Non-alcoholic fatty liver disease (NAFLD) is a hepatic metabolic syndrome arising from lipid metabolic imbalance, with its prevalence increasing globally. In this study, we observed a significant up-regulation of interferon regulatory factor 8 (IRF8) in the liver of NAFLD model mice and patients. Overexpression of IRF8 induced lipid accumulation in the mouse primary hepatocytes. Mice with adeno-associated virus-mediated IRF8 overexpression exhibited hepatic steatosis due to up-regulated peroxisome proliferator-activated receptor γ (PPARγ) expression and increased fatty acid uptake and lipogenesis. In vitro, small interfering RNA-mediated IRF8 knockdown attenuated triglyceride accumulation by dampening PPARγ expression through transcriptional inhibition of brain and muscle ARNT-like 1. The PPARγ-specific antagonist GW9662 abolished the effect of IRF8 overexpression. Furthermore, adeno-associated virus-mediated IRF8 knockdown in the mouse liver markedly alleviated hepatic steatosis and obesity-related metabolic syndrome. These findings indicate that IRF8 plays a vital role in modulating hepatic lipid metabolism in a PPARγ-dependent manner and provide a previously unknown insight into NAFLD therapeutic strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.

The prevalence of nonalcoholic steatohepatitis (NASH) is rising annually, posing health and economic challenges, with limited treatments available. Diosgenin, a natural steroidal compound found in various plants, holds potential as a therapeutic candidate. Recent studies have confirmed diosgenin's anti-inflammatory and metabolism-modulating properties. However, its therapeutic effects on NASH and the underlying mechanisms are still unclear. This study aims to explore diosgenin's protective effects and pharmacological mechanisms against NASH using network pharmacology, molecular docking, and experimental validation. We gathered potential targets of diosgenin and NASH from various databases to generate protein-protein interaction (PPI) networks. GO and KEGG pathway enrichment analyses identified key targets and mechanisms. Molecular docking confirmed the binding capacity between diosgenin and core target proteins. Additionally, a NASH cell model was developed to validate the pharmacological effects of diosgenin. Our investigation identified nine key targets (ALB, AKT1, TP53, VEGFA, MAPK3, EGFR, STAT3, CASP3, IGF1) that interact with diosgenin. Molecular docking indicated potential bindings interactions, while enrichment analyses revealed that diosgenin may enhance fatty acid metabolism via the PI3K-Akt pathway. Cellular experiments confirmed that diosgenin activates this pathway, reduces SCD1 expression, and decreases triglyceride and IL-6 levels. Our study elucidates that diosgenin may ameliorate triglyceride deposition and inflammation through the PI3K-Akt pathway.

NAFLD is a global and complex liver disease caused by multiple factors. Intrahepatocellular steatosis is the primary prerequisite for the occurrence and development of NAFLD. It has been shown that miR-125b-5p is highly correlated with NAFLD, and ESRRA is a factor that regulates lipid metabolism. The purpose of our study is to investigate whether miR-125b-5p regulates FFA-induced steatosis in L02 cells by targeting ESRRA.

Estrogen-related receptor alpha (ESRRA) was identified as a direct target of miR-125b-5p through database prediction and a dual-luciferase reporter gene assay. L02 cells were induced with free fatty acids (OA:PA, 2:1) at concentrations of 0.3 mM, 0.6 mM, 0.9 mM, 1.2 mM and 1.5 mM for 24 h, 48 h and 72 h, respectively. The degree of hepatocyte steatosis and triglyceride content were separately manifested by oil red O staining and colorimetric method. Cell viability per group was detected by CCK-8 assay. Eventually, 0.9 mM and 24 h were screened out as the optimal concentration and time for establishing the in-vitro model of hepatic steatosis. Followingly, miR-125b-5p and ESRRA were knocked down by transient transfection. We monitored the expressions of lipid metabolism factors SREBP-1c, ACC1 and FAS. The data showed that knockdown of ESRRA led to down-regulation of the expressions of SREBP-1, ACC1 and FAS. Meanwhile, knockdown of ESRRA and miR-125b-5p resulted that the expressions of ESRRA, SREBP-1, ACC1 and FAS rebounded.

MiR-125b-5p down-regulates the expressions of lipid metabolism-related factors by negatively regulating ESRRA, thereby improving hepatic steatosis.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with potential progression to cirrhosis and impaired regeneration post-resection. A key mechanism underlying lipotoxicity is endoplasmic reticulum (ER) stress, particularly the activation of the unfolded protein response (UPR). This study investigates the interplay between lipid accumulation, endoplasmic reticulum (ER) stress, and cellular outcomes, focusing on the balance between autophagy and apoptosis. We cultured primary human hepatocytes (PHH) in a free fatty acid (FFA)-enriched medium for 120 h, assessing lipid accumulation, metabolism, and the expression of selected UPR markers. Additionally, we investigated the effects of lipid load on cell activity and growth in proliferating HepG2 cells. We observed that FFA uptake consistently induced ER stress, shifting cellular responses toward apoptosis under high lipid loads. Donor-specific differences were evident, particularly in lipid storage, excretion, and sensitivity to lipotoxicity. Some donors exhibited limited triglyceride (TAG) storage and excretion, leading to an excess of FFA whose metabolic fate remains unclear. Proliferation was more sensitive to lipid accumulation than overall cell activity, with even low FFA concentrations impairing growth, highlighting the vulnerability of regenerative processes to steatosis. The study elucidates how ER stress pathways, such as PERK-CHOP and IRE1α-JNK, are differentially activated in response to lipid overload, tipping the balance toward apoptosis in severe cases. The limited activation of repair mechanisms, such as autophagy, further emphasizes the critical role of ER stress in determining hepatocyte fate. The donor-dependent variability highlights the need for personalized strategies to mitigate lipotoxic effects and enhance liver regeneration in steatosis-related conditions.

Polycystic ovary syndrome (PCOS) is linked to non-alcoholic fatty liver disease (NAFLD). Biochemical, sex hormonal, and anthropometric indicators have been explored for screening NAFLD in PCOS patients. However, the accuracy of NAFLD screening using these indicators in PCOS patients remains uncertain. This study aimed to identify biochemical, sex hormonal, and anthropometric indicators associated with NAFLD in overweight and obese PCOS patients and assess the diagnostic efficacy of combined indicators.

This cross-sectional study (Clinical trial number ChiCTR1900020986; Registration date January 24th, 2019) involved 87 overweight or obese women with PCOS (mean age 29 ± 4 years). Measurements included anthropometric indices, biochemistry, sex hormone levels, and liver proton density fat fraction (PDFF). Correlation analysis, intergroup comparisons, and logistic regression analysis were used to identify risk factors for NAFLD (PDFF > 5.1%). The receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value were used to determine cut-off values and evaluate diagnostic accuracy.

