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Metabolic dysfunction associated-steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) is the liver manifestation of metabolic syndrome, which is characterized by insulin resistance, hyperglycemia, hypertension, dyslipidemia, and/or obesity. Environmental pollutant exposure has been recently identified as a risk factor for developing MASH. Heterocyclic amines (HCAs) are mutagens generated when cooking meat at high temperatures or until well-done. Recent epidemiological studies reported that dietary HCA exposure may be linked to insulin resistance and type II diabetes, and we recently reported that HCAs induce insulin resistance and glucose production in human hepatocytes. However, no previous studies have examined the effects of HCAs on hepatic lipid homeostasis. In the present study, we assessed the effects of two common HCAs, MeIQx (2-amino-3, 8-dimethylimidazo [4, 5-f] quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4, 5-b] pyridine), on lipid homeostasis in cryopreserved human hepatocytes. Exposure to a single concentration of 25 μM MeIQx or PhIP in human hepatocytes led to dysregulation of lipid homeostasis, typified by significant increases in lipid droplets and triglycerides. PhIP significantly increased expression of lipid droplet-associated genes, PNPLA3 and HSD17B13, and both HCAs significantly increased PLIN2. Exposure to MeIQx or PhIP also significantly increased expression of several key genes involved in lipid synthesis, transport and metabolism, including FASN, DGAT2, CPT1A, SCD, and CD36. Furthermore, both MeIQx and PhIP significantly increased intracellular cholesterol and decreased expression of PON1 which is involved in cholesterol efflux. Taken together, these results suggest that HCAs dysregulate lipid production, metabolism, and storage. The current study demonstrates, for the first time, that HCA exposure may lead to fat accumulation in hepatocytes, which may contribute to hepatic insulin resistance and MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by multiple factors that lead to the buildup of steatosis and fat deposition in hepatocytes. These changes are the primary hallmarks of the disease and result in significant impairment of liver function. Consequently, the quality of life of patients and their ability to work are adversely affected. The pathogenesis of MASLD involves both Western and Chinese medicines, with these mechanisms markedly influencing the onset and progression of MASLD; they are not independent but rather interrelated. Conducting histopathological diagnosis of MASLD in the liver is challenging in humans. Consequently, both in vivo and in vitro models are essential. Researchers must select appropriate methods and model types to establish MASLD models that most suitably mimic the human body. Currently, both pharmacological and non-pharmacological treatments have some efficacy in improving the condition of MASLD and the combination of the two is more helpful in providing more effective treatment for patients, but further research and clinical trials are needed to verify in the future. Therefore, the present review comprehensively summarized the pathogenesis, model and treatment of MASLD. It will provide an important basis for subsequent research on MASLD.

Hydroxysteroid 17β‐dehydrogenase 13 (HSD17B13) loss‐of‐function gene variants are associated with a decreased risk of metabolic dysfunction‐associated steatotic liver disease (MASLD). Our RNA‐seq analysis of steatotic liver from obese mice ± fenretinide treatment identified major beneficial effects of fenretinide on expression of hepatic genes including Hsd17b13. We sought to determine the relationship between Hsd17b13 expression and MASLD and to validate it as a therapeutic target by liver‐specific knockdown. Hsd17b13 expression, which is unique to hepatocytes and associated with the lipid droplet, was elevated in multiple models of MASLD and normalised with the prevention of obesity and steatotic liver. Direct, liver‐specific, shRNA‐mediated knockdown of Hsd17b13 (shHsd17b13) in high‐fat diet (HFD)‐obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia. shHsd17b13 decreased elevated serum alanine aminotransferase (ALT), serum fibroblast growth factor 21 (FGF21) levels, and markers of liver fibrosis, for example, expression of Timp2. shHsd17b13 knockdown in HFD‐obese mice and Hsd17b13 overexpression in cells reciprocally regulated expression of lipid metabolism genes, for example, Cd36. Global lipidomic analysis of liver tissue revealed a major decrease in diacylglycerols (e.g. DAG 34:3) with shHsd17b13 expression and an increase in phosphatidylcholines containing polyunsaturated fatty acids (PUFA) for example, phosphatidylcholine (PC) 34:3 and PC 42:10. Expression of key genes involved in phospholipid and PUFA metabolism, for example, Cept1, was also reciprocally regulated suggesting a potential mechanism of Hsd17b13 biological function and role in MASLD. In conclusion, Hsd17b13 knockdown in HFD‐obese adult mice was able to alleviate MASLD via regulation of fatty acid and phospholipid metabolism, thereby confirming HSD17B13 as a genuine therapeutic target for MASLD and the development of liver fibrosis. What is the central question of this study? Hydroxysteroid 17β‐dehydrogenase 13 (HSD17B13) loss‐of‐function gene variants are associated with a decreased risk of metabolic dysfunction‐associated steatotic liver disease (MASLD) and metabolic dysfunction‐associated steatohepatitis (MASH): what is the relationship between Hsd17b13 expression and MASLD and can HSD17B13 be validated as a therapeutic target by liver‐specific knockdown? What is the main finding and its importance? Liver‐specific shRNA knockdown of Hsd17b13 in obese mice markedly improved hepatic steatosis and markers of liver health, for example, serum alanine aminotransferase and fibroblast growth factor 21 levels. Hsd17b13 influenced the expression of lipid/phospholipid metabolism genes and phosphatidylcholines PC 34:3 and PC 42:10. Our study suggests a mechanism of Hsd17b13's biological function and a strong rationale behind targeting HSD17B13 for MASLD/MASH.

Patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) may exhibit altered pharmacokinetics (PK) and pharmacodynamics (PD) of drugs compared with healthy populations. However, no physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model has been specifically developed for MASLD. Acetaminophen (APAP), a widely used analgesic, was selected to develop a PBPK/PD model predicting PK/PD changes of APAP and its metabolites in MASLD‐related populations. Based on a comprehensive review of published APAP PK studies and examination of existing PBPK models, a simultaneous parent‐metabolite PBPK model for APAP was developed and optimized in healthy people. The model simulated the dynamics of APAP and its five major metabolites: APAP‐glucuronide (APAP‐glu), APAP‐sulfate (APAP‐sul), N‐acetyl‐p‐benzoquinone imine (NAPQI), APAP‐cysteine (APAP‐cys), and APAP‐mercapturate (APAP‐merc). The validated model was expanded to MASLD‐related populations, including overweight, obese, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and cirrhosis with different severities. Finally, a PD model was integrated to correlate APAP's PK with pain relief scores. The PBPK model reproduced published clinical PK data for APAP and its metabolites in healthy and MASLD‐related populations. At therapeutic doses, the toxic NAPQI remained at very low levels. APAP's pain relief efficacy was retained, but onset time may change in MASLD‐related populations. This PBPK/PD approach provides a strategy for projecting drug exposure in MASLD‐related populations, even without specific PK or PD data. It highlights modeling's utility for personalized medicine in MASLD patients and MASLD treatment drug development. Study Highlights What is the current knowledge on the topic? ○Currently, there is not too much evidence about the PK changes of drugs in MASLD patients compared with healthy populations. What question did this study address? ○What is the difference in the drug PK and PD between the MASLD‐related population and the healthy population? What does this study add to our knowledge? ○The bioavailability of APAP and its metabolites can be changed in the MASLD‐related population compared with healthy or non‐MASLD populations. The NAPQI can vary several times, but is within a very low‐level range. The analgesic effect may be retained, but the onset time is varied. How might this change drug discovery, development, and/or therapeutics? ○This PBPK/PD approach provides a general strategy for projecting drug exposure in MASLD‐related populations, even in the absence of specific PK or PD data. The established PBPK/PD model strategy can be a powerful supporting tool for MASLD treatment drug development. It highlights the utility of modeling approaches for dose optimization in metabolic liver diseases.

Aims/Introduction We conducted a 5 year post‐trial monitoring study of our previous randomized 24 week, open‐label, active‐controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction‐associated steatotic liver disease (MASLD), identical to those of pioglitazone. Materials and Methods In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated. Results At 5 years, the mean liver‐to‐spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (−4.0%, P = 0.0075 and −7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB‐4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone. Conclusions Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years. Ipragliflozin significantly improves MASLD and glycemic parameters, reduces body weight, visceral fat, and fibrosis markers. SGLT2 inhibitors may be a potent therapeutic strategy for the long‐term management of patients with type 2 diabetes complicated by MASLD, given their ability to improve insulin resistance, a key driver of MASLD pathology.

