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 and determine triglyceride content within the cells per group. The data showed that knockdown of ESRRA led to down-regulation of the expressions of SREBP-1, ACC1, FAS and triglyceride content. Meanwhile, knockdown of ESRRA and miR-125b-5p resulted that the expressions of ESRRA, SREBP-1, ACC1, FAS and triglyceride content rebounded.

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

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as an important public health concern that poses a significant threat to human health and imposes a substantial economic burden. Research has demonstrated that ubiquitin ligase-mediated substrate protein ubiquitination is a pivotal factor influencing liver lipid homeostasis and metabolic abnormalities in MAFLD. Nevertheless, the specific enzyme molecules implicated in this regulatory process remain to be elucidated. We have published a transcriptome-overexpressing ubiquitin ligase, membrane-associated ring-CH-type finger 2 (MARCH2), in HepG2 cells, and subsequent reanalysis of these transcriptome data revealed a close association between MARCH2 and lipid metabolism.

By employing a range of methodologies, including recombinant adeno-associated virus (rAAV) transduction, lentiviral transduction, immunoblotting, quantitative PCR, tissue section staining, ubiquitination assays, serum biochemical analysis, immunoprecipitation, and mass spectrometry, this study investigated the functions and mechanisms of MARCH2 in the progression of MAFLD at the molecular, cellular, and organismal levels.

Overexpression of MARCH2, but not its catalytically inactive ligase variant, inhibited lipid accumulation in HepG2 cells. Additionally, MARCH2 undergoes K48-linked self-polyubiquitination and subsequent proteasomal degradation in response to oleic acid/palmitic acid stimulation. Furthermore, knockout of MARCH2 exacerbates the progression of MAFLD-related phenotypes, including increased body weight, impaired glucose tolerance, reduced insulin sensitivity, hypercholesterolemia, hepatic lipid accumulation, and steatosis, in high-fat diet-fed mice, irrespective of sex. Mechanistically, MARCH2 facilitates the polyubiquitination and degradation of fatty acid synthase (FASN) in the de novo lipogenesis pathway. And liver-specific overexpression of MARCH2 by rAAV effectively reduces FASN levels and further ameliorates MAFLD in ob/ob mice.

MARCH2 undergoes self-ubiquitination and plays an important role in maintaining the liver lipid homeostasis of MAFLD, and drug intervention in the MARCH2-FASN axis is a promising approach for treating systemic metabolic abnormalities in MAFLD.

Fatty liver disease, a growing global health issue, is closely tied to metabolic disorders. The 2023 definition of metabolic-associated steatotic liver disease (MASLD) incorporates cardiometabolic risk factors, but the potential role of persistent organic pollutants (POPs) like polychlorinated biphenyls (PCBs), remains underexplored. Investigating the impact of environmental toxins on liver health is crucial for understanding emerging public health risks.

1080 participants were included from the 1999-2018 National Health and Nutrition Examination Survey (NHANES). We employed weighted generalized linear models, weighted quantile sum regression, and Bayesian kernel machine regression to assess the relationship between serum PCB levels and MASLD, with NAFLD included for comparison. Protein interaction and enrichment analyses were also conducted to explore the underlying mechanisms.

PCB146, PCB156, PCB187, PCB174, and PCB180 were significantly associated with an increased MASLD risk in the GLM. Significant positive associations were found between serum PCB mixtures and MASLD in the WQS model (β: 0.411, p: 0.0056) and BKMR model (p < 0.05), with PCB180 contributing the most (β: 0.644, PIP: 0.903). NAFLD did not show significant associations. Network pharmacological analysis demonstrated enrichment in the regulation of lipolysis of adipocytes and the cAMP signaling pathway, and PPAR-γ and MAOA show significant importance in the protein-protein interaction networks.

This study underscores the epidemiological and mechanical link between MASLD and PCB exposure, highlighting the superiority of MASLD in identifying the impact of POPs on liver disease risk and particularly identifying PCB180 as a sentinel marker for PCB surveillance.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial chronic condition that requires a systematic approach for effective management. Multi-effect therapeutic drugs derived from traditional Chinese medicine are increasingly being recognized as promising alternatives for NAFLD intervention. Hyperoside, a natural flavone glycoside found in Cuscuta chinensis Lam, Forsythia suspensa, and Crataegus pinnatifida Bge, has been shown to effectively mitigate NAFLD in rats. However, the underlying mechanism through which hyperoside alleviates NAFLD remains unclear.