Liver PDFF was 7.69% (3.93%, 14.80%) in overweight and obese PCOS patients, with 67.8% diagnosed with NAFLD. NAFLD was associated with increased body mass index (BMI), abdominal circumference (AC), and triglyceride, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), glucose, insulin, and free testosterone (FT) levels, and with decreased high-density lipoprotein-cholesterol (HDL-C) and sex hormone-binding globulin (SHBG) levels (P < 0.05). Risk factors for NAFLD in PCOS included BMI > 26.8 kg/m2, AC > 88.3 cm, triglyceride > 1.57 mmol/L, TC > 4.67 mmol/L, LDL-C > 3.31 mmol/L, glucose > 4.83 mmol/L, insulin > 111.35 pmol/L, FT > 7.6 pg/mL and SHBG < 25 nmol/L (β = 1.411-2.667, P < 0.005). A multi-indicator model including triglycerides, LDL-C, glucose, insulin, and SHBG showed higher diagnostic accuracy (AUC = 0.899, P < 0.001) for screening NAFLD in PCOS patients than single indicators (AUC = 0.667-0.761, P < 0.05).

Overweight and obese PCOS patients have higher incidences of liver PDFF and NAFLD. A multi-indicator model including triglycerides > 1.57 mmol/L, LDL-C > 3.31 mmol/L, glucose > 4.83 mmol/L, insulin > 111.35 pmol/L, and SHBG < 25 nmol/L is highly accurate for screening NAFLD in overweight and obese PCOS patients.

Procyanidins have strong potential for antioxidation and decreasing hepatic fat accumulation thus preventing non-alcoholic fatty liver disease (NAFLD). Procyanidin A2 (PCA2), predominately found in cranberries, avocado, peanut red skins and litchi fruit pericarp, is poorly absorbed in the gastrointestinal tract. However, literatures about its metabolic profile by gut microbiota and effects on lipid metabolism are limited. Therefore, the metabolites of PCA2 by human intestinal microbiota as well as their antioxidant and hypolipidemic potential were investigated.

PCA2 was incubated with human intestinal microbiota and the metabolites produced were characterized by UPLC-Q-TOF-MS. The antioxidant and hypolipidemic potential of PCA2 and its microbial metabolites (MPCA2) were evaluated and compared.

The metabolism of PCA2 resulted in the formation of 14 metabolites, and the highest antioxidant capacity values were reached after 6 h incubation. In addition, PCA2 and MPCA2 were effective in reducing oxidative stress and lipid accumulation induced by oleic acid (OA) in HepG2 cells. They significantly promoted the phosphorylation of AMP-activated protein kinase (AMPK) and thus stimulated hepatic lipolysis by up-regulating of the expression of carnitine palmitoyl transferase I (CPT-I) and suppressed hepatic lipogenesis by down-regulation of the expression of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA) reductase, fatty acid synthase (FAS) and sterol regulatory element binding proteins 1c (SREBP-1c).

Our results indicated that PCA2 and MPCA2 were effective to prevent OA-induced lipid accumulation and oxidative stress in HepG2 cells, implying that microbial metabolites may play a crucial role in the realization of human health effects of PCA2.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent chronic liver condition characterized by lipid accumulation and inflammation, often progressing to severe liver damage. We aim to review the pathophysiology, diagnostics, and clinical care of MASLD, and review highlights of advances in proteomic technologies. Recent advances in proteomics technologies have improved the identification of novel biomarkers and therapeutic targets, offering insight into the molecular mechanisms underlying MASLD progression. We focus on the application of mass spectrometry-based proteomics including single cell proteomics, proteogenomics, extracellular vesicle (EV-omics), and exposomics for biomarker discovery, emphasizing the potential of blood-based panels for noninvasive diagnosis and personalized medicine. Future research directions are presented to develop targeted therapies and improve clinical outcomes for MASLD patients.

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising due to rapid lifestyle changes. Although females may be less prone to MASLD than males, specific studies on MASLD in females should still be conducted. Previous research has shown that sex hormone levels are strongly linked to MASLD in females. By reviewing a large number of experimental and clinical studies, we summarized the pathophysiological mechanisms of estrogen, androgen, sex hormone-binding globulin, follicle-stimulating hormone, and prolactin involved in the development of MASLD. We also analyzed the role of these hormones in female MASLD patients with polycystic ovarian syndrome or menopause, and explored the potential of targeting sex hormones for the treatment of MASLD. We hope this will provide a reference for further exploration of mechanisms and treatments for female MASLD from the perspective of sex hormones.

PNPLA3-I148M genotype is the strongest predictive single-nucleotide polymorphism for liver fat. We examine whether PNPLA3-I148M modifies associations between oxidative gaseous air pollutant exposure (Oxwt) with i) liver fat and ii) multi-omics profiles of miRNAs and metabolites linked to liver fat. Participants were 69 young adults (17-22 years) from the Meta-AIR cohort. Prior-month residential Oxwt exposure (redox-weighted oxidative capacity of nitrogen dioxide and ozone) was spatially interpolated from monitoring stations via inverse-distance-squared weighting. Liver fat fraction was assessed by MRI. Serum miRNAs and metabolites were assayed via NanoString nCounter and LC-HRMS, respectively. Multi-omics factor analysis (MOFA) was used to identify latent factors with shared variance across omics layers. Multivariable linear regression models adjusted for age, sex, body mass index, and genotype with liver fat or MOFA factors as an outcome and examined PNPLA3 (rs738409; CC/CG vs. GG) as a multiplicative interaction term. Overall, a standard deviation difference in Oxwt exposure was associated with 8.9% relative increase in liver fat (p = 0.04) and this relationship differed by PNPLA3 genotype (p-value for interaction term: pintx<0.001), whereby relative increases in liver fat for GG and CC/CG participants were 71.8% and 2.4%, respectively. There was no main effect of Oxwt on MOFA Factor 1 expression (p = 0.85), but there was an interaction with PNPLA3 genotype (pintx = 0.01), whereby marginal slopes were 0.211 and -0.017 for GG and CC/CG participants, respectively. MOFA Factor 1 in turn was associated with liver fat (p = 0.006). MOFA Factor 1 miRNAs targeted genes in Fatty Acid Biosynthesis and Metabolism and Lysine Degradation pathways. MOFA Factor 9 was also associated with liver fat and was comprised of branched-chain keto acid and amino acid metabolites. The effects of Oxwt exposure on liver fat is exacerbated in young adults with two PNPLA3 risk alleles, potentially through differential effects on miRNA and/or metabolite profiles.

