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Obesity and metabolic syndrome affect the majority of the US population. Patients with obesity are at increased risk of developing type 2 diabetes (T2DM), obstructive sleep apnea (OSA), and metabolic dysfunction-associated steatotic liver disease (MASLD), each of which carry the risk of further complications if left untreated and lead to adverse outcomes. The rising prevalence of obesity and its comorbidities has led to increased mortality, decreased quality of life, and rising healthcare expenditures. This phenomenon has resulted in the intensive investigation of exciting therapies for obesity over the past decade, including more treatments that are still in the pipeline. In our present report, we aim to solidify the relationships among obesity, T2DM, OSA, and MASLD through a comprehensive review of current research. We also provide an overview of the surgical and pharmacologic treatment classes that target these relationships, namely bariatric surgery, the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptor agonists.

IntroductionCigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD+) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR.MethodsC57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks.ResultsOur results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD+ signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling.ConclusionWe conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS.

Purpose: This study investigated the anti-inflammatory effect of clodronate, a vesicular nucleotide transporter (VNUT) inhibitor, on intestinal-failure-associated liver disease (IFALD) in a rat model of short bowel syndrome (SBS). Methods: The rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. The animals were divided into the following groups: TPN/SBS (Control group), TPN/SBS/intravenous administration of low-dose clodronate (20 mg/kg twice per week; Low group), or TPN/SBS/intravenous administration of high-dose clodronate (60 mg/kg twice per week; High group). On day 7, the rats were euthanized. Hepatic steatosis and hepatocellular injury were also assessed. Results: Hepatic steatosis and lobular inflammation in the liver were observed in all groups. The High group showed histologically reduced hepatic steatosis compared with the Control group. IL-6 and Nlrp3 expression in the High group was significantly suppressed compared to that in the Control group. The expression of other inflammatory cytokines tended to be lower in the High dose group than in the control group. The lipid metabolism gene expression in the liver specimens showed no significant differences among the groups. Conclusion: The high-dose administration of clodronate may, therefore, inhibit hepatic steatosis and inflammation associated with IFALD in patients with SBS. [ABSTRACT FROM AUTHOR]

Background: Bardet–Biedl syndrome (BBS) is a rare autosomal-recessive ciliopathy with pathogenic variants in 26 BBS genes. It affects multiple organs, including the kidney and liver, with varying degrees regarding extent and time of first manifestation. Structural renal anomalies are an early feature and end-stage kidney disease (ESKD) cumulates to 25% in adulthood. Early-onset hyperphagia-associated obesity is another major symptom and contributes to liver pathology, presenting as steatosis/fibrosis. Aim of this study is the evaluation of high-end ultrasound (US) technologies in BBS patients regarding their potential to discriminate liver and kidney tissue pathology at an early stage. Materials and methods: Patients with genetically proven BBS were recruited from the University Children's Hospital of Essen and from BBS patient days hosted in Germany. Acute illness was an exclusion criterion. Clinical and laboratory data were extracted from patients' digital records or medical letters. High-resolution ultrasound (US) imaging was utilized, including attenuation imaging (ATI), shear wave elastography (SWE) and dispersion (SWD) of liver tissue. Results: 49 BBS patients (24/49 male; 1.1–51.0 years, mean 17.8 years) were included in the study. Mean body weight (SDS 2.13 ± 1.33) and BMI (SDS 2.64 ± 1.18) were increased. Structural kidney abnormalities (dysplasia, cysts) were present in 75% (36/48), and persistent fetal lobulation in 44% (21/48). Renal function was impaired in 27% (13/49) of whom 3 had ESKD (kidney transplantation (n = 2), hemodialysis (n = 1)). Elevation of liver enzymes was detected in 38% (16/42). In 51% (25/49) ATI of liver tissue was increased, indicating hepatic steatosis, and correlated with BMI SDS, liver size, and enzymes. SWE was elevated in 61% (30/49), suggesting hepatic fibrosis, and it correlated with BMI and GGT. Patients with pathogenic variants in BBS10 showed a tendency towards higher ATI, reduced GFR, and higher BMI SDS. Conclusions: We detected kidney and liver abnormalities in a higher percentage of BBS patients than previously reported, indicating a high sensitivity and diagnostic yield of the evaluated high-end US applications. ATI detected liver pathology early (partially prior to liver enzymes) and revealed differences related to the affected genes. Evidence of tissue pathology at an early stage may improve diagnostics and the evaluation of therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD), characterized by excess liver fat, is common in women with a history of gestational diabetes mellitus (GDM). While breastfeeding improves postpartum lipid levels, its impact on NAFLD in these women is not well studied. We aimed to investigate the relationship between the duration and intensity of breastfeeding and the amount of liver fat and prevalence of NAFLD in women with previous GDM at approximately 1 year postpartum. Methods: This prospective cohort study was conducted at a university hospital in Bangkok, Thailand between November 2021 and February 2024. Overall, 130 women who had experienced GDM in their most recent pregnancy were followed up for 1 year postpartum. We collected data on breastfeeding practices and quantified liver fat using controlled attenuation parameters (CAPs) during transient elastography. NAFLD was defined as a CAP of ≥ 302 dB/m. Women were divided into three groups according to the duration and intensity of breastfeeding: group 1 (breastfeeding for < 6 months), group 2 (breastfeeding for ≥ 6 months and exclusive breastfeeding [EBF] for < 6 months), and group 3 (breastfeeding for ≥ 6 months and EBF for 6 months). Results: Overall, 57 (43.8%), 26 (20.0%), and 47 (36.2%) participants were categorized into groups 1, 2, and 3, respectively. Group 3 had the lowest CAPs, followed by groups 2 and 1. The median values (interquartile ranges) of the CAPs were 219.0 (189.0–271.0) dB/m, 257.5 (205.3–317.3) dB/m, and 279.0 (191.5–324.0) dB/m for groups 3, 2, and 1, respectively (p = 0.034). NAFLD prevalence was significantly lower in group 3 compared to groups 2 and 1 (19.1% vs. 38.5% vs. 43.9%, respectively; p = 0.026). Multivariate analysis showed that breastfeeding for ≥ 6 months and EBF for 6 months reduced the risk of NAFLD, with an adjusted odds ratio of 0.34 (95% confidence interval 0.14, 0.95). Conclusions: Breastfeeding for ≥ 6 months, particularly EBF for the first 6 months, may offer a practical strategy to reduce the risk of NAFLD in women with prior GDM. Trial registration: Thai Clinical Trials Registry: Registration no. TCTR20211027008. Date of registration: October 27, 2021. Date of initial participant enrollment: November 1, 2021. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently confers an increased risk of vascular thrombosis; however, the marketed antiplatelet drugs are investigated for the prevention and treatment of MASLD in patients with these coexisting diseases. Methods: To determine whether clopidogrel could ameliorate high-fat diet (HFD)-induced hepatic steatosis in mice and how it works, mice were fed on normal diet or HFD alone or in combination with or without clopidogrel for 14 weeks, and primary mouse hepatocytes were treated with palmitate/oleate alone or in combination with the compounds examined for 24 h. Body weight, liver weight, insulin resistance, triglyceride and total cholesterol content in serum and liver, histological morphology, transcriptomic analysis of mouse liver, and multiple key MASLD-associated genes and proteins were measured, respectively. Results and discussion: Clopidogrel mitigated HFD-induced hepatic steatosis (as measured with oil red O staining and triglyceride kit assay) and reduced elevations in serum aminotransferases, liver weight, and the ratio of liver to body weight. Clopidogrel downregulated the expression of multiple critical lipogenic (Acaca / Acacb , Fasn , Scd1 , Elovl6 , Mogat1 , Pparg , Cd36 , and Fabp4), profibrotic (Col1a1 , Col1a2 , Col3a1 , C ol4a1 , Acta2 , and Mmp2), and proinflammatory (Ccl2 , Cxcl2 , Cxcl10 , Il1a , Tlr4 , and Nlrp3) genes, and enhanced phosphorylation of AMPK and ACC. However, compound C (an AMPK inhibitor) reversed enhanced phosphorylation of AMPK and ACC in clopidogrel-treated primary mouse hepatocytes and alleviated accumulation of intracellular lipids. We concluded that clopidogrel may prevent and/or reverse HFD-induced hepatic steatosis in mice, suggesting that clopidogrel could be repurposed to fight fatty liver in patients. [ABSTRACT FROM AUTHOR]

