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.

A healthy diet has been recommended for non-alcoholic fatty liver disease (NAFLD). We aim to investigate the associations of diet quality indices with the risk of developingmetabolic-associated fatty liver disease (MAFLD).

We conducted this nested case-control study by recruiting 968 cases with MAFLD and 964 controls from the participants of the baseline phase of the Sabzevar Persian Cohort Study (SPCS). MAFLD was defined as having a fatty liver index ≥ 60 plus at least one of the following: overweight or obese, Type II diabetes mellitus, or evidence of metabolic dysregulation. Healthy Eating Index-2015 (HEI-2015) and Alternative Healthy Eating Index-2010 (AHEI-2010) were calculated from a validated food frequency questionnaire. We estimated the associations of HEI-2015 and AHEI-2010 with MAFLD risk using multivariable logistic regression.

Among those in the highest relative to the lowest quintile of HEI-2015 and AHEI-2010, the multivariable-adjusted odds ratios (OR) were 0.45 (95% CI [confidence interval] 0.29-0.69; P trend = 0.002) and 0.55 (95% CI 0.35-0.85; P trend = 0.04), respectively.

The results of our study suggest that there is a significant associationbetween adherence to a healthy diet, indicated by a higher score of HEI or AHEI, and a reduced likelihood of developingMAFLD.

The online version contains supplementary material available at 10.1007/s40200-024-01544-x.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play a crucial role in the genetic regulation of lipid metabolism and energy homeostasis. There is increasing evidence to suggest that PPARs may have a significant impact on the development and progression of acne, including its role in regulating lipid production, inhibiting keratinocyte proliferation, and reducing acne-related inflammation. As such, PPARs present themselves as promising therapeutic targets for both the prevention and treatment of acne. This article provides an overview of the role of PPARs in the pathological processes underlying acne, with particular emphasis on inflammation and lipid regulation.

The prevalence of obesity has reached epidemic proportions worldwide, posing a significant public health concern due to its association with various chronic diseases and healthcare costs. In addition to traditional risk factors such as diet and physical activity, emerging evidence suggests that environmental pollutants, termed obesogens, may contribute to the obesity epidemic. Obesogens are endocrine-disrupting chemicals (EDCs) that can alter lipid homeostasis, promote adipogenesis, and disrupt metabolic regulation, leading to increased adiposity and obesity risk. This review explores available data from human studies published in the last decade, along with the mechanisms underlying obesogenic action, including their effects on adipocyte differentiation, adipose tissue development, and metabolic regulation. Overall, 75 studies were analyzed. Early-life exposure during critical developmental windows has been shown to increase obesity risk later in life, potentially through epigenetic modifications and transgenerational effects. Epidemiological studies provide evidence of associations between prenatal or early-life exposure and increased obesity risk in offspring. Additionally, study found more consistent associations between exposure to some EDCs (including phthalates, parabens, and bisphenols) and obesity or metabolic outcomes in children and women, while results for other chemicals (i.e. PFAS and organochlorine pesticides) were more heterogeneous, especially in adolescents and adults. Key findings indicate consistent associations between phthalate exposure and obesity in children, with mixed results for adults. Future research should focus on elucidating the full spectrum of obesogens, their mechanisms of action, and their implications for obesity risk across generations. This knowledge will inform preventive strategies and public health interventions aimed at addressing the obesity epidemic and its associated health burden.

Pemafibrate helps regulate fatty acid dynamics in the liver, potentially preventing metabolic dysfunction-associated steatohepatitis (MASH). However, its effect on intestinal long-chain fatty acid (LCFA) metabolism in MASH remains unclear. Thus, we aimed to examine the influence of pemafibrate on intestinal LCFA metabolism and hepatic fibrosis in a MASH rat model.

Sprague-Dawley rats were fed a high-fat and high-cholesterol diet to induce MASH and then divided into pemafibrate-treated (pemafibrate (+)) and untreated (pemafibrate (-)) groups. Triglyceride deposition in the small intestine and fibrosis, along with α-smooth muscle actin level in the liver, were evaluated. Furthermore, the mRNA expression levels of genes associated with lipid metabolism in the small intestine and markers of fibrosis and hepatic stellate cells activation in the liver were measured.

The pemafibrate-treated group had markedly lower triglyceride deposition and lipid absorption in the intestine, and significantly lower levels of molecules involved in intestinal lipid regulation than the pemafibrate-untreated group. Moreover, hepatic fibrosis significantly improved, and the mRNA levels of fibrosis-related molecules and hepatic stellate cell activation factors significantly decreased in the pemafibrate-treated compared with those in the pemafibrate-untreated group.