Both alternate-day fasting (ADF) and calorie restriction (CR) are effective weight loss strategies. However, most individuals find it difficult to adhere to CR. Furthermore, CR can induce an excessive loss of not only fat but also muscle mass. This study aimed to compare the effects of ADF and pair-feeding (PF) CR on metabolic pathways underlying obesity in mice with high-fat diet (HFD)-induced obesity.

Male C57BL/6N Tac mice (n = 10 per group) were fed an HFD for 8 weeks to establish a diet-induced obesity model. Mice were then continued on the HFD with either alternate-day access to food or PF for the next 8 weeks. We measured body weight, adiposity, plasma biomarkers, and molecular mechanisms involving lipolysis and autophagy.

Both ADF and PF resulted in comparable weight and fat loss. Compared with PF, ADF showed a significant reduction in liver weight and hepatic triglyceride levels. ADF significantly increased plasma ketone body levels and white adipose tissue lipolysis. Compared with PF, ADF tended to activate autophagy elongation and autophagosome formation, which were insignificant.

These findings indicated that ADF is a promising intervention for metabolic diseases, potentially due to its superior efficacy in promoting ketogenesis and lipolysis compared with PF.

Myocardial infarction is a leading cause of death in individuals with non-alcoholic fatty liver disease (NAFLD). The two diseases share elevated very low-density lipoproteins (VLDL) carrying both triglycerides and cholesterol; however, in NAFLD mainly triglycerides accumulate in liver cells while in myocardial infarction mainly cholesterol accumulates in the atherosclerotic plaque. We hypothesized that VLDL triglycerides preferentially associate with risk of NAFLD, while VLDL cholesterol preferentially associates with risk of myocardial infarction.

We examined 25,428 individuals without clinically diagnosed NAFLD or myocardial infarction at baseline, nested within 109,776 individuals from the prospective Copenhagen General Population Study and followed these individuals for a mean of 10 years. VLDL triglycerides, VLDL cholesterol, and low-density lipoprotein (LDL) cholesterol were determined using nuclear magnetic resonance spectrometry.

Continuously higher VLDL triglycerides were associated with continuously higher risk of NAFLD; however, this was not the case for VLDL cholesterol, LDL cholesterol, or apolipoprotein B. In contrast, continuously higher VLDL cholesterol, LDL cholesterol, and plasma apolipoprotein B were all associated with continuously higher risk of myocardial infarction. Compared to individuals with both VLDL triglycerides and VLDL cholesterol ≤66th percentile, the hazard ratios for NAFLD in individuals with VLDL triglycerides >66th percentile were 1.61(95 % confidence intervals:1.25-2.06) at high VLDL cholesterol and 1.41(0.90-2.21) at low VLDL cholesterol. Corresponding hazard ratios for myocardial infarction in individuals with VLDL cholesterol >66th percentile were 1.51(1.36-1.67) at high VLDL triglycerides and 1.42(1.18-1.69) at low VLDL triglycerides.

VLDL triglycerides predominated in NAFLD while VLDL cholesterol predominated in myocardial infarction; however, VLDL cholesterol was also elevated slightly in NAFLD while VLDL triglycerides was also elevated in myocardial infarction.

Spinal cord injury (SCI) is a serious trauma of the central nervous system (CNS). SCI induces a unique lipid-dense environment that results in the deposition of large amounts of lipid droplets (LDs). The presence of LDs has been shown to contribute to the progression of other diseases. Lipophagy, a selective type of autophagy, is involved in intracellular LDs degradation. Fatty acid translocase CD36, a multifunctional transmembrane protein that facilitates the uptake of long-chain fatty acids, is implicated in the progression of certain metabolic diseases, and negatively regulates autophagy. However, the precise mechanisms of LDs generation and degradation in SCI, as well as whether CD36 regulates SCI via lipophagy, remain unknown. In this study, we investigated the role of LDs accumulation in microglia for SCI, as well as the regulatory mechanism of CD36 in microglia lipophagy during LDs elimination in vivo and in vitro. SCI was induced in mice by applying moderate compression on spina cord at T9-T10 level. Locomotion recovery was evaluated at days 0, 1, 3, 7 and 14 following the injury. PA-stimulated BV2 cells was established as the in vitro lipid-loaded model. We observed a marked buildup of LDs in microglial cells at the site of injury post-SCI. More importantly, microglial cells with excessive LDs exhibited elevated activation and stimulated inflammatory response, which drastically triggered the pyroptosis of microglial cells. Furthermore, we found significantly increased CD36 expression, and the breakdown of lipophagy in microglia following SCI. Sulfo-N-succinimidyl oleate sodium (SSO), a CD36 inhibitor, has been shown to promote the lipophagy of microglial cells in SCI mice and PA-treated BV2 cells, which enhanced LDs degradation, ameliorated inflammatory levels and pyroptosis of microglial cells, and ultimately promoted SCI recovery. As expected, inhibition of lipophagy with Baf-A1 reversed the effects of SSO. We conclude that microglial lipophagy is essential for the removal of LDs during SCI recovery. Our research implies that CD36 could be a potential therapeutic target for the treatment and management of SCI.

ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.