Background: Silymarin, the predominant compound of milk thistle, is an extract took out from milk thistle (Silybum marianum) seeds, containing a mixture of flavonolignans with strong antioxidant capability. Methods: The experiment was conducted using 70 Lohmann LSL‐Lite hens at 80 weeks of age with 7 treatments each with 10 replicates. Treatments included: (1) control diet without silymarin, (2) daily intake of 100 mg silymarin powder/kg body weight (BW) (PSM100), (3) daily intake of 200 mg silymarin powder/kg BW (PSM200), (4) daily intake of 100 mg nano‐silymarin/kg BW (NSM100), (5) daily intake of 200 mg nano‐silymarin/kg BW (NSM200), (6) daily intake of 100 mg lecithinized silymarin/kg BW (LSM100) and (7) daily intake of 200 mg lecithinized silymarin/kg BW (LSM200). The birds were housed individually, and diets were fed for 12 weeks. Results: Scanning electron microscopy showed that NSM was produced with the average particle size of 20.30 nm. Silymarin treatment improved serum antioxidant enzyme activity. All groups receiving silymarin showed a decrease in liver malondialdehyde content, expression of fatty acid synthase, tumour necrosis factor alpha, interleukin 6 (IL‐6) genes in the liver, and hepatic steatosis than the control, except those fed the PSM100 diet. There were decreases in liver dry matter and fat contents, non‐alcoholic fatty liver disease and hepatocyte ballooning, and an increase in glutathione peroxidase gene expression and a decrease in iNOS gene expression in birds fed the NSM100, NSM200, LSM100 and LSM200 diets compared to the control group. Moreover, all groups receiving silymarin showed a significant decrease in liver weight compare to the control group. Conclusions: Overall, the effects of silymarin when converted to NSM or LSM and offered at the level of 200 mg/kg BW were more pronounced on the hepatic variables and may be useful in the prevention of the liver disease in older laying hens. [ABSTRACT FROM AUTHOR]

Background: The earliest manifestation of alcohol‐associated liver disease (ALD) is steatosis characterized by deposition of fat in specialized organelles called lipid droplets (LDs). While alcohol administration causes a rise in LD numbers in the hepatocytes, little is known regarding their characteristics that allow their accumulation and size to increase. The aim of the present study is to gain insights into underlying pathophysiological mechanisms by investigating the ethanol‐induced changes in hepatic LD proteome as a function of LD size. Methods: Adult male Wistar rats (180–200 g BW) were fed with ethanol liquid diet for 6 weeks. At sacrifice, large‐, medium‐, and small‐sized hepatic LD subpopulations (LD1, LD2, and LD3, respectively) were isolated and subjected to morphological and proteomic analyses. Results: Morphological analysis of LD1‐LD3 fractions of ethanol‐fed rats clearly demonstrated that LD1 contained larger LDs compared with LD2 and LD3 fractions. Our preliminary results from principal component analysis showed that the proteome of different‐sized hepatic LD fractions was distinctly different. Proteomic data analysis identified over 2000 proteins in each LD fraction with significant alterations in protein abundance among the three LD fractions. Among the altered proteins, several were related to fat metabolism, including synthesis, incorporation of fatty acid, and lipolysis. Ingenuity pathway analysis revealed increased fatty acid synthesis, fatty acid incorporation, LD fusion, and reduced lipolysis in LD1 compared to LD3. Overall, the proteomic findings indicate that the increased level of protein that facilitates fusion of LDs combined with an increased association of negative regulators of lipolysis dictates the generation of large‐sized LDs during the development of alcohol‐associated hepatic steatosis. Conclusion: Several significantly altered proteins were identified in different‐sized LDs isolated from livers of ethanol‐fed rats. Ethanol‐induced increases in specific proteins that hinder LD lipid metabolism led to the accumulation and persistence of large‐sized LDs in the liver. [ABSTRACT FROM AUTHOR]

The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants noninvasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in 10 medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from SHAP (Shapley Additive exPlanations), were compared with Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index using the area under receiver-operating characteristic curve (AUROC) and decision curve analysis (DCA). Of 1,198 eligible patients, the random forest model achieved AUROCs of 0.778 (95% confidence interval [CI], 0.749–0.807) for diagnosing advanced fibrosis (random forest advanced fibrosis model) and 0.777 (95% CI, 0.748–0.806) for diagnosing cirrhosis (random forest cirrhosis model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the random forest advanced fibrosis model obtained an AUROC of 0.825 (95% CI, 0.787–0.862) in patients with hepatitis B virus DNA ≥105 IU/mL, and the random forest cirrhosis model had an AUROC of 0.828 (95% CI, 0.774–0.883) in female patients. The 2 models outperformed Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index in the training cohort, and also performed well in the validation cohort. The random forest models provide reliable, noninvasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the comanagement of the 2 diseases. ClinicalTrials.gov, Number: NCT05766449. [Display omitted] [ABSTRACT FROM AUTHOR]

This study aims to reevaluate upper reference limit (URL) for alanine aminotransferase (ALT) by considering the changing epidemiology of major liver diseases. We employed histological and metabolic parameters in Asian living liver donors. We performed a retrospective analysis of 5455 potential living liver donors from 2005 to 2019. Participants were screened for hepatitis B, C, HIV, and alcohol use. Histologically and metabolically healthy participants were assessed using the Prati criteria (body mass index <23 kg/m2, triglyceride ≤200 mg/dL, fasting glucose ≤105 mg/dL, total cholesterol ≤220 mg/dL). The updated ALT-URL was determined as the 95th percentile among participants without hepatic steatosis and who met the Prati criteria. The median age was 30 years, with a male predominance (66.2%). Among 5455 participants, 3162 (58.0%) showed no hepatic steatosis, with 1553 (49.1%) meeting both the criteria for no steatosis and the Prati criteria for metabolic health. The updated URL for ALT in these participants was 34 U/L for males and 22 U/L for females, which was significantly lower than conventionally accepted values. Using this revised ALT-URL, 72.8% of males with ALT levels ≥34 U/L and 55.0% of females with ALT levels ≥22 U/L showed signs of steatosis, whereas 32.7% of males and 22.2% of females met the criteria for metabolic syndrome. Our study provided the newly established reference intervals for ALT levels in a metabolically and histologically verified Asian population. The proposed URL for ALT are 34 U/L and 22 U/L for males and females, respectively. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To study the relationship between qualitative and semi-quantitative assessment of diffuse liver steatosis in ultrasound. Patients and Methods: This was a case-control study, conducted in the Campus University Hospital Centre of Lome (Togo) over a 3-month period. It included 40 patients showing ultrasonographic signs of diffuse hepatic steatosis and 40 volunteers (healthy) whose echostructure and echogenicity of the hepatic parenchyma were normal. The B-mode sonographic grade of steatosis was compared with the hepatorenal echogenicity gradient and the ultrasound attenuation coefficient. Results: The average body mass index in patients was 30.87 ± 4.65 kg/m2 versus 24.25 ± 4.30 kg/m2 in the healthy group (p < 0.00001). Hepatomegaly was observed in 57.5% of the patients versus 17.5% in the healthy group (p = 0.0005). The average hepatorenal echogenicity ratio was 1.18 ± 0.07 in patients versus 1.01 ± 0.03 in the healthy group (p < 0.00001). The average difference in hepatorenal echogenicity was 9.30 ± 3.41 dB in patients versus 1.52 ± 1.07 dB in the healthy group (p < 0.00001). The attenuation of ultrasound waves increased with the grade of steatosis, averaging 0.08 ± 0.23 dB/cm/MHz (ranging from −0.33 to 0.61 dB/cm/MHz) in patients versus −0.24 ± 0.21 (ranging from −0.69 to 0.19 dB/cm/MHz) in the healthy group (p < 0.00001). Conclusion: Despite the advancements in new ultrasound technologies today, qualitative methods continue to be effective for the detection of hepatic steatosis and could prove useful in monitoring the effectiveness of hepatic steatosis treatment. [ABSTRACT FROM AUTHOR]

Hepatic steatosis, a common liver disorder, can progress to severe conditions such as nonalcoholic steatohepatitis and cirrhosis. While olfactory receptors are primarily known for detecting odorants, emerging evidence suggests that they also influence liver lipid metabolism. This study generated a mouse model with a specific knockout of olfactory receptor 23 (MOR23) to investigate its role in hepatic steatosis. MOR23 knockout mice on a normal diet showed a slight increase in liver weight compared to wild‐type (WT) mice. When fed a high‐fat diet (HFD), these knockout mice exhibited accelerated hepatic steatosis, indicated by increased liver weight and hepatic triglyceride levels. Our findings suggest that the cyclic adenosine monophosphate/protein kinase A/AMP‐activated protein kinase pathway is involved in the role of MOR23, leading to the upregulation of peroxisome proliferator‐activated receptor α, peroxisome proliferator‐activated receptor‐γ coactivator 1‐α, and their target β‐oxidation genes in the liver. MOR23 also appeared to regulate lipogenesis and free fatty acid uptake in HFD‐fed mice, potentially by influencing sterol regulatory element‐binding protein 1 activity. Notably, administering a potential MOR23 ligand, cedrene, attenuated hepatic steatosis in WT mice, but these effects were largely nullified in MOR23 knockout mice. These findings provide valuable insights into the in vivo role of MOR23 in hepatic steatosis development. [ABSTRACT FROM AUTHOR]