Pemafibrate reduced lipid droplet formation and LCFA absorption in the intestinal tract and alleviated hepatic fibrosis in MASH model rats.

Disorders of lipid metabolism, including hyperlipidemia, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease, are increasing across the globe. Bempedoic acid (BPA) is a first-in-class drug for the treatment of hypercholesterolemia and cardiac risk reduction, which may particularly benefit those who do not tolerate statins. Inhibition of hepatic ATP-citrate lyase (ACLY) is widely accepted as the main mediator of its observed clinical effects. However, BPA treatment also has ACLY-independent effects on lipid metabolism, as the structural similarity of BPA to endogenous fatty acids allows it to trigger multiple lipid-signaling pathways. Here, we review the molecular targets of BPA and related 'decoy fatty acid' drugs and identify areas where further study is warranted as these molecules are evaluated for clinical indications.

Inonotus obliquus (Fr.) Pilát, a traditional medicinal fungi, has been used to treat diabetes in China and Russia since the 16th century. Recent studies show Inonotus obliquus (Fr.) Pilát polysaccharides (IOP) have hypoglycemic and lipid-lowering effects in type 2 diabetes mellitus (T2DM) mice and can recover liver insulin resistance.

This study aims to assess the effect of IOP and its mechanisms in ameliorating insulin resistance and lipid metabolism disorders in T2DM.

The potential targets of IOP for T2DM were identified by network pharmacology and molecular docking. In vitro, an insulin resistance model in C2C12 cells was induced, and IOP's effects on glucose uptake, glycogen, lipid content, and lipid metabolism-related mRNAs were assessed. In vivo, a T2DM mice model was established. Blood glucose, lipids, glucose tolerance, and insulin sensitivity were evaluated. Histopathology was used to assess morphological changes in mice skeletal muscle. Western blotting was utilized to evaluate the expression levels of PI3K/AKT and AMPK/ACC1/CPT1 signaling pathway proteins both in vivo and in vitro.

Network pharmacology results showed IOP and T2DM targets were enriched in PI3K/AKT, insulin resistance, and lipid metabolism pathways. Cell experiments showed IOP enhanced glucose uptake and glycogen content, reduced lipid content, and improved lipid deposition in insulin-resistant C2C12 cells. Animal experiments showed IOP improved hyperglycemia and hyperlipidemia, enhanced glucose tolerance and insulin sensitivity, and reduced insulin resistance in T2DM mice. Western blot showed IOP activated PI3K/AKT and AMPK/ACC1/CPT1 pathways, promoting GLUT4 expression and translocation, and GSK3β phosphorylation.

In summary, the results indicated that IOP was able to ameliorate lipid-induced skeletal muscle insulin resistance in T2DM. The mechanism may be related to the PI3K/AKT and AMPK/ACC1/CPT1 signaling pathways.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key target for metabolic disorders that contribute to obesity and type 2 diabetes mellitus (T2DM). However, full agonists such as thiazolidinediones (TZDs) have limitations in terms of side effects. Selective PPARγ modulators (SPPARγMs) that target alternative binding pockets offer the potential for safer partial agonists. Here, we employed six computational algorithms (Fpocket, DeepSite, CavityPlus, DoGSiteScorer, CASTpFold, POCASA) to identify a novel allosteric pocket (pocket 6-5) in the PPARγ ligand-binding domain (LBD), localized at the helix 3 (H3), helix 2 (H2), helix 2'(H2'), and β-sheet interface. A virtual screening of 4,097 natural compounds from traditional Chinese medicine (TCM) libraries was conducted, which led to the identification of ginsenoside Rg5 (TWSZ-5) as a top hit. Molecular docking and molecular dynamics (MD) dynamics revealed TWSZ-5 stabilizes pocket 6-5 through hydrogen bonds with Ser342, Gln345, Lys261, and Lys263. TWSZ-5 promoted beige adipocyte differentiation in adipose-derived stem cells (ADSCs) in vitro, upregulating Ucp1, Prdm16, Cpt1α, and Pgc1α. The present study identifies TWSZ-5 as a novel SPPARγM that utilizes an allosteric binding pocket to enhance thermogenesis while mitigating adverse effects. These findings emphasize the potential of TCM derivatives and structure-based screening strategies to develop safer antidiabetic therapies with precision pharmacology.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1-4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases.