Non-alcoholic fatty liver disease (NAFLD) is the prevalent liver disease. Ovarian tumor domain-containing 7B (OTUD7B) is a deubiquitinating enzyme and its role in NAFLD remains unclear. In high-fat diet (HFD)-induced NAFLD mouse model and palmitic acid (PA)-treated HepG2 cells, OTUD7B expression was decreased. Adenoviral overexpression of OTUD7B in mice resulted in reduced body weight and liver injury, with decreased serum aminotransferase (ALT) and aspartate aminotransferase (AST) levels. OTUD7B overexpression attenuated hepatic lipid deposition (serum TG, TC, LDL-C, HDLC, and FFA levels), which might be through the suppression of lipogenesis and β-oxidation-related genes. The contents of hepatic inflammatory factors (TNF-α, IL-6, and IL-1β) were decreased following OTUD7B overexpression in NAFLD mice. A mechanism study indicated that the protective effect of OTUD7B overexpression might be associated with β-catenin signal activation. OTUD7B overexpression promoted PA-induced β-catenin activity in TopFlash assay, and increased total β-catenin and c-myc levels in cells. The increase in β-catenin levels was contributed to the stabilization via inhibiting K48-linked ubiquitination and proteasomal degradation by OTUD7B. NR4A2 role in NASH has been proved. NR4A2 ChIP-seq and RNA-seq data excluded transcriptional regulation of NR4A2 to OTUD7B, and it was experimentally evidenced that NR4A2 bound to OTUD7B promoter region and positively transcriptionally regulate OTUD7B expression. In summary, OTUD7B overexpression ameliorated hepatic inflammation and steatosis in NAFLD. The possible mechanism of OTUD7B might be through the inhibition of β-catenin degradation by removing K48-linked ubiquitination, which might be regulated by NR4A2.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and opisthorchiasis, caused by Opisthorchis viverrini (O. viverrini) infection, frequently co-exist in Northeast Thailand. However, the underlying pathophysiology remains unknown. We aimed to investigate the effect of a high-fat/high-fructose (HFF) diet combined with O. viverrini infection on MASLD. Four groups each of ten male golden hamsters were established: normal controls (NC), O. viverrini-infected (OV), HFF-fed, and HFF-fed plus O. viverrini infection (HFF+OV). After four months of treatment, histopathological study indicated substantial hepatic damage in groups given the HFF diet. In particular, the HFF+OV group demonstrated marked lipid-droplet accumulation, hepatocyte ballooning, inflammatory-cell clustering, and widespread fibrosis. Biochemical tests indicated that the HFF+OV group had the highest concentrations of alanine aminotransferase and triglycerides, but cholesterol and low-density lipoprotein levels had increased in both HFF groups. Increased expression of Tgf-β1 and α-SMA, indicative of greater fibrosis, was demonstrated by picrosirius-red staining in the HFF+OV group. There was a significant increase in levels of inflammatory markers (HMGB-1, p65, and F4/80) and expression of genes related to the synthesis of fatty acids and glucose. FTIR microspectroscopy revealed distinct changes in fatty acids and proteins, associated with the more pronounced histopathology and impaired liver function in the HFF+OV group. The findings indicate that the interplay of a HFF diet and O. viverrini infection aggravates the progression of MASLD by augmenting liver damage, inflammation, fibrogenesis, and metabolic dysfunction. This study highlights the significance of incorporating both nutritional and infection factors into the management of liver disorders, especially in areas where opisthorchiasis is common.

Nonalcoholic fatty liver disease (NAFLD) and its development into nonalcoholic steatohepatitis (NASH) are challenging health concerns globally. Clinically, the prevalence and severity of NAFLD/NASH are higher in men than in premenopausal women. NAFLD is strongly correlated with obesity, both of which are tied to high-fat/fructose-rich western diets. Therefore, we aimed to investigate sexual dimorphism in NAFLD pathogenesis in male and female C57BL/6 mice fed different diets. Male and female C57BL/67 mice were divided into four groups and kept on a chow (C), chow plus high fructose (CF), high fat (HF), and high fat plus high fructose (HFF) diet for 22 weeks. Liver tissues were collected at the end of the study and processed for NAFLD/NASH-related histology (H&E and trichrome staining), protein expression (SREBP1, SCAP, FABP4, α-SMA, TGF-β and L-PGDS), and biochemical parameters measurement. Our results displayed that female mice exhibited protection against NAFLD and diabesity on HF and HFF diets compared to male mice fed similar diets. Additionally, female mice showed protection from fibrosis compared to male mice. Both male and female mice fed HF and HFF diet groups displayed the cytosol-to-nuclear translocation of Lipocalin Prostaglandin D2 Synthase (L-PGDS). Cytoplasmic levels of L-PGDS were absent in females compared to low levels in males, revealing a possible sex-specific mechanism tied to fructose and fat metabolism. Collectively, female mice showed protection against NAFLD and diabesity relative to male mice, accompanied by differential regulation of hepatic lipocalin prostaglandin D2 synthase.

Hepatic steatosis/non-alcoholic fatty liver disease is a major public health delinquent caused by the excess deposition of lipid into lipid droplets (LDs) as well as metabolic dysregulation. Hepatic cells buildup with more fat molecules when a person takes high fat diet that is excessive than the body can handle. At present, millions of people in the world are affected by this problem. So, it is very important to know the effects of factors responsible for the disease. Here, the role of lipid droplet (LD) biogenesis and metabolism was analyzed and intended to investigate if defects in biogenesis/metabolic enzymes are responsible for the accumulation of lipids other than LDs in fatty liver disease in high-fat-induced conditions in mice model. To explore it, high-fat diet (HFD), fast food (FF), and soft drinks (SD) were administered to wild-type Swiss albino mice for 14 weeks following yogurt supplementation. After experimental period, glucose tolerance, enzyme function, lipid profile, plasma biochemistry, and other analytical tests were analyzed by auto-analyzer including different oxidative stress markers. Lipids from hepatic tissues were extracted, and purified by Floatation Assay and subsequently analyzed by different biochemical and chromatographic techniques. Histological architecture of hepatocytes was performed using Zeiss microscope. Finally, increased amount of lipids biogenesis/accumulation was found in liver tissues that causes Fatty liver disease. Significantly, HFD, FF, and SD were identified as factors for the increased LD biogenesis and or lipid metabolic disorder. Nevertheless, yogurt supplementation can homeostasis those LD formation and metabolic syndrome as it increases the down regulation of lipid biogenesis as well as lipid metabolic rate. So, yogurt supplementation was considered as a novel agent for decreasing LD biogenesis as well as excessive accumulation of fat in hepatocytes which can be used as therapeutics for the treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are both closely related to dyslipidemia. However, the relationship between dyslipidemia in patients with NAFLD and CKD is not yet clear. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is an innovative and comprehensive lipid index. The purpose of this study was to investigate the correlation between NHHR and CKD risk in NAFLD patients with or without fibrosis.

This study used data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020 for analysis, including a total of 4,041 subjects diagnosed with NAFLD. Among the NAFLD subjects, 3,315 individuals without liver fibrosis and 726 individuals with fibrosis. Weighted multivariate linear regression, weighted logistic regression, restricted cubic spline (RCS) curves, and subgroup analysis were used to evaluate the correlation between NHHR and CKD in patients with NAFLD.

Our findings indicate that in NAFLD subjects without liver fibrosis, the highest tertile of NHHR, as compared to the lowest tertile, was inversely related to glomerular filtration rate (eGFR) (β: -2.14, 95% CI: -3.97, -0.32, p < 0.05) and positively related to CKD (OR: 1.67, 95% CI: 1.12, 2.49, p < 0.05). No significant associations were observed between NHHR and eGFR, urinary albumin to creatinine ratio (ACR) in NAFLD subjects with liver fibrosis. The RCS revealed a linear relationship between NHHR and ACR, CKD in NAFLD subjects without liver fibrosis, while a U-shaped relationship was observed between NHHR and ACR, CKD in NAFLD subjects with liver fibrosis.