We aimed to compare the association of metabolic dysfunction‐associated fatty liver disease (MAFLD), metabolic dysfunction‐associated steatotic liver disease (MASLD), alcohol‐related liver disease (ALD), metabolic dysfunction and ALD (MetALD), and MASLD with viral hepatitis (MASLD‐Viral) with risks of cirrhosis, liver cancer, and mortality. The data of 464,556 adults from the UK Biobank (UKB), 13,526 adults from the National Health and Nutrition Examination Survey (NHANES), and 2554 adults from BeijngFH Health Cohort Study (FHCS) were included. Adjusted hazard ratios (aHR) and odds ratios were calculated using Cox and Logistic regression models, respectively. Compared with non‐SLD, the risk of liver cancer increased from MetALD (aHR 1.70 [95% CI 1.37, 2.09]), MASLD (1.91 [1.66, 2.21]), MAFLD (2.01 [1.76, 2.29]), ALD (3.16 [2.54, 3.93]), to MASLD‐Viral (22.0 [10.8, 44.4]) in a stepwise manner in the UKB; the risk of all‐cause mortality increased from MetALD, MASLD, MAFLD, ALD, to MASLD‐Viral in the NHANES. The odds ratio of liver fibrosis increased from MASLD, MAFLD, to MASLD‐Viral in the FHCS. In patients with diabetes, metformin plus other drugs were associated with higher risks of cirrhosis, liver cancer, and all‐cause mortality in MASLD or MAFLD. Prevention rather than antiglycemic treatment is important for patients with diabetic MASLD or MAFLD. This study analyzed the UK Biobank, NHANES III, and FHCS data to assess the prognostic and associative effects of new steatotic liver disease nomenclatures. It found that MAFLD, MASLD, and MetALD were associated with higher risks of liver‐related conditions and mortality, with diabetes and certain antiglycemic medications further heightening these risks .

Intermittent fasting (IF) has shown particularly promising short-term effects in improving metabolic dysfunction-associated steatotic liver disease (MASLD), although its long-term efficacy remains unclear. Heterophyllin B (HP-B), a cyclopeptide compound derived from Pseudostellaria heterophylla, is known for its potent anti-inflammatory and hypoglycemic properties. However, studies investigating the potential role of HP-B in the management of MASLD are lacking. In vitro, an OA/PA-induced lipid accumulation model was established using HepG2/Huh-7 cells. The therapeutic effects of HP-B and fasting-mimicking conditions were evaluated through Cell Counting Kit-8 assay, Oil Red O staining, reverse transcription-quantitative PCR, and western blot analysis. For in vivo studies, C57BL/6J mice were fed a high-fat diet and treated with HP-B, IF, or their combination. Mechanistic validation was performed via adenovirus-mediated GLP-1R knockdown. The present study aimed to explore whether HP-B can serve as an adjunctive supplement to enhance the benefits of IF in the treatment of MASLD. HepG2 and Huh-7 liver cancer cells treated with oleic acid/palmitic acid (OA/PA) presented significant lipid accumulation, which was attenuated by HP-B treatment and fasting. The combination treatment markedly reduced lipid levels and oxidative stress, as well as restored the mitochondrial membrane potential, with a synergistic effect over treatment alone. In addition, the combination of HP-B and fasting upregulated glucagon-like peptide-1 receptor (GLP-1R) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression, reversing the OA/PA-induced decline. In high-fat diet-fed mice, the combination treatment reduced hepatic lipid accumulation, decreased liver weight, decreased mouse body weight, and improved biochemical indices of liver function. The beneficial effects of HP-B and fasting were reversed after silencing GLP-1R with small interfering RNA or Ad-GLP-1R, emphasizing the critical role of GLP-1R in mediating these protective effects. In conclusion, the synergistic effects of HP-B and fasting on improving lipid metabolism and mitochondrial function are mediated primarily through the regulation of GLP-1R, making it a promising therapeutic target for the treatment of MASLD and other lipid metabolism-related disorders.

Metabolic dysfunction‐associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease globally. Previous studies have shown that MASLD is an independent risk factor for chronic kidney disease (CKD), but the variations in estimated glomerular filtration rate (eGFR) levels across countries with different ethnic backgrounds have not been extensively reported. We enrolled 3308 participants with biopsy‐proven MASLD from 34 centers in this multinational study and analyzed the associations between eGFR and histological severity of liver fibrosis in different countries. European participants had lower eGFR levels (92.2 ± 20.7 vs. 104.7 ± 17.3 mL/min/1.73 m2) and significant liver fibrosis (61.4 vs. 32.4%) than Asian individuals. In Asia, Chinese participants had the highest mean eGFR level at 105.8 mL/min/1.73 m2, while Malaysian participants had the lowest at 87.3 mL/min/1.73 m2 (p < 0.001). In Europe, French participants had the highest mean eGFR level at 95.3 mL/min/1.73 m2, while Romanian individuals had the lowest at 81.1 mL/min/1.73 m2 (p < 0.001). eGFR levels were inversely associated with liver fibrosis in Asian individuals (OR: 0.793, 95%CI: 0.685–0.917, p = 0.002), even after adjusting for traditional renal risk factors, but not in Europeans. Our findings provide the basis for further investigation of the burden of MASLD on CKD risk in different countries. A total of 3308 participants with biopsy‐proven MASLD from 34 centers were enrolled in the study. We collected liver biopsy pathological scores and clinical parameters and conducted correlation analysis. We finally found that eGFR levels are inversely associated with liver fibrosis in Asians, even after adjusting for traditional renal risk factors.