Background: The use of pre-operative very low-calorie diets (VLCD) is established within bariatric and gallbladder surgery. However, their use in patients with high BMI and hepatic steatosis (HS) requiring upper abdominal procedures is unclear. This review aims to assess the safety, adherence, and outcomes of a pre-operative VLCD prior to non-bariatric elective surgery. Methods: A systematic search on PubMed MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL and AMED was performed to identify the included studies. Studies were included, if they administered a VLCD to patients undergoing non-bariatric elective surgery and reported on outcomes. Results: Eight studies were included in this review and all administered a VLCD through either dietician led diet plans or meal replacement shakes. The adherence to the VLCD was heterogeneously measured but was excellent overall with a good safety profile. The VLCD was able to significantly reduce HS and resulted in a less technically difficult operation with reduced intra-operative blood loss. There was no significant impact on intraoperative or early post-operative outcomes. Conclusion: This review highlights that a VLCD can be administered safely during the pre-operative period and overall adherence is excellent, however heterogeneously measured. There was an overall positive impact on reducing hepatic steatosis, operative difficulty and intraoperative blood loss, however no significant impact on overall morbidity and mortality. [ABSTRACT FROM AUTHOR]

Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), is a worldwide liver disease without definitive or widely used therapeutic drugs in clinical practice. In this study, we confirm that 6-gingerol (6-G), an active ingredient of ginger (Zingiber officinale Roscoe) in traditional Chinese medicine (TCM), can alleviate fructose-induced hepatic steatosis. It was found that 6-G significantly decreased hyperlipidemia caused by high-fructose diets (HFD) in rats, and reversed the increase in hepatic de novo lipogenesis (DNL) and triglyceride (TG) levels induced by HFD, both in vivo and in vitro. Mechanistically, chemical proteomics and cellular thermal shift assay (CETSA)–proteomics approaches revealed that stearoyl-CoA desaturase (SCD) is a direct binding target of 6-G, which was confirmed by further CETSA assay and molecular docking. Meanwhile, it was found that 6-G could not alter SCD expression (in either mRNA or protein levels), but inhibited SCD activity (decreasing the desaturation levels of fatty acids) in HFD-fed rats. Furthermore, SCD deficiency mimicked the ability of 6-G to reduce lipid accumulation in HF-induced HepG2 cells, and impaired the improvement in hepatic steatosis brought about by 6-G treatment in HFD supplemented with oleic acid diet-induced SCD1 knockout mice. Taken together, our present study demonstrated that 6-G inhibits DNL by targeting SCD to alleviate fructose diet-induced hepatic steatosis. [ABSTRACT FROM AUTHOR]

The evolving landscape of chemical risk assessment is increasingly focused on developing tiered, mechanistically driven approaches that avoid the use of animal experiments. In this context, adverse outcome pathways have gained importance for evaluating various types of chemical-induced toxicity. Using hepatic steatosis as a case study, this review explores the use of diverse computational techniques, such as structure–activity relationship models, quantitative structure–activity relationship models, read-across methods, omics data analysis, and structure-based approaches to fill data gaps within adverse outcome pathway networks. Emphasizing the regulatory acceptance of each technique, we examine how these methodologies can be integrated to provide a comprehensive understanding of chemical toxicity. This review highlights the transformative impact of in silico techniques in toxicology, proposing guidelines for their application in evidence gathering for developing and filling data gaps in adverse outcome pathway networks. These guidelines can be applied to other cases, advancing the field of toxicological risk assessment. [ABSTRACT FROM AUTHOR]

Background/Objectives: We investigated the effects of ultraprocessed food (UPF) consumption on metabolic disorders (e.g., adiposity, metabolic associated steatotic liver disease [MASLD], and insulin resistance) in children and adolescents with obesity to improve dietary guidelines and public health strategies. Methods: The dietary intake of 149 participants (aged 8–17 years) was assessed with food diaries. The NOVA classification system was used to classify food according to the degree of processing. Metabolic outcomes, including the fat mass index (FMI), hepatic fat percentage, and insulin resistance, were measured via dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging proton density fat fraction (MRI-PDFF), and biochemical analysis, respectively. Results: Greater UPF consumption from baseline to the 6-month follow-up was significantly associated with increased insulin and decreased total cholesterol and LDL-cholesterol. UPF consumption was positively associated with the prevalence of MASLD (liver MRI-PDFF ≥ 5%; odds ratio T3 vs. T1 = 1.75; 95% confidence interval [CI] 1.03, 3.00), moderate-to-severe MASLD (liver MRI-PDFF ≥ 10%; OR T3 vs. T1 = 4.19; 95% CI 1.72, 10.22), and insulin resistance (OR T3 vs. T1 = 2.44; 95% CI 1.33, 4.48), after adjusting for covariates. A linear dose-response relationship was observed between UPF consumption and the odds of moderate-to-severe MASLD and insulin resistance. Conclusions: Greater UPF consumption was strongly associated with MASLD and insulin resistance in children and adolescents with obesity, underscoring the importance of reducing UPF consumption through dietary guidelines and public health interventions to mitigate the risk of obesity-related metabolic conditions in young populations. [ABSTRACT FROM AUTHOR]

Background: (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HMC), a homoisoflavonoid isolated from Portulaca oleracea, has significant anti-adipogenesis potential; it regulates adipogenic transcription factors. However, whether HMC improves hepatic steatosis in hepatocytes remains vague. This study investigated whether HMC ameliorates hepatic steatosis in free fatty acid-treated human hepatocellular carcinoma (HepG2) cells, and if so, its mechanism of action was analyzed. Methods: Hepatic steatosis was induced by a free fatty acid mixture in HepG2 cells. Thereafter, different HMC concentrations (10, 30, and 50 µM) or fenofibrate (10 µM, a PPARα agonist, positive control) was treated in HepG2 cells.Results: HMC markedly decreased lipid accumulation and triglyceride content in free fatty acid-treated HepG2 cell; it (10 and 50 μM) markedly upregulated protein expressions of pAMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. HMC (10 and 50 μM) markedly inhibited the expression of sterol regulatory element-binding protein-1c, fatty acid synthase, and stearoyl-coA desaturase 1, which are the enzymes involved in lipid synthesis. Furthermore, HMC (10 and 50 μM) markedly upregulated the protein expression of peroxisome proliferator-activated receptor alpha (PPARα) and enhanced the protein expressions of carnitine palmitoyl transferase 1 and acyl-CoA oxidase 1. Conclusion: HMC inhibits lipid accumulation and promotes fatty acid oxidation by AMPK and PPARα pathways in free fatty acid-treated HepG2 cells, thereby attenuating hepatic steatosis. [ABSTRACT FROM AUTHOR]

Objective To improve the isolation and culture methods for primary hepatocytes and to establish a hepatic steatosis cell model for enhancing experimental efficiency and model precision. Methods Improvements were made upon existing techniques for primary hepatocyte cultivation and steatosis model establishment. The technology oriented to optimize the retrograde cannulation and fixation procedures, meticulously calibrating the perfusion speed and duration for mouse liver digestion. The culture medium was supplemented with 2% fetal bovine serum (FBS) during the removal of liver capsules and filtration steps. Additionally, the induction parameters for the steatosis cell model were refined, including the selection of free fatty acid (FFA) types and optimize their concentrations, ratios, and precise induction durations. Results The optimized protocol yielded mouse primary hepatocytes with a viability exceeding 90%, demonstrating ample quantity, favorable morphology, and excellent overall condition. The steatosis cell model exhibited prominent cytoplasmic lipid droplets, impaired glucose and lipid metabolism, as well as mild inflammation and insulin resistance, closely mimicking key aspects of the disease in vivo. Conclusions The refined techniques facilitated the establishment of a stable and physiologically representative in vitro steatosis cell model, which may support further research of pathogenesis of the disease, identification of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Patients with non‐alcoholic fatty liver disease (NAFLD) often exhibit hepatic steatosis and dyslipidemia. Studies have shown that intestinal microorganisms are closely related to the occurrence of NAFLD and atherosclerosis. Our previous study has underscored the protective role of microRNA‐30a‐5p (miR‐30a‐5p) against atherosclerosis. Methods and Results: In the present study, we aimed to elucidate the effect and underlying mechanism of the intestinal microorganisms of miR‐30a‐5p knockout (KO) mice on NAFLD. Our findings demonstrated that KO exacerbated high‐fat diet (HFD)‐induced hepatic steatosis and disrupted liver function, as evidenced by elevated levels of total cholesterol, low‐density lipoprotein, alanine aminotransferase, aspartate transaminase, and total bile acids in serum. Fecal microbiota from HFD‐fed KO mice induced hepatic steatosis, dyslipidemia, and higher levels of enzymes indicative of liver damage in wild‐type mice. Remarkably, KO mice significantly intensified the above effects. 16s rDNA sequencing and metabolomics of the intestinal microbiota in the HFD‐treated KO and WT mice showed that the loss of miR‐30a‐5p resulted in intestinal microbiota imbalance and was highly related to the arachidonic acid metabolic pathway. Targeted metabolomic in the liver tissues unveiled upregulation of COX‐related (PGF2a, 8‐iso‐PGF2a and PGF2) and LOX‐related (LTB4, LTD4, 12S‐HETE and 15S‐HETE) factors in HFD‐treated KO mice. Immunohistochemistry and transcriptional analyses showed that miR‐30a‐5p affected arachidonic acid metabolism through the LOX/COX pathways. Besides, COX/LOX pathways and hepatic steatosis were reversed after reintroducing miR‐30a‐5p in HFD‐treated KO mice. Conclusions: This study reveals the pivotal mechanism by which miR‐30a‐5p and intestinal microbes regulate hepatic steatosis and abnormal lipid metabolism, offering promising avenues for NAFLD and atherosclerosis therapeutics. Highlights: MiR‐30a‐5p deletion aggravated hepatic steatosis and lipid disorder induced by an HFD in mice. Gut microbiota participated in the regulation of hepatic steatosis in the context of miR‐30a‐5p. Gut microbiota metabolism‐related arachidonic acid metabolic pathway contributed to miR‐30a‐5p‐regulated hepatic steatosis and lipid disorder. Reintroducing miR‐30a‐5p reversed hepatic steatosis and arachidonic acid metabolism disorder caused by HFD and miR‐30a‐5p deletion. [ABSTRACT FROM AUTHOR]