In patients with non-fibrotic NAFLD, a significantly elevated NHHR is closely associated with an increased risk of CKD and shows a linear relationship with CKD. In patients with fibrotic NAFLD, NHHR shows a U-shaped relationship with CKD. LD, Our findings underscore the practical utility of NHHR as a biomarker for early risk stratification of CKD in patients with NAFLD.

Proactively preventing postpartum weight retention (PPWR) is one of the effective intervention strategies to reduce the occurrence of obesity in women. Population studies have shown that serum folate levels are closely related to body weight. The regulation of folic acid on lipid metabolism has been fully confirmed in both in vivo and in vitro studies. For many years, folic acid supplementation has been widely used in periconceptional women due to its role in preventing fetal neural tube defects. However, whether folic acid supplementation prior to and throughout pregnancy exerts preventive effects on PPWR remains uncertain. This study aims to investigate the preventive effect of folic acid on PPWR in rats and further explore the underlying mechanisms.

In this study, pregnant rats were administered one of the dietary schedules: control diet (CON), high-fat diet (HF), control diet combined with folic acid (FA) and high-fat diet combined with folic acid (HF + FA).

We discovered that folic acid supplementation inhibited high-fat diet-induced elevations in body weight, visceral fat weight, liver weight, hepatic lipid levels and serum lipid levels at 1 week post-weaning (PW). Western blot analysis showed that folic acid supplementation inhibited the expression of endoplasmic reticulum (ER) stress-specific proteins including GRP78, PERK, eIF2α, IRE1α, XBP1 and ATF6, subsequently decreasing the expression of proteins related to lipid synthesis including SREBP-1c, ACC1 and FAS.

In conclusion, folic acid supplementation prior to and throughout pregnancy exerts preventive effects on high-fat diet-induced PPWR in rats, and the mechanism is associated with the inhibition of ER stress-mediated lipogenesis signaling pathways in the liver. Folic acid supplementation may serve as a potential strategy for preventing PPWR. In the future, the effectiveness of folic acid in PPWR prevention can be further verified by population studies.

Sea buckthorn (Hippophae rhamnoides L.) is a traditional Chinese medicinal and possesses a rich medical history in terms of treating gastric disorders, sputum and cough and liver injuries in oriental medicinal system. By reason of the complicated chemical constituents, the material basis and potential pharmacological mechanism of sea buckthorn acting on Non-alcoholic fatty liver disease (NAFLD) has not been clearly elucidated.

To explore the pharmacological efficacy and underlying mechanism of sea buckthorn triterpenoid acid enrichment (STE) in the treatment of NAFLD.

The approaches of Network pharmacology and experiment validation in vitro and in vivo were applied in this study. Firstly, targets of triterpenoid acid compounds and NAFLD were collected from databases. The crucial targets were screened by the construction of protein-protein interaction (PPI) network. Furthermore, the potential signaling pathways and targets affected by STE was predicted by GO together with KEGG enrichment analysis. Finally, the experiment validation was carried out through high-fat feeding NAFLD mice and lipid accumulation HepG2 cell model. Lipids and liver related biochemical indicators were determined, Oil Red O and H&E staining were employed to observe fat accumulation. In addition, the expression levels of proteins of key target and signal pathway anticipated in network pharmacology were detected to elaborated its action mechanism.

A total of 180 intersecting potential targets for enhancing NAFLD with STE were eventually identified. 6 key targets including AKT1, TNF, IL6, INS, JUN, STAT3 and TP53 were further identified and the AMPK-SREBP1 pathway was enriched. Animal experiment result showed that STE treatment could significantly reduce the levels of TG, TC, LDL-C, ALT and AST, increase the levels of HDL-C in serum, and improve lipid accumulation of epididymal fat and liver. The results of the lipid accumulation cell model indicated that STE and key compound oleanolic acid could diminish intracellular lipid levels of TG, TC, LDL-C and number of lipid droplets. Western blot results showed that the above beneficial effects could be achieved by regulating the expression of p-AMPK/AMPK, SREBP1, FAS, ACC, SCD protein.

This study confirmed the effect of STE on improving NAFLD and the potential action mechanism was involved in the regulation of the AMPK-SREBP1 pathway.

Probiotics are studied for their therapeutic potential in the treatment of several diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Part of the significant progress made in understanding the pathogenesis of steatosis has come from identifying the complex interplay between the gut microbiome and liver function. Recently, probiotics have shown beneficial effects for the treatment and prevention of steatosis and MASLD in rodent models and in clinical trials. Numerous studies have demonstrated the promising potential of lactic acid bacteria, especially the genus Lactobacillus. Lactobacillus is a prominent bile acid hydrolase bacterium that is involved in the biotransformation of bile acids. This genus' modulation of the gut microbiota also contributes to overall gut health; it controls gut microbial overgrowth, shapes the intestinal bile acid pool, and alleviates inflammation. This narrative review offers a comprehensive summary of the potential of Lactobacillus in the gut-liver axis to attenuate steatosis and MASLD. It also highlights the roles of Lactobacillus in hepatic lipid metabolism, insulin resistance, inflammation and fibrosis, and bile acid synthesis in attenuating MASLD.

The relationship between plasmatic fatty acid (FA) composition and liver fibrosis remains scarce in people living with HIV/AIDS (PLWHA). We aimed to evaluate the association of plasmatic FAs and liver fibrosis in HIV mono-infected individuals.

This case-control study included PLWHA with liver fibrosis (cases) and randomly selected subjects without fibrosis (controls) from the PROSPEC-HIV study (NCT02542020). Participants with viral hepatitis, abusive alcohol consumption and lipid supplements use were excluded. Liver fibrosis was defined using transient elastography (TE) by liver stiffness measurement (LSM) ≥ 7.1 kPa or ≥ 6.2 kPa with M or XL probe, respectively. All HIV mono-infected participants with liver fibrosis identified at the baseline PROSPEC-HIV visit were included. Controls (1:1) were randomly selected among those HIV mono-infected participants without liver fibrosis. Plasmatic FA profile, dietary lipid intake, anthropometric measures, and blood samples were assessed. Plasmatic fatty acid was analyzed using gas chromatography and intake of fats lipids were assessed by two 24-h dietary recall (24-HDR). Multivariate logistic regression models adjusted by age, sex at birth and duration of antiretroviral therapy (ART) were performed.