Background This study aimed to investigate the association between handgrip strength (HGS) and cardiovascular disease (CVD) in individuals with metabolic dysfunction‐associated steatotic liver disease (MASLD) using data from the UK Biobank cohort. Methods A total of 201 563 participants were enrolled in this study. The HGS was measured using a Jamar J00105 hydraulic hand dynamometer. MASLD was defined as the presence of hepatic steatosis accompanied by one or more cardiometabolic criteria. Hepatic steatosis was identified using a fatty liver index ≥ 60. Advanced liver fibrosis was defined by a fibrosis‐4 (FIB‐4) score > 2.67. To examine the differences in the incidence of CVD, male and female participants were divided into non‐MASLD, MASLD with high HGS, MASLD with middle HGS, and MASLD with low‐HGS groups. Results Of the study participants, 75 498 (37.5%) were diagnosed with MASLD, with a mean age of 56.5 years, and 40.6% were male. The median follow‐up duration was 13.1 years. The frequency of incident CVD events increased significantly across groups: 10.9% in non‐MASLD, 13.3% in MASLD with high HGS, 14.8% in MASLD with middle HGS, and 18.4% in MASLD with low HGS for males (p < 0.001). In females, the frequency of incident CVD events was 6.1% in non‐MASLD, 9.2% in MASLD with high HGS, 10.7% in MASLD with middle HGS, and 13.3% in MASLD with low HGS (p < 0.001). Using the non‐MASLD group as a reference, multivariate‐adjusted hazard ratios (HRs) (95% confidence intervals [CI]) for CVD varied according to HGS in individuals with MASLD. In males with MASLD, HRs (95% CI) were 1.03 (0.96–1.10) for high HGS, 1.14 (1.07–1.21) for middle HGS, and 1.38 (1.30–1.46) for low HGS; in females with MASLD, they were 1.07 (0.97–1.18) for high HGS, 1.25 (1.14–1.37) for middle HGS, and 1.56 (1.43–1.72) for low HGS. The incidence of CVD events increased as HGS decreased in participants with MASLD, regardless of the presence or absence of advanced liver fibrosis (all p < 0.001). Conclusions This large prospective cohort study using the UK Biobank showed that in MASLD, a decrease in HGS was associated with increased CVD risk.

Background The association between estradiol/testosterone (E2/T) ratio and metabolic dysfunction‐associated steatotic liver disease (MASLD) remains controversial. Moreover, few studies have explored their relationship in men with type 2 diabetes mellitus. We aimed to investigate the association of the E2/T ratio with MASLD in type 2 diabetes mellitus male patients. Methods This real‐world observational study was performed in 1441 male type 2 diabetes mellitus patients. MASLD was determined by abdominal ultrasonography. The clinical characteristics and prevalence of MASLD were compared across the E2/T ratio quartiles. The association of the E2/T ratio and quartiles with MASLD was also evaluated using binary logistic regression. Results After adjusting for age and diabetes duration (DD), MASLD prevalence significantly increased across the E2/T ratio quartiles (37.7%, 42.6%, 53.1%, and 69.3%, respectively, P < 0.001 for trend). Fully adjusted logistic regression showed that both the E2/T ratio (OR: 2.201, 95% CI: 1.380–3.511, P = 0.001) and quartiles (P = 0.001) were positively associated with MASLD in males with type 2 diabetes mellitus. Furthermore, C‐reactive protein (CRP) levels were significantly higher in patients with MASLD compared with those without (P < 0.001), and obviously increased across the E2/T ratio quartiles after controlling for age and DD (P = 0.016 for trend). Conclusions The E2/T ratio was independently and positively associated with the increased risk of MASLD in male type 2 diabetes mellitus patients, which may be attributed to the close association between the E2/T ratio and inflammation. The E2/T ratio may serve as a simple and practical indicator to assess the risk of MASLD in male type 2 diabetes mellitus patients. The E2/T ratio showed an independent and positive association with the risk of MASLD in male patients with type 2 diabetes mellitus, potentially reflecting its link with inflammation. The E2/T ratio may serve as a simple and practical indicator for assessing MASLD risk in this population.