Background and Objectives: Metabolic syndrome (MetS) is a condition marked by a complex array of physiological, biochemical, and metabolic abnormalities, including central obesity, insulin resistance, high blood pressure, and dyslipidemia (characterized by elevated triglycerides and reduced levels of high-density lipoproteins). The pathogenesis develops from the accumulation of lipid droplets in the hepatocyte (steatosis). This accumulation, in genetically predisposed subjects and with other external stimuli (intestinal dysbiosis, high caloric diet, physical inactivity, stress), activates the production of pro-inflammatory molecules, alter autophagy, and turn on the activity of hepatic stellate cells (HSCs), provoking the low grade chronic inflammation and the fibrosis. This syndrome is associated with a significantly increased risk of developing type 2 diabetes mellitus (T2D), cardiovascular diseases (CVD), vascular, renal, pneumologic, rheumatological, sexual, cutaneous syndromes and overall mortality, with the risk rising five- to seven-fold for T2DM, three-fold for CVD, and one and a half–fold for all-cause mortality. The purpose of this narrative review is to examine metabolic syndrome as a "systemic disease" and its interaction with major internal medicine conditions such as CVD, diabetes, renal failure, and respiratory failure. It is essential for internal medicine practitioners to approach this widespread condition in a "holistic" rather than a fragmented manner, particularly in Western countries. Additionally, it is important to be aware of the non-invasive tools available for assessing this condition. Materials and Methods: We conducted an exhaustive search on PubMed up to July 2024, focusing on terms related to metabolic syndrome and other pathologies (heart, Lung (COPD, asthma, pulmonary hypertension, OSAS) and kidney failure, vascular, rheumatological (osteoarthritis, rheumatoid arthritis), endocrinological, sexual pathologies and neoplastic risks. The review was managed in accordance with the PRISMA statement. Finally, we selected 300 studies (233 papers for the first search strategy and 67 for the second one). Our review included studies that provided insights into metabolic syndrome and non-invasive techniques for evaluating liver fibrosis and steatosis. Studies that were not conducted on humans, were published in languages other than English, or did not assess changes related to heart failure were excluded. Results: The findings revealed a clear correlation between metabolic syndrome and all the pathologies above described, indicating that non-invasive assessments of hepatic fibrosis and steatosis could potentially serve as markers for the severity and progression of the diseases. Conclusions: Metabolic syndrome is a multisystem disorder that impacts organs beyond the liver and disrupts the functioning of various organs. Notably, it is linked to a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors. Non-invasive assessments of hepatic fibrosis and fibrosis allow clinicians to evaluate cardiovascular risk. Additionally, the ability to assess liver steatosis may open new diagnostic, therapeutic, and prognostic avenues for managing metabolic syndrome and its complications, particularly cardiovascular disease, which is the leading cause of death in these patients. [ABSTRACT FROM AUTHOR]

Exosomes derived from mesenchymal stem cells have shown promise in treating metabolic disorders, yet their specific mechanisms remain largely unclear. This study investigates the protective effects of exosomes from human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) against adiposity and insulin resistance in high-fat diet (HFD)-induced obese mice. HFD-fed mice treated with hWJMSC-derived exosomes demonstrated improved gut barrier integrity, which restored immune balance in the liver and adipose tissues by reducing macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, these exosomes normalized lipid metabolism including lipid oxidation and lipogenesis, which alleviate lipotoxicity-induced endoplasmic reticulum (ER) stress, thereby decreasing fat accumulation and chronic tissue inflammation in hepatic and adipose tissues. Notably, hWJMSC-derived exosomes also promoted browning and thermogenic capacity of adipose tissues, which was linked to reduced fibroblast growth factor 21 (FGF21) resistance and increased adiponectin production. This process activated the AMPK-SIRT1-PGC-1α pathway, highlighting the role of the FGF21–adiponectin axis. Our findings elucidate the molecular mechanisms through which hWJMSC-derived exosomes counteract HFD-induced metabolic dysfunctions, supporting their potential as therapeutic agents for metabolic disorders. [ABSTRACT FROM AUTHOR]

To verify the prevalence of positive Fibrosis-4 (FIB-4) score, a screening test for metabolic-associated liver disease, in a large population-based sample in the Tuscany Italian Region, and to identify sub-populations at higher risk which could be targeted by specific screening programs. Population-based survey performed in the Italian region of Tuscany, with Tuscany health informative system's administrative data. We included 594,923 subjects, of which 32% had available data for the FIB-4 calculation. The overall proportion of subjects with an FIB-4 value > 1.3, was 41.6% of those with available exams, and 12,8% of the whole population, whereas 5.4% and 1.7% had FIB-4 >2.67. In those younger than 80 years, FIB >1.3 had a 33.1% and 9.4%. People with diabetes mellitus had higher figures (52.8.% and 28.9% for FIB>1.3). Among subjects aged 70 years or over, 74.9% of those with available data and 38.4% of the general population had a FIB-4>1.3, whereas 32% and 16% had a FIB-4 > 2. The relevant proportion of FIB-4 positivity in the general population poses a significant burden for further screening with liver elastography. Targeting people with diabetes, excluding people older than 80 years and/or adopting a FIB-4 threshold of 2 in those aged more than 70 years could increase the cost-effectiveness of the screening procedures. • Individuals with a Fibrosis-4 (FIB-4 score) >1.3 should undergo liver elastography, according to Italian and international guidelines. • In a sample of Tuscan population free of liver disease, 12.8% (95%CI, 12.7%-12.8%) of subjects had FIB-4 >1.3. • If applying a 1.3 threshold for those < than 70 year old, and a 2 threshold for those ≥ 70 years, the prevalence would be 7.8% (95%CI, 7.7%-7.8%). • A higher prevalence was observed among people with diabetes: 28.9% (95% CI 28.5%-29.3%), but not in those with dyslipidemia. • Targeting people with diabetes and using 2 FIB-4 threshold in those >70 years may increase screening cost-effectivenes. [ABSTRACT FROM AUTHOR]

Background: Hepatic steatosis is characterized by lipid accumulation in hepatocytes. Cheong-sang-gyeon-tong-tang is a major prescription for all types of headaches in traditional East Asian medicine. Objective: This study aimed to investigate the pharmacological effects of Cheong-sang-gyeon-tong-tang extract (CG) on high-fat diet (HFD)-induced hepatic steatosis in mice and to explore the underlying mechanism. Results: Treatment with CG significantly reduced body weight, liver weight, and epididymal fat mass, as well as improved the serum and hepatic lipid profiles in the HFD-induced fatty liver mouse model. Further, CG alleviated lipid accumulation in HFD-fed mice by controlling lipid metabolism, including triglyceride and cholesterol synthesis, and fatty acid oxidation at the mRNA level. CG also regulated the expression of cholesterol regulatory proteins in HFD-induced fatty liver mice. Conclusions: These results indicate that CG alleviates hepatic steatosis by regulating cholesterol homeostasis in HFD-induced fatty liver mice, thus improving our understanding of the mechanisms by which CG improves hepatic steatosis. Therefore, we propose CG as a therapeutic candidate for lipid metabolic disorders such as fatty liver disease. [ABSTRACT FROM AUTHOR]