A total of 142 participants (71 cases and 71 controls) [62 % female, median age = 46 (IQR, 37-53) years, 14.8 % with diabetes, median CD4 count = 655 cells/mm3, 96.5 % under ART] were included. Higher percentages of plasmatic palmitc acid (16:0) and saturated fatty acids (SFA) were observed in participants with liver fibrosis (cases) compared to those without (controls). Presence of higher percentage of plasmatic palmitc acid (16:0) was associated with an increased odds for liver fibrosis [adjusted OR = 1.23 (95%CI 1.04-1.46); p = 0.02] in multivariate models.

This study showed the potential role of the plasmatic FA composition in the pathogenesis of liver fibrosis in PLWHA.

This study investigated whether a standard calorie diet that is high in glucose and deficient in dietary fibre (described as HGD [high glucose diet]) induces hepatic fat accumulation in mice. We evaluated hepatic steatosis at 7 days and 14 days after the commencement of the HGD. Hepatic triglycerides and areas of oil droplets increased in the HGD group both at day 7 and day 14, whereas weight gain, weight of epididymal fat, and plasma levels of triglycerides were unaffected by HGD consumption. A microarray analysis of the livers revealed that the expression of lipogenesis-related genes was the most affected by HGD consumption. Furthermore, HGD consumption induced the expression of hepatic proteins of fatty acid synthetase, acetyl-CoA carboxylase alpha, and stearoyl-CoA desaturase 1, which are known to be involved in the synthesis of triglyceride. These results indicate that HGD consumption causes fat accumulation in the liver, with an increase in enzymes that are involved in de novo lipogenesis without an accompanying weight or obesity phenotype. Our new findings suggest that HGD consumption could serve as a breeding ground for liver steatosis.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in recent years, but the pathogenesis is not fully understood. Therefore, it is important to establish an effective animal model for studying NAFLD.

Adult zebrafish were fed a normal diet or a high-fat diet combined with egg yolk powder for 30 days. Body mass index (BMI) was measured to determine overall obesity. Serum lipids were measured using triglyceride (TG) and total cholesterol (TC) kits. Liver lipid deposition was detected by Oil Red O staining. Liver injury was assessed by measuring glutathione aminotransferase (AST) and glutamic acid aminotransferase (ALT) levels. Reactive oxygen species (ROS) and malondialdehyde (MDA) were used to evaluate oxidative damage. The level of inflammation was assessed by qRT-PCR for pro-inflammatory factors. H&E staining was used for pathological histology. Caspase-3 immunofluorescence measured apoptosis. Physiological disruption was assessed via RNA-seq analysis of genes at the transcriptional level and validated by qRT-PCR.

The high-fat diet led to significant obesity in zebrafish, with elevated BMI, hepatic TC, and TG. Severe lipid deposition in the liver was observed by ORO and H&E staining, accompanied by massive steatosis and ballooning. Serum AST and ALT levels were elevated, and significant liver damage was observed. The antioxidant system in the body was severely imbalanced. Hepatocytes showed massive apoptosis. RNA-seq results indicated that several physiological processes, including endoplasmic reticulum stress, and glucolipid metabolism, were disrupted.

Additional feeding of egg yolk powder to adult zebrafish for 30 consecutive days can mimic the pathology of human nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by over 5% hepatic fat accumulation without secondary causes. The prevalence of NAFLD has escalated in recent years due to shifts in dietary patterns and socioeconomic status, making it the most prevalent chronic liver disease and a significant public health concern globally. Serum uric acid (SUA) serves as the end product of purine metabolism in the body and is intricately linked to metabolic syndrome. Elevated SUA levels have been identified as an independent risk factor for the incidence and progression of NAFLD. This paper reviews the relationship between SUA and NAFLD, the underlying mechanisms of SUA involved in NAFLD, and the potential benefits of SUA-lowering therapy in treating NAFLD. The aim is to raise awareness of SUA management in patients with NAFLD, and to encourage further investigation into pharmacological interventions in this area.

Clinical and genetic studies strongly support a significant connection between nonalcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD) and identify ASCVD as the primary cause of death in NAFLD patients. Understanding the molecular factors and mechanisms regulating these diseases is critical for developing novel therapies that target them simultaneously. Our preliminary immunoblotting experiments demonstrated elevated expression of nidogen 2 (NID2), a basement membrane glycoprotein, in human atherosclerotic vascular tissues and murine steatotic livers. Therefore, we investigated the role of NID2 in regulating hepatosteatosis and atherosclerosis utilizing Western diet-fed Apoe-/- mice with/without NID2 overexpression. Quantitative real-time PCR confirmed increased NID2 mRNA expression in multiple organs (liver, heart, kidney, and adipose) of NID2-overexpressing mice. Male mice with NID2 overexpression exhibited higher liver and epididymal white adipose tissue mass, increased hepatic lipid accumulation, and fibrosis. Additionally, these mice developed larger atherosclerotic lesions in the whole aortas and aortic roots, with increased necrotic core formation. Mechanistic studies showed reduced AMPK activation in the livers of NID2-overexpressing mice compared with controls, without any effects on hepatic inflammation. In conclusion, these findings suggest that NID2 plays a deleterious role in both hepatosteatosis and atherosclerosis, making it a potential therapeutic target for these conditions.

The Angiopoietin-like 4 (ANGPTL4) and ETS Variant Transcription Factor 4 (ETV4) are involved in the metabolic transition and carcinogenesis in the liver. However, the role of ETV4 in the development of non-alcoholic fatty liver disease (NAFLD) is currently unknown. Our study reveals that ETV4 expression was upregulated in the diet-induced non-alcoholic fatty liver disease, and plays a critical role in the dysregulated lipid metabolism. We demonstrate a mechanism by which ANGPTL4 regulates lipid homeostasis via involving the AMPK/ETV4 axis. Transient knockdown of ETV4 abolished the ANGPTL4-induced expression of Srebp1c, Acc and Fasn. Insulin treatment potentially increased the physical association of ETV4 with SREBP1, and promotes nuclear translocation and transcriptional activity of SREBP1. In addition, we show that combined therapy with omega-3 fatty acids and diacylglycerol O-acyltransferase inhibitor 1 (DGAT1) inhibitor (A-922500) counteracted the ANGPTL4-ETV4 axis-induced lipogenesis in vitro, and in vivo in obese mice via activation of GPR120-βarrestin2-AMPK pathway. Finally, we demonstrate that targeted pharmacologic therapy using GalNac-ETV4 siRNA that specifically inhibits ETV4 gene expression in the liver protects against diet-induced NAFLD, obesity and dyslipidemia. Hence, our study reveal previously unrecognized role of ETV4 in the NAFLD, and provides rationale targeting ETV4 to treat NAFLD.

