (TG) deposition. However, the level of SIRT3 expression and its effects on lipid metabolism in dairy cows have not been characterized. Here we studied the hepatic expression of SIRT3 in cows with fatty liver and the role of SIRT3 in fatty acid metabolism in bovine hepatocytes. This in vivo study involved 10 healthy cows and 10 cows with fatty liver, from which we collected samples of liver tissue and blood. Primary hepatocytes were isolated from Holstein calves and treated with 0, 0.5, or 1.0 mM nonesterified fatty acids (NEFA) for 24 h or transinfected with SIRT3 overexpression adenovirus (Ad-SIRT3)/SIRT3-short interfering (si)RNA for 48 h. Cows with fatty liver displayed lower serum glucose concentrations but higher serum NEFA and β-hydroxybutyrate concentrations relative to healthy cows. Cows with fatty liver also had significant lower mRNA and protein abundance of hepatic SIRT3. Incubation of primary hepatocytes with NEFA reduced SIRT3 abundance in primary hepatocytes in a dose-dependent manner. Fatty acid (1 mM) treatment also markedly increased the abundance of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) but significantly decreased the abundance of carnitine palmitoyltransferase I (CPT1A), carnitine palmitoyltransferase II (CPT2), and acyl-CoA oxidase (ACO). Knockdown of SIRT3 by SIRT3-siRNA downregulated the mRNA abundance of CPT1A, CPT2, and ACO. In contrast, overexpression of SIRT3 by Ad-SIRT3 upregulated the mRNA abundance of CPT1A, CPT2, and ACO; downregulated the mRNA abundance of ACC1 and FAS; and consequently, decreased intracellular TG concentrations. Overexpression of SIRT3 ameliorated exogenous NEFA-induced TG accumulation by downregulating the abundance of ACC1 and FAS and upregulating the abundance of CPT1A, CPT2, and ACO in calf hepatocytes. Our data demonstrated that cows with fatty liver had lower hepatic SIRT3 contents, and an increase in SIRT3 abundance by overexpression mitigated TG deposition by modulating the expression of lipid metabolism genes in bovine hepatocytes. These data suggest a possible role of SIRT3 as a therapeutic target for fatty liver disease prevention in periparturient dairy cattle., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Obesity has recently become a prevalent health threat worldwide. Although emerging evidence has suggested a strong link between the pentose phosphate pathway (PPP) and obesity, the role of transketolase (TKT), an enzyme in the nonoxidative branch of the PPP that connects PPP and glycolysis, remains obscure in adipose tissues. In this study, we specifically deleted TKT in mouse adipocytes and found no obvious phenotype upon normal diet feeding. However, adipocyte TKT abrogation attenuated high-fat diet-induced obesity, reduced hepatic steatosis, improved glucose tolerance, alleviated insulin resistance, and increased energy expenditure. Mechanistically, TKT deficiency accumulated nonoxidative PPP metabolites and decreased glycolysis and pyruvate input into the mitochondria, leading to increased lipolytic enzyme gene expression and enhanced lipolysis, fatty acid oxidation, and mitochondrial respiration. Therefore, our data not only identify a novel role of TKT in regulating lipolysis and obesity but also suggest that limiting glucose-derived carbon into the mitochondria induces lipid catabolism and energy expenditure., (© 2020 by the American Diabetes Association.)