The autophagy-lysosome pathway plays an essential role in promoting lipid catabolism and preventing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). Transcription factor EB (TFEB) enhances the autophagy-lysosome pathway by regulating the expression of genes related to autophagy and lysosome biogenesis. Therefore, targeting TFEB provides a novel strategy for the treatment of lipid metabolic diseases. In this study, the antiallergic drug desloratadine was screened and identified as a novel TFEB agonist. Desloratadine effectively induced translocation of TFEB to the nucleus and promoted autophagy and lysosome biogenesis. Desloratadine-induced TFEB activation was dependent on AMPK rather than mTORC1. Moreover, desloratadine treatment enhanced clearance of lipid droplets in cells induced by fatty acids oleate and palmitate. Furthermore, high-fat diet (HFD) induced obesity mouse model experiments indicated treatment with desloratadine markedly reduced the body weight of HFD-fed mice, as well as the levels of hepatic triglycerides and total cholesterol, serum glutamic pyruvic transaminase and glutamic-oxaloacetic transaminase. Oil red O staining showed the liver fat was significantly reduced after desloratadine treatment, and H&E staining analysis demonstrated hepatocellular ballooning was improved. In addition, autophagy and lysosomal biogenesis was stimulated in the liver of desloratadine treated mice. Altogether, these findings demonstrate desloratadine ameliorates hepatic steatosis through activating the TFEB-mediated autophagy-lysosome pathway, thus desloratadine has an exciting potential to be used to treat fatty liver disease. [ABSTRACT FROM AUTHOR]

Background: Living donor liver transplantation using hepatic steatosis-improved grafts mitigates donor shortage. Herein, we aimed to evaluate the safety and feasibility of right-lobe adult-to-adult living donor liver transplantation using grafts improved through donor weight loss. Methods: In this retrospective study conducted in a single institution in the Republic of Korea, we reviewed the medical records of living liver donors who lost ≥ 10% of their body weight to improve steatosis before right lobe donation between January 2015 and December 2020. Overall, 1040 right-lobe donors were included, with 150 and 890 donors in the weight loss and control (non-steatosis) groups, respectively. Results: We performed 1:1 individual matching using the greedy matching method, by which 124 patients were included in each group. The median period from the date of the first visit to donation was 113 (interquartile range: 78–184) days in the weight loss group. As body weight changed from 82.8 ± 13.7 kg to 70.8 ± 11.8 kg (p < 0.0001), body mass index also improved from 27.8 ± 3.9 kg/m2 to 23.8 ± 3.1 kg/m2 (p < 0.0001). No significant between-group differences existed in the postoperative laboratory data for living donors and recipients. The incidence of postoperative complications in donors was comparable between the groups (control group, 9.7%; weight loss group, 13.7%; p = 0.3185). The graft and recipient survival rates were comparable between the groups (p = 1.000). Conclusion: Weight loss through diet and exercise significantly could improve hepatic steatosis in living donor candidates for liver transplantation, with the surgical outcomes in recipients and donors being equivalent to those in recipients and non-steatotic donors. [ABSTRACT FROM AUTHOR]

Purpose: Non-alcoholic fatty liver disease (NAFLD) prevalence and severity may be higher in people with human immunodeficiency virus (HIV) than the general population, and vary with sex and age. We explored NAFLD characteristics by gender. Methods: Adult transgender women (TW), cisgender women (CW), and cisgender men (CM) with HIV on antiretroviral therapy and without other known causes of liver disease underwent screening for NAFLD (2017–2020). Circulating factors associated with NAFLD were measured. Hepatic steatosis and fibrosis were assessed using transient elastography by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. Analysis of variance/Wilcoxon testing compared normally/non-normally distributed variables, respectively. Logistic regression evaluated factors associated with CAP and LSM. Results: Participants (n=194) had median age 48 years and body mass index 28.3 kg/m2; 42% were CM, 37% TW, and 21% CW; 95% were non-white; and 16% had diabetes, 40% dyslipidemia, and 49% hypertension. NAFLD prevalence was 59% using CAP ≥248 dB/m (≥S1 steatosis), 48% using CAP ≥260 dB/m (≥S2 steatosis), and 32% using CAP ≥285 dB/m (≥S3 steatosis). Compared to CM and CW, TW had the highest median CAP scores, were more likely to have ≥S2 steatosis, and had the highest insulin resistance, interleukin-6, and fetuin-A values. TW off versus on gender-affirming hormone therapy (GAHT) had slightly higher median CAP scores. Conclusion: TW on GAHT had less hepatic steatosis than TW not on GAHT, although overall NAFLD severity was greater than expected for TW compared to CM and CW. The effects of estrogen supplementation and androgen deprivation on liver health in TW require further study. [ABSTRACT FROM AUTHOR]

Background and Objectives: Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and secondary pulmonary fibrosis (SPF), is a progressive lung disease that significantly impairs respiratory function. Accurate differentiation between IPF and SPF is crucial for effective management. This study explores the association between pulmonary fibrosis and hepatic conditions, evaluating the utility of various hemogram-derived ratios and hepatic fibrosis scores in distinguishing between IPF and SPF. Materials and Methods: We conducted a retrospective study involving patients diagnosed with IPF or SPF at the "Leon Daniello" Clinical Hospital of Pneumology in Cluj-Napoca, Romania. Pulmonary fibrosis was confirmed via imaging techniques, and hepatic steatosis and fibrosis were assessed using non-invasive scores. We analyzed clinical, laboratory, and pulmonary function data, focusing on hemogram-derived ratios and hepatic scores. Statistical analyses, including ROC curves, were used to evaluate the effectiveness of these biomarkers in differentiating IPF from SPF. Results: We included a total of 38 patients with IPF and 28 patients with SPF. Our findings revealed that IPF patients had a significantly higher FIB-4 score compared to SPF patients, suggesting increased hepatic fibrosis risk in IPF, as well as an increased RDW/PLT ratio. Conversely, SPF patients exhibited elevated PLR, PNR, and SII, reflecting a more pronounced inflammatory profile. PLR and PNR demonstrated the highest discriminatory ability between IPF and SPF, while traditional hepatic fibrosis scores showed limited differentiation capabilities. No significant differences in pulmonary function tests were observed across hepatic fibrosis risk categories. Conclusions: The study highlights the value of biomarkers like PLR and PNR in differentiating between IPF and SPF, offering additional diagnostic insights beyond traditional imaging. Integrating hepatic assessments into the management of pulmonary fibrosis could improve diagnostic accuracy and patient care. [ABSTRACT FROM AUTHOR]

Indole is a microbial metabolite produced by the gut microbiota through the degradation of dietary tryptophan, known for its well‐established anti‐inflammatory and antioxidant properties. In this study, we collected fecal samples from mice fed a high‐fat diet (HFD) and those on a standard diet (SD), then conducted 16S rRNA sequencing to analyze their gut microbiota. The analysis revealed distinct differences in the dominant bacterial species between the two groups, with a significant decrease in indole‐producing probiotics in the HFD mice compared to the SD group. Then we administered oral indole treatment to male C57BL/6J mice with HFD‐induced NAFLD and observed a significant improvement in hepatic steatosis and inflammation. Notably, indole alleviated the HFD‐induced decline in serum Angiotensin‐(1–7) [Ang‐(1–7)] levels and Angiotensin‐Converting Enzyme 2 (ACE2) expression. To further investigate the role of indole and ACE2 in NAFLD, we conducted experiments using ACE2 knockout (ACE2KO) mice that were also induced with HFD‐induced NAFLD and treated with indole. Interestingly, the protective effects of indole were compromised in the absence of ACE2. In HepG2 cells, indole similarly stimulated ACE2 expression and, in an ACE2‐dependent manner, reduced ROS generation, maintained mitochondrial membrane potential stability, and increased SIRT3 expression. In summary, our results highlight the formation of a biologically active gut‐liver axis between the gut microbiota and the liver through the tryptophan metabolite indole, which mitigates NAFLD in an ACE2‐dependent manner. Elevating dietary tryptophan and increasing indole levels may represent an effective approach for preventing and treating NAFLD. [ABSTRACT FROM AUTHOR]

Background: Semiquantitative and quantitative sonographic techniques have the potential for screening and surveillance of children at risk of nonalcoholic fatty liver disease. Objective: To determine diagnostic performance and interobserver agreement of hepatorenal index (HRI) for pediatric ultrasound-based liver fat quantification. Materials and methods: In an institutional review board (IRB)-approved retrospective study (April 2014 to April 2023), children (< 18 years) with clinically performed magnetic resonance imaging (MRI) scans for liver fat quantification were assessed. Inclusion criteria required availability of abdominal ultrasound within 3 months of quantitative MRI. Three blinded readers subjectively assessed for sonographic hepatic steatosis and calculated HRI. MRI proton density fat fraction (PDFF) was the reference standard. Interobserver agreement, correlation with PDFF, and optimal HRI (using ROC analysis) values were analyzed. The significance level was set at p < 0.05. Results: A total of 41 patients (25 male) with median (interquartile range (IQR)) age of 13 (10–15) years were included. Median (IQR) MRI PDFF was 11.30% (2.70–17.95%). Hepatic steatosis distribution by MRI PDFF included grade 0 (34%), grade 1 (15%), grade 2 (22%), and grade 3 (29%) patients. Intraclass correlation coefficient for HRI among the three readers was 0.61 (95% CI 0.43–0.75) (p < 0.001). Moderate correlation was observed between manually estimated HRI and PDFF for each reader (r = 0.62, 0.67, and 0.67; p < 0.001). Optimal HRI cutoff was found to be 1.99 to diagnose hepatic steatosis (sensitivity 89%, specificity 93%). Median (IQR) HRI for each MRI grade of hepatic steatosis (0–4) was as follows: 1.2 (1.1–1.5), 2.6 (1.1–3.3), 3.6 (2.6–5.4), 5.6 (2.6–10.9), respectively (p < 0.001). Conclusion: Ultrasound-estimated HRI has moderate interobserver agreement and moderate correlation with MRI-derived PDFF. HRI of 1.99 maximizes accuracy for identifying pediatric liver fat. [ABSTRACT FROM AUTHOR]