There is a clinical need for a simple test implementable at the primary point of care to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) in the population. Blood plasma samples from adult patients with varying phenotypes of MASLD were used to identify a minimal set of lipid analytes reflective of underlying histologically confirmed MASLD. Samples were obtained from the NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database prospective cohort study (MASLD group; N = 301). Samples of control subjects were obtained from cohort studies at the University of California San Diego (control group; N = 48). Plasma samples were utilized for targeted quantitation of circulating eicosanoids, related bioactive metabolites, and polyunsaturated fatty acids by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) lipidomics analysis. Bioinformatic approaches were used to discover a panel of bioactive lipids that can be used as a diagnostic tool to identify MASLD. The final panel of fifteen lipid metabolites consists of 12 eicosanoid metabolites and 3 free fatty acids that were identified to be predictive for MASLD by multivariate area under the receiver operating characteristics curve (AUROC) analysis. The panel was highly predictive for MASLD with an AUROC of 0.999 (95% CI = 0.986-1.0) with only one control misclassified. A validation study confirmed the resulting MASLD LIPIDOMICS SCORE, which may require a larger-scale prospective study to optimize. This predictive model should guide the development of a non-invasive "point-of-care" test to identify MASLD patients requiring further evaluation for the presence of metabolic dysfunction-associated steatohepatitis.

Introduction: Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), especially in patients with comorbid diabetes and obesity. This study investigated the effects of GLP-1RAs on hepatic steatosis and fibrosis in patients with MASLD, as measured by changes in vibration-controlled transient elastography (VCTE) and other clinical parameters in a real-world clinical setting. Methods: We conducted a single-center, retrospective analysis of 96 patients with MASLD from a multidisciplinary care clinic who completed VCTE at baseline and follow-up within 6-24 months to compare changes in controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as well as other metabolic markers, between GLP-1RA users and nonusers using two-sample t-tests and Wilcoxon rank-sum tests. We also assessed whether improvements in hepatic steatosis, defined as a change in CAP >38 dB/m as previously described in the literature, were associated with improvement in fibrosis. Results: GLP-1RA use resulted in significant improvements in weight (-8.1 kg vs. -3.5 kg, P = 0.009), body mass index (BMI) (-2.9 kg/m2 vs. -1.3 kg/m2, P = 0.012), alanine aminotransferase (-15.0 IU/L vs. -4.0 IU/L, P = 0.017), aspartate aminotransferase (-5.0 IU/L vs. -1.0 IU/L, P = 0.021), glycated hemoglobin (HbA1c) (-0.7% vs. 0.1%, P = 0.019), and CAP (-59.9 dB/m vs. -29.1 dB/m, P = 0.016). Responders also had significant improvements in weight (-9.2 kg vs. -1.9 kg, P < 0.001), BMI (-3.3 kg/m2 vs. -0.7 kg/m2, P < 0.001), diastolic blood pressure (-6.1 mmHg vs. -0.7 mmHg, P = 0.028), HbA1c (-0.8% vs. 0.3%, P < 0.001), and LSM (-1.5 kPa vs. 0.1 kPa, P < 0.001). Conclusions: Patients with MASLD treated with GLP-1RAs showed significant improvements in hepatic steatosis and multiple other metabolic parameters, with weight loss as the proposed mechanism for this liver improvement. In addition, change in CAP >38 dB/m was associated with improvements in LSM and other metabolic parameters, suggesting the clinical utility of VCTE in the surveillance of MASLD.

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCS) constitute a functional communication platform for ER and mitochondria, and they play a crucial role in the lipid homeostasis of the liver. However, it remains unclear about the exact effects of MERCs on the neutral lipid synthesis of the liver.

In this study, the role and mechanism of MERCS in palmitic acid (PA)-induced neutral lipid imbalance in the liver was explored by constructing a lipid metabolism animal model based on yellow catfish. Given that the structural integrity of MERCS cannot be disrupted by the si-mitochondrial calcium uniporter (si-mcu), the MERCS-mediated Ca2+ signaling in isolated hepatocytes was intercepted by transfecting them with si-mcu in some in vitro experiments.

The key findings were: (1) Hepatocellular MERCs sub-proteome analysis confirmed that, via activating Ip3r-Grp75-voltage-dependent anion channel (Vdac) complexes, excessive dietary PA intake enhanced hepatic MERCs. (2) Dietary PA intake caused hepatic neutral lipid deposition by MERCs recruiting Seipin, which promoted lipid droplet biogenesis. (3) Our findings provide the first proof that MERCs recruited Seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling, apart from MERCs's structural integrity. Noteworthy, our results also confirmed these mechanisms are conservative from fish to mammals.

The findings of this study provide a new insight into the regulatory role of MERCS-recruited SEIPIN in hepatic lipid synthesis via Ip3r-Grp75-Vdac complex-mediated Ca2+ signaling, highlighting the critical contribution of MERCS in hepatic lipid homeostasis.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing globally. MASLD is characterized by clinically significant liver steatosis, and a subset of patients progress to more severe metabolic-disorder-associated steatohepatitis (MASH) with liver inflammation and fibrosis. Cannabinoid receptor 1 (CB1) antagonism is a proven therapeutic strategy for the treatment of the phenotypes that underlie MASLD, though work on early centrally penetrant compounds largely ceased following adverse psychiatric indications in humans. We present here preclinical testing of a CB1 neutral antagonist, N-[1-[8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4l]methanesulfonamide (RTI-348), with minimal brain exposure when administered to mice. In a diet-induced model of MASLD-induced MASH, administration of RTI-348 decreased the total body and liver weight gain. Animals treated with RTI-348 showed reduced steatosis. Furthermore, they produced lower plasma alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), biomarkers associated with liver damage. Mice maintained on the MASH diet had elevated expression of genes associated with profibrogenesis, immune response, and extracellular matrix remodeling, and treatment with RTI-348 mitigated these diet-induced changes in gene expression. Using an intracranial electrical self-stimulation model, we also demonstrated that RTI-348 does not produce an anhedonia response, as seen with the first-generation CB1 inverse agonist rimonabant. Altogether, the results herein point to RTI-348 as a promising neutral antagonist for MASH.

Steatotic liver disease (SLD) is the most common chronic liver disease strongly associated with metabolic dysfunction, but its pathogenesis remains incompletely understood. Exploring plasma circulating metabolites may help in elucidating underlying mechanisms and identifying new biomarkers for SLD.

We examined cross-sectionally the association between plasma metabolites and SLD as well as liver enzymes using data from 4 population-based cohort studies (Rotterdam study, Avon Longitudinal Study of Parents and Children, The Insulin Resistance Atherosclerosis Family Study, and Study of Latinos). Metabolites were assessed in the Nightingale platform (n = 225 metabolites) by nuclear magnetic resonance spectroscopy and in the Metabolon platform (n = 991 metabolites) by ultra-high-performance liquid chromatography-mass spectrometry. Serum levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase) were measured and SLD was diagnosed by ultrasound or computed tomography scan. Logistic and linear regression models were performed per cohort and meta-analyzed. A false discovery rate < 0.05 was considered as significant threshold.