Background: Recent shifts in lifestyles and diets have caused the incidence of obesity to increase rapidly, resulting in a serious threat to modern human health. There is a growing interest the use of plant or fungi derived supplements as a safe and effective means to treat obesity. In recent times, edible-medicinal fungi have garnered attention as therapeutics owing to their biocompatibility and effectiveness. Attempts to determine the therapeutic effects of these fungi have become a prime focus in drug discovery programs. Therefore, this study aimed to determine the anti-obesity effects of P. eryngii chitin in rats with obesity induced by administration of a high fat diet., Methods: To investigate the therapeutic effects of chitin from Pleurotus eryngii on high fat diet-induce obesity, we treated obese rats with different concentrations of chitin from P. eryngii for 4 weeks, using Lipitor as positive control. The living condition, food intake, body weight, perirenal adipose tissue, periepididymal adipose tissue, adipose tissue coefficient, serum lipid levels, including total cholesterol (TC), total glyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), were measured, and levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), themalonaldehyde (MDA), and superoxide dismutase (SOD) activity in liver were determined. The rats were also monitored for pathological changes in the liver and aorta., Results: These studies indicated that administration of chitin from P. eryngii could significantly decrease obese rat food utilization rates and accumulation of adipose tissue in the body, thus preventing development of increased body weight. The treatment also significantly reduced serum lipid levels, including levels of TC, TG and LDL-C. Treatment with P. eryngii-derived chitin also enhanced ALT and AST enzymatic activity, enhanced SOD enzymatic activity, and reduced the MDA content of the liver, as well as significantly reducing the liver index and alleviating liver steatosis and aortic atherosclerosis resulting from obesity., Conclusions: In conclusion, chitin from P. eryngii had therapeutic effects on hyperlipidemia, fatty liver, and aortic atherosclerosis resulting from obesity in rats.

Background: The ling-gui-zhu-gan (LGZG) decoction is a classic formula in traditional chinese medicine (TCM) and is widely used in clinical settings. Recently, the LGZG decoction was demonstrated to have an effect in alleviating hepatic steatosis induced by a high-fat diet (HFD). However, the mechanisms underlying this therapeutic effect remain unclear. The present study was designed to evaluate the effect and explore possible mechanisms of action of the LGZG decoction in nonalcoholic fatty liver disease (NAFLD)., Methods: Liver tissue and blood samples were harvested. Liver steatosis, triglyceride (TG), liver total cholesterol (TC), liver low-density lipoprotein (LDL), serum almandine aminotransferase (ALT), aspartate aminotransferase (AST), and free fatty acid (FFA) were assayed. N6-methyladenosine (m6A) levels were estimated using an m6A RNA methylation quantification kit and immunohistochemistry. The m6A methylome was detected through methylated RNA immunoprecipitation sequencing (MeRIP-seq), followed by data analysis. The expression levels of differentially methylated genes (DMGs) were determined using real-time polymerase chain reaction and western blotting., Results: The LGZG decoction significantly alleviated hepatic steatosis and reduced m6A levels. MeRIP-seq revealed the coding sequence (CDS) domain to be the most critical modification site for m6A methylation, and the molecular functions of DMGs predominantly included insulin-like growth factor receptor binding and fatty acid metabolism and degradation. Further, LGZG treatment could reduce the m6A methylation levels of suppressor of cytokine signaling 2 (SOCS2), along with the expression of SOCS2 at mRNA and protein levels., Conclusions: The LGZG decoction is an effective formula for treating NAFLD, and the possible mechanisms underlying its action could be related to N6-methyladenosine modification-medicated SOCS2., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier Masson SAS.)

Selenoneine is a novel organic selenium compound markedly found in the blood, muscles, and other tissues of fish. This study aimed to determine whether selenoneine attenuates hepatocellular injury and hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). Mice lacking farnesoid X receptor (FXR) were used as a model for fatty liver disease, because they exhibited hepatomegaly, hepatic steatosis, and hepatic inflammation. Fxr -null mice were fed a 0.3 mg Se/kg selenoneine-containing diet for four months. Significant decreases in the levels of hepatomegaly, hepatic damage-associated diagnostic markers, hepatic triglycerides, and total bile acids were found in Fxr -null mice fed with a selenoneine-rich diet. Hepatic and blood clot total selenium concentrations were 1.7 and 1.9 times higher in the selenoneine group than in the control group. A marked accumulation of selenoneine was found in the liver and blood clot of the selenoneine group. The expression levels of oxidative stress-related genes ( heme oxygenase 1 ( Hmox1 ), glutathione S-transferase alpha 1 ( Gsta1 ), and Gsta2 ), fatty acid synthetic genes ( stearoyl CoA desaturase 1 ( Scd1 ) and acetyl-CoA carboxylase 1 ( Acc1 )), and selenoprotein ( glutathione peroxidase 1 ( Gpx1 ) and selenoprotein P ( Selenop )) were significantly decreased in the selenoneine group. These results suggest that selenoneine attenuates hepatic steatosis and hepatocellular injury in an NAFLD mouse model.