Background: This study investigates the hypolipidemic effects of a mixed extract of Salvia miltiorrhiza and Paeonia lactiflora (USCP119) in HFD-fed hamsters and in vitro cellular models. Methods: Over an 8-week period, HFD-fed hamsters were assigned to one of six groups: normal diet, HFD control, HFD with 50 mg/kg USCP119, HFD with 100 mg/kg USCP119, HFD with 50 mg/kg USCP119 twice daily (BID), and HFD with omega-3 fatty acids. Key outcomes assessed included body weight, serum triglycerides (TG), total cholesterol (TC), liver weight, hepatic TG levels, and epididymal fat. In cellular models, the impact of USCP119 on lipid accumulation and adipogenic markers was evaluated. Results: USCP119 treatment at 50 mg/kg BID resulted in the lowest weight gain (15.5%) and the most significant reductions in serum TG and hepatic TG levels compared to the HFD control. The 100 mg/kg dose also led to substantial reductions in serum TG and TC levels and notable decreases in low-density lipoprotein cholesterol. USCP119 at 50 mg/kg once daily reduced TG and TC levels but was less effective than the higher doses. In cellular models, USCP119 was non-toxic up to 400 µg/mL and effectively reduced lipid accumulation, modulated adipogenic markers, and enhanced AMPK signaling, improving lipid metabolism and insulin sensitivity. Conclusions: All USCP119 treatments demonstrated effectiveness in managing hyperlipidemia and related metabolic disorders, with variations in impact depending on the dosage. The ability of USCP119 to reduce fat accumulation, improve lipid profiles, and enhance insulin sensitivity highlights its potential as a valuable dietary supplement for addressing high-fat diet-induced hyperlipidemia and metabolic disturbances. [ABSTRACT FROM AUTHOR]

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, characterized by excess lipid deposition. Insulin resistance (IR) serves as a fundamental pathogenic factor in MAFLD. However, currently, there are no approved specific agents for its treatment. Farrerol, a novel compound with antioxidant and anti‐inflammatory effects, has garnered significant attention in recent years due to its hepatoprotective properties. Despite this, the precise underlying mechanisms of action remain unclear. In this study, a network pharmacology approach predicted protein tyrosine phosphatase non‐receptor type 1 (PTPN1) as a potential target for farrerol's action in the liver. Subsequently, the administration of farrerol improved insulin sensitivity and glucose tolerance in MAFLD mice. Furthermore, farrerol alleviated lipid accumulation by binding to PTPN1 and reducing the dephosphorylation of the insulin receptor (INSR) in HepG2 cells and MAFLD mice. Thus, the phosphoinositide 3‐kinase/serine/threonine‐protein kinases (PI3K/AKT) signalling pathway was active, leading to downstream protein reduction. Overall, the study demonstrates that farrerol alleviates insulin resistance and hepatic steatosis of MAFLD by targeting PTPN1. [ABSTRACT FROM AUTHOR]

Mounting clinical evidence suggests that a comprised intestinal barrier contributes to the progression of nonalcoholic steatohepatitis (NASH); nevertheless, the precise mechanism remains elusive. This study unveils a significant upregulation of nuclear receptor‐binding SET domain protein 2 (NSD2) in the intestines of obese humans and mice subjected to a high‐fat cholesterol diet (HFCD). Intestine‐specific NSD2 knockout attenuated the progression of intestinal barrier impairment and NASH, whereas NSD2 overexpression exacerbated this progression. Mechanistically, NSD2 directly regulates the transcriptional activation of Ern1 by demethylating histone H3 at lysine 36 (H3K36me2), thus activating the ERN1–JNK axis to intensify intestinal barrier impairment and subsequently foster NASH progression. These findings elucidate the crucial role of NSD2‐mediated H3K36me2 in intestinal barrier impairment, suggesting that targeting intestinal NSD2 can represent a novel therapeutic approach for NASH. [ABSTRACT FROM AUTHOR]

Introduction: Non-alcoholic fatty liver disease (NAFLD) is significantly linked to obesity, insulin resistance (IR), metabolic syndrome, and type 2 diabetes (T2DM). There isn't a single biomarker used to diagnose NAFLD. Objectives: Analyzing the association between triglyceride and glucose index (TyG) with NAFLD in T2DM. Methods: This cross-sectional study aimed to assess the efficacy of TyG as a potential NAFLD biomarker. The study was conducted on 103 diabetes outpatient clinics at the Dr. Soetomo General Academic Hospital from August to October 2023. Sixty-seven subjects experienced steatosis, while those who did not experience steatosis were 36. The statistical analysis used in this study is binary logistic regression with p <0.05. Results: The receiver operating characteristic curves (ROC) analysis showed a TyG cut-off value of 9.334 (AUC = 0.660). Analysis of the risk of TyG on the incidence of steatosis was carried out using binary logistic regression. The results showed that TyG was a significant risk factor for steatosis. Patients with a TyG value above 9.334 risk developing steatosis 3.567 times greater than patients with a TyG value below 9.334 (OR 95% = 1.373 – 9.270, p = 0.009). Conclusion: A significant association between TyG and NAFLD in T2DM patients, which the TyG index may be a more effective, valuable, and uncomplicated measure for detecting and controlling NAFLD. [ABSTRACT FROM AUTHOR]