This study aims to explore the specific mechanisms by which hyperoside intervenes in the progression of NAFLD.

In this study, a high-fat diet was used to induce the NAFLD model in rats. An integrated analysis, including mass spectrometry-based lipidomics, TMT-based proteomics, 16S rRNA sequencing, and bile acid-targeted metabolomics, was employed to identify significantly altered metabolites and proteins. Western blotting, molecular docking, and isothermal titration calorimetry were conducted to analyze the direct targets of action.

The results indicate that hyperoside activates farnesoid X receptor (FXR), promoting fatty acid oxidation and the efflux of bile acids from the liver. Additionally, hyperoside inhibits hepatic ATP citrate lyase (ACLY) and works synergistically with activated FXR to suppress de novo lipogenesis. Hyperoside also inhibits intestinal microbes linked to bile-salt hydrolase (BSH) activity, which enhances the production of ileal bile acids (BAs), particularly conjugated BAs, thus reducing the liver toxicity of endogenous BAs.

Our findings suggest that hyperoside alleviates NAFLD by modulating fatty acid and bile acid metabolism through FXR and ACLY, suggesting its potential as a multi-effect candidate drug for the treatment of NAFLD.

Genes play an important role in regulating insulin signaling, adipokines, oxidative stress, lipid metabolism, and inflammation in susceptibility and progression of Metabolic dysfunction-associated steatotic liver disease (MASLD). Among various genes, the LepR gene influences insulin sensitivity and controls lipid metabolism, contributing to the development of MASLD. Our previous study reported that a novel congenic mouse (WSB.db) with a LepR mutation exhibited resistance to MASLD. To further evaluate this strain for resistance, we fed this new mouse strain with LepR mutation and B6.db mice, the mouse model of metabolic disease with a high-fat diet as a second hit for 12 weeks and evaluated the pathophysiology, serum biochemistry, Quantitative real-time polymerase chain reaction (qPCR) to determine the expression of specific genes involved in the development of fatty changes in the liver and hepatic transcriptome signatures in liver tissue. In contrast to db/db (B6.db) mice, which exhibited all the pathological hallmarks for MASLD, the LepR mutant congenic strain was still resistant to developing liver steatosis. Transcriptome analysis with KEGG PATHWAY: hsa04932 revealed significant upregulation of AMPKγ3 and MApk10 (JNK3) in WSB.db mice, suggesting that congenic mice with the LepR mutation are resistant to MASLD without the liver pathology to effect. These results propose that the LepR mutation has a different impact on liver pathology depending on genetic background, indicating upregulation of specific genes in the development of MASLD. This study will facilitate the identification of therapeutic targets against MASLD with LepR mutation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic and progressive liver disease with an increasing global burden that starts with an early stage of simple steatosis (MASL) which frequently progresses to liver cirrhosis and hepatocellular carcinoma (HCC). Despite its widespread occurrence, the MASL or steatotic stage, characterized by excessive fat accumulation in the liver and considered reversible and benign, has not been extensively studied. To study MASL effectively, it is imperative to have a clinically relevant model system that focuses solely on steatosis, in a progressive and time-dependent manner, recapitulating molecular changes associated with human disease. We established a chronic cellular model of MASL using a primary immortalized human hepatocyte cell line treated with a low dose mixture of fatty acids. This model mimics the pattern of chronic disease progression, shows minimal lipotoxicity, exhibits progressive lipid accumulation (from early to moderate steatosis), and demonstrates macrosteatosis, a hallmark of MASL. To determine whether this model recapitulates both morphological and molecular aspects of steatosis, we measured the expression of key genes and pathways found to be dysregulated in a recently available early MASL patient dataset as well as a non-human primate model of MASL. In support of the relevance of our model, we observed increased fatty acid uptake, lipogenesis, mitochondrial activity, metabolic rewiring, and autophagic alterations that significantly overlap with the pathological features of human and non-human primate MASL. In conclusion, we generate a relevant cellular model of steatosis that can serve as a robust platform for screening of existing chemical libraries to identify potent inhibitors of MASL as well as discovering novel therapeutic targets by mechanistically studying altered molecular signatures associating early stages of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.