Several metabolites were significantly associated with SLD and liver enzymes, of which 21 metabolites were associated with both traits. The most significant associations were observed with phenylalanine, triglycerides in (high-density lipoprotein, intermediate-density lipoprotein, and small low-density lipoprotein), fatty acid (FA) ratios of (18:2 linoleic acid-to-total FA, omega 6 FA-to-total FA, and polyunsaturated FA-to-total FA) from the Nightingale and glutamate and sphingomyelin from the Metabolon platform. Other associated metabolites were mainly involved in lipid, amino acid, carbohydrates, and peptide metabolism.

Our study indicates a landscape of circulating metabolites associated with SLD. The identified metabolites may contribute to a better understanding of the metabolic pathways underlying SLD and hold promising for potential biomarkers in early diagnosis and monitoring of the disease.

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.

This study aimed to develop and validate a clinical model for predicting the risk of nonalcoholic fatty liver disease (NAFLD) by using data from a cross-sectional study. This investigation utilized data from the Dryad database and employed multivariable logistic regression analysis, restricted cubic spline, and nomogram analysis to achieve comprehensive insights. The discrimination and calibration of the nomogram were evaluated using the receiver operating characteristic curve and calibration plot. A total of 1072 patients were included in the study, including 456 with non-NAFLD and 616 with NAFLD. Significant differences were observed in terms of sex, body mass index (BMI), tobacco, hypertension, diabetes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST ratio, uric acid (UA), fasting blood glucose (FBG), triglyceride (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, and diastolic blood pressure (P < .05 for all comparisons). Multivariable logistic regression analysis indicated that sex, BMI, diabetes, ALT/AST ratio, UA, FBG, and TG were associated with an increased risk of NAFLD. Restricted cubic spline indicated a nonlinear relationship between the risk of NAFLD and variables including ALT/AST ratio, FPG, TG, and UA (P for nonlinearity < .01). The variables in the nomogram included BMI, diabetes, ALT/AST ratio, UA, FBG, and TG. The value of area under the curve was 0.790, indicating that the nomogram prediction model exhibited significant discriminatory accuracy. A reliable clinical model for predicting the risk of NAFLD was developed using readily available clinical data. The model can assist clinicians in identifying individuals with an increased risk of NAFLD, enabling early interventions for preventing and managing this prevalent liver disease.

Exposure to fine particulate matter (PM2.5) is a significant risk factor for hepatic steatosis. The N6-methyladenosine (m6A) is implicated in metabolic disturbances triggered by exogenous environmental factors. However, the role of m6A in mediating PM2.5-induced hepatic steatosis remains unclear. Herein, male C57BL/6J mice were subjected to PM2.5 exposure throughout the entire heating season utilizing a real-ambient PM2.5 whole-body inhalation exposure system. Concurrently, HepG2 cell models exposed to PM2.5 were developed to delve the role of m6A methylation modification. Following PM2.5 exposure, significant hepatic lipid accumulation and elevated global m6A level were observed both in vitro and in vivo. The downregulation of YTHDC2, an m6A-binding protein, might contribute to this alteration. In vitro studies revealed that lipid-related genes CEPT1 and YWHAH might be targeted by m6A modification. YTHDC2 could bind to CDS region of them and increase their stability. Exposure to PM2.5 shortened mRNA lifespan and suppressed the expression of CEPT1 and YWHAH, which were reversed to baseline or higher level upon the enforced expression of YTHDC2. Consequently, our findings indicate that PM2.5 induces elevated m6A methylation modification of CEPT1 and YWHAH by downregulating YTHDC2, which in turn mediates the decrease in the mRNA stabilization and expression of these genes, ultimately resulting in hepatic steatosis.

Metabolic dysfunction associated fatty liver disease (MAFLD) is a common cause of liver disease in children and adolescents. The relationship between insulin resistance (IR) and MAFLD in children with short stature remains largely unknown. The present study was to investigate the relationship between the triglyceride-glucose (TyG) index and alanine aminotransferase (ALT) levels in children with short stature. A total of 1754 children with short stature were enrolled. Anthropometric, biochemical and hormonal indexes were collected through physical measurement examinations and laboratory tests. A nonlinear association was found between the TyG index and ALT. The inflection point of the curve was at a TyG index of 8.24. In multivariate piecewise linear regression, only when the TyG index was greater than 8.24 was there a significant positive association between the TyG index and ALT (β 5.75, 95% CI 3.30, 8.19; P < 0.001). However, when the TyG index was less than 8.24, there was no significant association between the TyG index and ALT (β -0.57, 95% CI -1.84, 0.71; P = 0.382). This study demonstrated a nonlinear relationship between TyG index and ALT in children with short stature. This finding suggests that a high TyG index is associated with elevated ALT in children with short stature.

Non-alcoholic steatohepatitis (NASH) has emerged as a significant global health concern, closely linked to the obesity epidemic and metabolic syndrome. This review explores emerging therapies for NASH that go beyond traditional lifestyle modifications. The complex pathophysiology of NASH, involving insulin resistance, lipotoxicity, oxidative stress, and chronic inflammation, offers multiple targets for therapeutic intervention. While lifestyle changes remain fundamental, their limitations in achieving sustained improvements highlight the need for effective pharmacological and interventional therapies. This review discusses novel pharmacological approaches, including farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, and agents addressing metabolic dysfunction, inflammation, and fibrosis. Promising candidates such as obeticholic acid, lanifibranor, and semaglutide are highlighted, along with combination therapies targeting multiple pathways simultaneously. Non-pharmacological interventions, including bariatric surgery, endoscopic bariatric and metabolic therapies, and innovative exercise regimens, are also examined for their potential in NASH management. Despite significant advancements, NASH drug development faces challenges due to the disease's complexity, patient heterogeneity, and stringent regulatory requirements. This review also addresses these limitations and explores future directions, including personalized medicine approaches, non-invasive diagnostic tools, and the potential of microbiome modulation and regenerative therapies. The evolving landscape of NASH research emphasizes the need for multidisciplinary approaches integrating advances in diagnostics, therapeutics, and digital health technologies. As the field progresses, the focus remains on developing more effective, personalized, and accessible strategies for preventing, diagnosing, and treating NASH, with the ultimate goal of improving outcomes for patients affected by this increasingly prevalent liver disease.