8-Prenylgenistein (8PG), a genistein derivative, is present in fermented soybeans (Glycine max), including cheonggukjang (CGJ), and exhibits osteoprotective, osteogenic, and antiadipogenic properties. However, the hepatoprotective effects of 8PG and its underlying molecular mechanisms remain largely unexplored. Here, we identified the high binding affinity of 8PG with AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), which acts as a potent AMPK activator that counteracts hepatic steatosis. Notably, 8PG exhibited better pharmacokinetics with greater absorption and higher plasma binding than the positive controls for the target proteins. Moreover, 8PG exerted non-carcinogenic activity in rats and significantly increased AMPK phosphorylation. Compound C, an AMPK inhibitor, did not antagonize 8PG-activated AMPK in HepG2 cells. 8PG significantly attenuated palmitate-induced lipid accumulation and enhanced phosphorylated AMPK and its downstream target, acetyl-CoA carboxylase. Further, 8PG activated nuclear SIRT1 at the protein level, which promoted fatty acid oxidation in palmitate-treated HepG2 cells. Overall, 8PG acts as a potent AMPK activator, further attenuating hepatic steatosis via the SIRT1-mediated pathway and providing new avenues for dietary interventions to treat metabolic dysfunction-associated steatotic liver disease (MASLD). [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a rising global burden, affecting one in four adults. Despite the increasing prevalence of NAFLD, the exact cellular and molecular mechanisms remain unclear, and effective therapeutic strategies are still limited. In vitro models of NAFLD are critical to understanding the pathogenesis and searching for effective therapies; thus, we evaluated the effects of free fatty acids (FFAs) on NAFLD hallmarks and their association with the modulation of Annexin A2 (ANXA2) and Keratin 17 (KRT17) in HepG2 cells. Our results show that oleic and palmitic acids can differentially induce intracellular lipid accumulation, cell death, and promote oxidative stress by increasing lipid peroxidation, protein carbonylation, and antioxidant defense depletion. Moreover, a markedly increased expression of inflammatory cytokines demonstrated the activation of inflammation pathways associated with lipotoxicity and oxidative stress. ANXA2 overexpression and KRT17 nuclear translocation were also observed, supporting the role of both molecules in the progression of liver disease. Taken together, these data provide insights into the interplay between ANXA2 and KRT17 in NAFLD, paving the way for understanding molecular mechanisms involved with the disease and developing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: The influence of alcohol intake on metabolic dysfunction‐associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. Methods: This observational cohort study included 6349 patients who underwent more than two health check‐ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. Results: The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1–69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469–0.964, p <.05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009–3.196, p <.05) and females (OR: 16.74, 95% CI: 3.877–72.24, p <.001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p <.05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p <.05) who showed MAFLD remission. Conclusions: Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic recurrence is one of the main causes of treatment failure in patients with colorectal cancer liver metastasis (CRLM). Hepatic steatosis was reported to provide fertile soil for metastasis. The effect of irinotecan-inducted hepatic steatosis on the progression of liver metastasis remains to be verified. Therefore, we aim to clarify the effect of hepatic steatosis on postoperative intrahepatic recurrence in CRLM and whether it is relevant to irinotecan-based chemotherapy. Methods: Data for a total of 284 patients undergoing curative surgical treatment for CRLMs were retrospectively reviewed between March 2007 and June 2018. Hepatic steatosis score (HSS) was established by combining Liver to Spleen CT ratio (LSR) and Uric acid to HDL-cholesterol ratio (UHR) to detect the presence of hepatic steatosis. Results: The evaluation model is consistent with pathological results and has high prediction ability and clinical application value. Patients with HSS high risk (HSS-HR) had significantly worse prognosis than those with HSS low risk (HSS-LR) (3-year intrahepatic RFS: 42.7% vs. 29.4%, P = 0.003; 5-year OS: 45.7% vs. 26.5%, P = 0.002). Univariate and multivariate analysis confirmed its essential role in the prediction of intrahepatic RFS. Besides, patients treated with preoperative irinotecan chemotherapy were more likely to end up with HSS-HR than those with non-irinotecan chemotherapy (63.3% vs. 21.8%, P < 0.001). Furthermore, irinotecan chemotherapy is relevant to worse prognosis in baseline HSS-HR patients. Conclusion: In summary, patients with HSS-HR had significantly worse 5-year OS and 3-year intrahepatic RFS. Irinotecan chemotherapy is more likely to lead to HSS-HR and pre-existing hepatic steatosis may be a worse prognostic factor limiting patients underwent IRI-based chemotherapy. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is a common metabolic liver disease worldwide. Currently, satisfactory drugs for NAFLD treatment remain lacking. Obesity and diabetes are the leading causes of NAFLD, and compounds with anti-obesity and anti-diabetic activities are considered suitable candidates for treating NAFLD. In this study, biochemical and histological assays revealed that a natural lignan schisanhenol (SAL) effectively decreased lipid accumulation and improved hepatic steatosis in free fatty acid (FFA)-treated HepG2 cells and high-fat diet (HFD)-induced NAFLD mice. Further, molecular analyses, microRNA (miRNA)-seq, and bioinformatics analyses revealed that SAL may improve NAFLD by targeting the miR-802/adenosine monophosphate-activated protein kinase (AMPK) pathway. Liver-specific overexpression of miR-802 in NAFLD mice significantly impaired SAL-mediated liver protection and decreased the protein levels of phosphorylated (p)-AMPK and PRKAB1. Dual-luciferase assay analysis further confirmed that miR-802 inhibits hepatic AMPK expression by binding to the 3' untranslated region of mouse Prkab1 or human PRKAA1. Additionally, genetic silencing of PRKAA1 blocked SAL-induced AMPK pathway activation in FFA-treated HepG2 cells. The results demonstrate that SAL is an effective drug candidate for treating NAFLD through regulating miR-802/AMPK-mediated lipid metabolism. A natural compound, schisanhenol (SAL), exerts anti-NAFLD effects by inhibiting miR-802 and activating the AMPK signaling pathway to regulate lipid homeostasis. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant global health issue. The condition is closely linked to metabolic dysfunctions such as obesity and type 2 diabetes. The gut–liver axis, a bidirectional communication pathway between the liver and the gut, plays a crucial role in the pathogenesis of NAFLD. This review delves into the mechanisms underlying the gut–liver axis, exploring the influence of gut microbiota, intestinal permeability, and inflammatory pathways. This review also explores the potential therapeutic strategies centered on modulating gut microbiota such as fecal microbiota transplantation; phage therapy; and the use of specific probiotics, prebiotics, and postbiotics in managing NAFLD. By understanding these interactions, we can better comprehend the development and advancement of NAFLD and identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

The antidiabetic drug metformin has a wide range of metabolic effects and may also reduce the risk of obesity-related diseases. The aim of the current study was to investigate if metformin could counteract meldonium-induced fatty liver. Four groups of male C57BL/6J mice were fed a low-fat control diet, or low-fat diets supplemented with metformin, meldonium, or metformin and meldonium for three weeks. Meldonium treatment led to 5.2-fold higher hepatic triacylglycerol (TAG) levels compared to control, and metformin lowered the meldonium-induced lipid accumulation insignificantly by 21%. Mice treated with metformin and meldonium demonstrated significantly lower weight gain, visceral adipose tissue weight and plasma levels of TAG compared to meldonium alone. The hepatic mRNA level of carnitine palmitoyl transferase 1 was increased 2-fold with combined meldonium and metformin treatment compared to meldonium treatment (p < 0.001). Increased hepatic expression of genes involved in fatty acid oxidation and lipid transport was observed in the combination group compared to control, and increased gene expression of the mitochondrial uncoupling protein UCP2 was observed compared to the meldonium group. In addition, the product of fatty acid oxidation, acetylcarnitine, increased in plasma in metformin-treated mice. Altogether, metformin treatment influenced hepatic lipid metabolism and lowered plasma TAG in meldonium-induced fatty liver in mice. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory markers, TLR4, and the cytokines IL17A/F, as well as their connections with the degree of hepatic steatosis and the risk of hepatic fibrosis (defined by the FIB-4 score) in MASLD patients. Methods: The study cohort included 80 patients diagnosed with MASLD. The IL-17A/F and TLR4 serum concentrations were determined using the ELISA method. Results: We found a significant difference in the CAR levels (C-reactive protein to albumin ratio) when comparing MASLD patients with severe steatosis to those with mild/moderate steatosis (Student's t test, t (71) = 2.32, p = 0.023). The PIV (pan-immune inflammatory value) was positively correlated with the SII (systemic immune inflammation index), (r = 0.86, p < 0.0001) and the CAR (r = 0.41, p = 0.033) in MASLD patients with severe steatosis. In contrast, increased values of the LMR (lymphocyte to monocyte ratio) were significantly associated, with decreased levels of the SII (ρ = −0.38, p = 0.045). We also found a positive correlation between the CAR and the SII (r = 0.41, p = 0.028). In patients with mild/moderate steatosis, a significant positive correlation was observed between the SII and IL17A (r = 0.36, p = 0.010), the PIV and the CAR (r = 0.29, p = 0.011), the PIV and the SII (r = 0.87, p < 0.0001) and the PIV and IL17A (r = 0.3, p = 0.036). A negative correlation was observed between the LMR and the SII (r = −0.55, p < 0.0001) and the CAR and IL17F (r = −0.37, p = 0.011). Regarding the inflammatory markers, the PIV (336.4 vs. 228.63, p = 0.0107), and the SII (438.47 vs. 585.39, p = 0.0238) had significantly lower levels in patients with an intermediate–high risk of hepatic fibrosis as compared with the patients with a low risk of hepatic fibrosis. The PNI (prognostic nutritional index) (47.16 vs. 42.41, p = 0.0392) had significantly different levels in patients with the likelihood of hepatic fibrosis than those with a low risk of hepatic fibrosis. Conclusions: Regarding the inflammatory markers, the PIV and the SII hold promise as biomarkers for discriminating between MASLD patients with an intermediate–high risk and those with a low risk of hepatic fibrosis. Our findings underscore the role of IL-17A and its potential relationship with inflammatory markers in MASLD pathogenesis and the progression to hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Background Bardet–Biedl syndrome (BBS) is a rare autosomal-recessive ciliopathy with pathogenic variants in 26 BBS genes. It affects multiple organs, including the kidney and liver, with varying degrees regarding extent and time of first manifestation. Structural renal anomalies are an early feature and end-stage kidney disease (ESKD) cumulates to 25% in adulthood. Early-onset hyperphagia-associated obesity is another major symptom and contributes to liver pathology, presenting as steatosis/fibrosis. Aim of this study is the evaluation of high-end ultrasound (US) technologies in BBS patients regarding their potential to discriminate liver and kidney tissue pathology at an early stage. Materials and methods Patients with genetically proven BBS were recruited from the University Children’s Hospital of Essen and from BBS patient days hosted in Germany. Acute illness was an exclusion criterion. Clinical and laboratory data were extracted from patients’ digital records or medical letters. High-resolution ultrasound (US) imaging was utilized, including attenuation imaging (ATI), shear wave elastography (SWE) and dispersion (SWD) of liver tissue. Results 49 BBS patients (24/49 male; 1.1–51.0 years, mean 17.8 years) were included in the study. Mean body weight (SDS 2.13 ± 1.33) and BMI (SDS 2.64 ± 1.18) were increased. Structural kidney abnormalities (dysplasia, cysts) were present in 75% (36/48), and persistent fetal lobulation in 44% (21/48). Renal function was impaired in 27% (13/49) of whom 3 had ESKD (kidney transplantation (n = 2), hemodialysis (n = 1)). Elevation of liver enzymes was detected in 38% (16/42). In 51% (25/49) ATI of liver tissue was increased, indicating hepatic steatosis, and correlated with BMI SDS, liver size, and enzymes. SWE was elevated in 61% (30/49), suggesting hepatic fibrosis, and it correlated with BMI and GGT. Patients with pathogenic variants in BBS10 showed a tendency towards higher ATI, reduced GFR, and higher BMI SDS. Conclusions We detected kidney and liver abnormalities in a higher percentage of BBS patients than previously reported, indicating a high sensitivity and diagnostic yield of the evaluated high-end US applications. ATI detected liver pathology early (partially prior to liver enzymes) and revealed differences related to the affected genes. Evidence of tissue pathology at an early stage may improve diagnostics and the evaluation of therapeutic approaches.