Global hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in human MASLD patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different strategies substantially alleviated MASLD progression. Knockout (KO) of TET1 slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, and CD36 were significantly decreased upon TET1 depletion. Consistently, liver specific TET1 KO led to improvement of MASLD progression. Mechanistically, TET1 promoted CD36 expression through transcriptional upregulation via DNA demethylation control. Overexpression of CD36 reversed the impacts of TET1 downregulation on fatty acid uptake in hepatocytes. More importantly, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Conclusively, liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.

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.

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.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.

There is a growing consensus on addressing the global plastic pollution problem by advocating for bioplastics. While starch-based plastics are prevalent, the potential health implications of starch-based microplastics (SMPs) remain largely unexplored. This is particularly concerning given their potential for accidental ingestion and subsequent interference with blood glucose metabolism. Our research provides the first investigation into the distribution and adverse effects of long-term exposure to environmentally relevant doses of SMPs in female mice, approximately 14-81 particles per mouse per day. After three months of exposure, SMPs were found to infiltrate the liver, intestine, and ovarian tissues, causing microstructural lesions. Exposure to SMPs also resulted in elevated blood glucose levels, increased hepatic oxidative stress, and disrupted lipid metabolism. A multiomics analysis further uncovered abnormalities in gene expression and microbiota, as well as enriched pathways related to insulin regulation and circadian rhythms in the exposed mice. Our results indicate that prolonged exposure to environmentally relevant doses of SMPs can have widespread health effects in mice, potentially disrupting circadian rhythms by inducing insulin resistance. This suggests that the safety of bioplastics requires further evaluation before their large-scale application in food packages.

Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.Study underscores sotagliflozin's potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.

This review aims to summarize the current scientific understanding on the complex interplay between sterol regulatory element-binding proteins (SREBPs) and metabolic dysfunction associated steatotic liver disease (MASLD) by critically examining a few significant molecular pathways. Additionally, the review explores the potential of both natural and synthetic SREBP inhibitors as promising therapeutic candidates for MASLD.

SREBPs are central regulators of lipid homeostasis, with SREBP-1c primarily controlling fatty acid synthesis and SREBP-2 regulating cholesterol metabolism. Dysregulation of SREBP activity, often triggered by excessive caloric intake, insulin resistance, or endoplasmic reticulum (ER) stress, contributes to the development of metabolic syndrome and MASLD. SREBP-1c overexpression leads to increased de novo lipogenesis (DNL), hepatic lipid accumulation, and insulin resistance, while SREBP-2 modulates cholesterol metabolism via miRNA-33 and ABCA1 regulation leading to the pathogenesis of MASLD. The PI3K-Akt-mTORC1 pathway plays a critical role in SREBP activation, linking nutrient availability to lipid synthesis. Synthetic SREBP inhibitors, such as fatostatin and 25-hydroxycholesterol, and natural compounds, including kaempferol and resveratrol, show promise in modulating SREBP activity in vivo.

While targeting SREBP pathways presents a promising avenue for mitigating MASLD, further scientific investigation is imperative to identify and validate potential molecular targets. Although current studies on synthetic and natural SREBP inhibitors demonstrate encouraging results, rigorous pre-clinical and clinical research is warranted to translate these findings into effective MASLD treatments.

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.

Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern that is closely linked to metabolic syndrome, yet no approved pharmacological treatment exists. The Mediterranean diet (MD) emerged as a first-line dietary intervention for NAFLD, offering metabolic and hepatoprotective benefits. Now conceptualized as a complex chemical matrix rich in bioactive compounds, the MD exerts antioxidant and anti-inflammatory effects, improving insulin sensitivity and lipid metabolism. Mitochondria play a central role in NAFLD pathophysiology, influencing energy metabolism, oxidative stress, and lipid homeostasis. Emerging evidence suggests that the MD's bioactive compounds enhance mitochondrial function by modulating oxidative phosphorylation, biogenesis, and mitophagy. However, most research has focused on individual compounds rather than the MD as a whole, leaving gaps in understanding its collective impact as a complex dietary pattern. This narrative review explores how the MD and its bioactive compounds influence mitochondrial health in NAFLD, highlighting key pathways such as mitochondrial substrate control, dynamics, and energy efficiency. A literature search was conducted to identify relevant studies on the MD, mitochondria, and NAFLD. While the search was promising, our understanding remains incomplete, particularly when current knowledge is limited by the lack of mechanistic and comprehensive studies on the MD's holistic impact. Future research integrating cutting-edge experimental approaches is needed to elucidate the intricate diet-mitochondria interactions. A deeper understanding of how the MD influences mitochondrial health in NAFLD is essential for developing precision-targeted nutritional strategies that can effectively prevent and manage the disease.

Lipids play crucial roles in various biological functions and diseases. However, a gap exists in databases providing information of lipids functions based on curated information. Consequently, LipidFun is purposed as the first lipid function database with sentence-level evidence detailing lipid-related phenotypes and biological functions.

Potential lipid functions were extracted from the biomedical literature using natural language processing techniques, with accuracy and reliability ensured through manual curation by four domain experts. LipidFun constructs classification systems for lipids, biological functions, and phenotypes for named entity recognition. Sentence-level evidence is extracted to highlight connections to lipid-associated biological processes and diseases. Integrating these classification systems and a large amount of sentence-level evidence allows LipidFun to provide an overview of lipid-phenotype and lipid-biological function associations through concise visualizations. Overall, LipidFun unravels the relationships between lipids and biological mechanisms, underscoring their overarching influence on physiological processes.

LipidFun is available at https://lipidfun.bioinfomics.org/.

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.

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.

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.

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.

Pterocarpus soyauxii (P. soyauxii) is a Fabaceae family traditionally used to treat menopausal disorders. This study aims to investigate the effect of P. soyauxii on menopause-related non-alcoholic fatty liver disease (NAFLD) and to determine its mechanisms of action and signaling pathways. The pharmacokinetic and dynamic properties and the toxicological profile of P. soyauxii compounds were assessed using the SwissADME and Protox III databases. A pharmacology network was constructed to identify active compound targets and corresponding genes. Compound target and protein-protein interaction networks were created using Cytoscape software. Molecular docking studies were conducted to assess the binding affinity of P. soyauxii compounds with specific proteins. In vitro experiments evaluated the antioxidant properties of P. soyauxii. In vivo studies using ovariectomized (Ovx) rat models underlined pathways and effects of P. soyauxii on biochemical and histological features linked with NAFLD. Findings suggest that P. soyauxii compounds are readily absorbed through the intestine and exhibit a relatively low level of toxicity. Protein-protein interaction, compound-target networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed several pathways and target proteins of P. soyauxii compounds. Indeed, they target specific proteins such as estrogen receptor alpha/beta ERα/β, nicotinamide adenine dinucleotide phosphate oxidase (NADPH-O), epidermal growth factor receptor (EGFR), MAPK1, peroxisome proliferator-activated receptors alpha/gamma (PPARα/G), and HMG-CoA reductase. Molecular docking revealed that P. soyauxii compounds demonstrate high binding affinity to various proteins. In vitro, P. soyauxii inhibits the oxidative power of OH, H2O2, and NO. In vivo, P. soyauxii significantly (p < 0.01, p < 0.001, and p < 0.01, respectively) reduces ALAT (25.14%), hepatic cholesterol (15.27%), and malondialdehyde (MDA) (26.78%) levels at 200 mg/kg and prevents steatosis in the liver. These findings suggest that P. soyauxii may have a protective role against menopause-related NAFLD.

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.

Cholelithiasis is a common biliary system disease with a high incidence worldwide. Abnormal lipid metabolism has been shown to play a key role in the mechanism of gallstones. Therefore, recent research literature on the genes, proteins, and molecular substances involved in lipid metabolism during the pathogenesis of gallstones has been conducted. This study aimed to determine the role of lipid metabolism in the pathogenesis of gallstones and provide insights for future studies using previous research in genomics, metabolomics, transcriptomics, and other fields.

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.

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.

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.

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.