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized by excess liver fat, is common in women with a history of gestational diabetes mellitus (GDM). While breastfeeding improves postpartum lipid levels, its impact on NAFLD in these women is not well studied. We aimed to investigate the relationship between the duration and intensity of breastfeeding and the amount of liver fat and prevalence of NAFLD in women with previous GDM at approximately 1 year postpartum. Methods This prospective cohort study was conducted at a university hospital in Bangkok, Thailand between November 2021 and February 2024. Overall, 130 women who had experienced GDM in their most recent pregnancy were followed up for 1 year postpartum. We collected data on breastfeeding practices and quantified liver fat using controlled attenuation parameters (CAPs) during transient elastography. NAFLD was defined as a CAP of ≥ 302 dB/m. Women were divided into three groups according to the duration and intensity of breastfeeding: group 1 (breastfeeding for

Backgrounds/Aims Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant is closely associated with the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood. Methods The Tm6sf2167K knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of Tm6sf2167K KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC). Results The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury in HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFD-induced Tm6sf2167K KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice. Conclusions The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.

Objective To improve the isolation and culture methods for primary hepatocytes and to establish a hepatic steatosis cell model for enhancing experimental efficiency and model precision. Methods Improvements were made upon existing techniques for primary hepatocyte cultivation and steatosis model establishment. The technology oriented to optimize the retrograde cannulation and fixation procedures, meticulously calibrating the perfusion speed and duration for mouse liver digestion. The culture medium was supplemented with 2% fetal bovine serum (FBS) during the removal of liver capsules and filtration steps. Additionally, the induction parameters for the steatosis cell model were refined, including the selection of free fatty acid (FFA) types and optimize their concentrations, ratios, and precise induction durations. Results The optimized protocol yielded mouse primary hepatocytes with a viability exceeding 90%, demonstrating ample quantity, favorable morphology, and excellent overall condition. The steatosis cell model exhibited prominent cytoplasmic lipid droplets, impaired glucose and lipid metabolism, as well as mild inflammation and insulin resistance, closely mimicking key aspects of the disease in vivo. Conclusions The refined techniques facilitated the establishment of a stable and physiologically representative in vitro steatosis cell model, which may support further research of pathogenesis of the disease, identification of potential therapeutic targets.

Omar Alqudah,1 Hamzeh Feras Alshahwan,2,&ast; Jehad Feras Alsamhouri,2,&ast; Saif Yamin,2,&ast; Ahmad Kaffaf,2,&ast; Mohannad Alassaf,2,&ast; Zaid Alwarawrah3 1Department of Medicine, Division of Hepatology and Gastroenterology, Jordan University Hospital and School of Medicine, The University of Jordan, Amman, Jordan; 2School of Medicine, The University of Jordan, Amman, Jordan; 3School of Medicine, University of Mu’tah, Al-Karak, Jordan&ast;These authors contributed equally to this workCorrespondence: Hamzeh Feras Alshahwan, Email alshahwanhamzeh@gmail.comPurpose: The most prevalent chronic liver disease in both developed and developing nations is Metabolic dysfunction-associated Steatotic Liver Disease (MASLD). The condition increases the risk of comorbidities and liver-related morbidity and mortality. The public’s awareness and medical personnel’s understanding are essential in creating countermeasures to stop the disease’s spread; a positive attitude is essential for early screening. This study aimed to explore the knowledge and attitudes of Jordanians living in Amman toward MASLD to determine the public’s awareness and medical personnel’s understanding of the disease.Materials and Methods: A cross-sectional study was conducted using an online self-administered questionnaire that included 5 items for knowledge and 8 for attitude. Demographic questions were also included to further examine how demographic factors affected knowledge and attitude.Results: Among 906 responders, (63.4%) were females, and (36.6%) were males. The majority age group was 18– 30 (56.2%). Only 49.5% had previous knowledge of MASLD, (44.6%) believed they were at risk of developing it. There is a statistical significance between age, gender, educational level, and having a good knowledge of MASLD and a positive attitude towards it (p< 0.05).Conclusion: Generally, Jordan’s population has a fair knowledge of MASLD and a positive attitude towards it. Warranting more research into the reasons behind it, and more awareness campaigns.Keywords: nonalcoholic fatty liver disease, NAFLD, MASLD, hepatic steatosis, liver health, patient education, public health awareness, medical literacy, Metabolic Dysfunction-Associated Steatotic Liver Disease

Aim. To study the impact of type 2 diabetes mellitus (DM2) on the severity of liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Materials and methods. To conduct a paired case-control study 2989 patients were examined at the Federal Research Center of Nutrition, Biotechnology and Food Safety. Pairs were matched by gender and age and distributed into groups: NAFLD + DM2+ (n=313), NAFLD + DM2- (n=313) and a control group of patients without NAFLD and without DM2 (n=313). The severity of liver steatosis was determined by measuring the controlled attenuation parameter. The severity of liver fibrosis was determined by measuring the liver stiffness measurement. Body composition of the patients was determined using bioimpedance measurements. Indicators of lipid and carbohydrate metabolism, and the serum activity of liver enzymes was determined by standard biochemical methods. Results. In NAFLD + DM2+ group compared to NAFLD + DM2- group, and in NAFLDM + DM2-compared to the control group, weight, BMI, waist and hip circumference, waist-to-hip ratio were higher, while in all. In NAFLD + DM2+ and NAFLD + DM2- groups the volume of fat mass directly correlated with the level of blood triglycerides (r=0.21), HbA1с (r=0.32) and fasting blood glucose (r=0.35), and inversely correlated with high-density lipoproteins (r=-0.19). In NAFLD + DM2+ group versus NAFLD + DM2- group severe steatosis (S3, 78% versus 59.4%; p0.001) and severe fibrosis (F4, 8% vs 2.6%; p0.001) was more common; 70% of patients in the NAFLD + DM2- group had no liver fibrosis according to elastography (F0), while in the NAFLD + DM2+ group only 43.2% of patients had no liver fibrosis (p0.0001). Conclusion. When NAFLD is accompanied by DM2, there is an increase in total fat mass, the severity of steatosis and liver fibrosis, and an associated deterioration of lipid metabolism. More than half of these patients have various stages of liver fibrosis, which indicates the progressive nature of the disease.

Chronic hepatitis B (CHB) infection is responsible for 40% of the global burden of hepatocellular carcinoma (HCC) with a high case fatality rate. The risk of HCC differs among CHB subjects owing to differences in host and viral factors. Modifiable risk factors include viral load, use of antiviral therapy, co-infection with other hepatotropic viruses, concomitant metabolic dysfunctionassociated steatotic liver disease or diabetes mellitus, environmental exposure, and medication use. Detecting HCC at early stage improves survival, and current practice recommends HCC surveillance among individuals with cirrhosis, family history of HCC, or above an age cut-off. Ultrasonography with or without serum alpha feto-protein (AFP) every 6 months is widely accepted strategy for HCC surveillance. Novel tumor-specific markers, when combined with AFP, improve diagnostic accuracy than AFP alone to detect HCC at an early stage. To predict the risk of HCC, a number of clinical risk scores have been developed but none of them are clinically implemented nor endorsed by clinical practice guidelines. Biomarkers that reflect viral transcriptional activity and degree of liver fibrosis can potentially stratify the risk of HCC, especially among subjects who are already on antiviral therapy. Ongoing exploration of these novel biomarkers is required to confirm their performance characteristics, replicability and practicability.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant global health issue. The condition is closely linked to metabolic dysfunctions such as obesity and type 2 diabetes. The gut–liver axis, a bidirectional communication pathway between the liver and the gut, plays a crucial role in the pathogenesis of NAFLD. This review delves into the mechanisms underlying the gut–liver axis, exploring the influence of gut microbiota, intestinal permeability, and inflammatory pathways. This review also explores the potential therapeutic strategies centered on modulating gut microbiota such as fecal microbiota transplantation; phage therapy; and the use of specific probiotics, prebiotics, and postbiotics in managing NAFLD. By understanding these interactions, we can better comprehend the development and advancement of NAFLD and identify potential therapeutic targets.