Metabolic aberrations are fundamental to the complex pathophysiology and challenges associated with diabetic wound healing. These alterations, induced by the diabetic environment, trigger a cascade of events that disrupt the normal wound-healing process. Key factors in this metabolic alternation include chronic hyperglycemia, insulin resistance, and dysregulated lipid and amino acid metabolism. In this review, we summarize the underlying mechanisms driving these metabolic changes in diabetic wounds, while emphasizing the broad implications of these disturbances. Additionally, we discuss therapeutic approaches that target these metabolic anomalies and how their integration with existing wound-healing treatments may yield synergistic effects, offering promising avenues for innovative therapies.

Diabetic kidney disease (DKD) is one of the major complications of diabetes, and its pathological progression is closely associated with lipid metabolic reprogramming. Under diabetic conditions, renal cells undergo significant lipid metabolic abnormalities, including increased lipid uptake, impaired fatty acid oxidation, disrupted cholesterol efflux, and enhanced lipid catabolism, as adaptive responses to metabolic stress. These changes result in the accumulation of lipids such as free fatty acids, diacylglycerol, and ceramides, leading to lipotoxicity that triggers inflammation and fibrosis. Hypoxia in the DKD microenvironment suppresses fatty acid oxidation and promotes lipid synthesis through the HIF-1α pathway, while chronic inflammation exacerbates lipid metabolic disturbances via inflammatory cytokines, inflammasomes, and macrophage polarization. Targeting lipid metabolism represents a promising therapeutic strategy for alleviating DKD; however, further clinical translational studies are warranted to validate the efficacy and safety of these approaches.

DNA methylation plays a crucial role in species development and environmental adaptation. In mammals, there are significant dietary changes from infancy to adulthood. Notably, the red panda transitions from milk consumption as juveniles to a bamboo-based diet as adults, with significant alterations in food characteristics and nutritional content. However, the regulatory role of DNA methylation in this process remains unclear. In this study, we investigate the regulatory role of DNA methylation on the expression of digestive and metabolic genes in the liver and pancreas during the red panda's dietary transition from suckling stage to adulthood.

Our findings reveal significant differences in DNA methylation patterns before and after dietary transition, highlighting the specific alterations in the methylation profiles of genes involved in lipid, carbohydrate, and amino acid metabolism. We found that perilipin-4 (PLIN4) is hypomethylated and highly expressed in the liver of adult red pandas, facilitating lipid droplet formation and storage, crucial for adapting to the low-fat content in bamboo. In contrast, genes like lipoprotein lipase (LPL), crucial for lipid breakdown, exhibited hypermethylated with low-expression patterns, reflecting a reduced lipid metabolism capacity in adults. Carbohydrate metabolism-related genes like ADH4 and FAM3C are hypomethylated and highly expressed in adults, enhancing glycogen production and glucose utilization. Genes involved in protein metabolism like CTSZ and GLDC, exhibit hypomethylated with high-expression and hypermethylated with low-expression patterns in the pancreas of adults, respectively, contributing to protein metabolism balance post-weaning.

This study reveals the regulatory role of DNA methylation in the dietary transition of red pandas from milk to bamboo and provides methylation evidence for the molecular regulation of adaptive expression of digestive and metabolic genes in red pandas with specialized diets.

2-Ethylhexyl diphenyl phosphate (EHDPHP) is ubiquitous in various environmental media and organisms. Due to its susceptibility to biotransformation, its primary product 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPHP) is almost at equal level in organisms. However, their hepatotoxicity remains unclear. In this study, adult zebrafish were exposed to 5, 35, or 245 µg/L of EHDPHP for 28 days. Distinct metabolic dysfunction-associated steatotic liver disease (MASLD) was observed in treated zebrafish, indicated by increased hepatic lipid levels (total cholesterol, triglycerides, nonesterified fatty acids, and fat droplets), steatosis (hepatic ballooning), and inflammation (tnf-α and il-6). Combined the in vitro hepatic cell test, molecular docking and molecular dynamics simulation, it was revealed that peroxisome proliferator-activated receptor gamma (pparγ) was upregulated upon EHDPHP exposure, thereby facilitating lipid synthesis and hepatic lipid accumulation. Notably, its main metabolite 5-OH-EHDPHP induced stronger hepatocyte toxicity and PPARγ transcription. Additionally, serious liver function damage was observed, with aspartate aminotransferase, alanine transaminase, albumin, and γ-glutamyl transferase levels markedly disrupted. This increases the risk of development of cardiovascular disease, hepatic cirrhosis or other chronic conditions. Collectively, the results demonstrate that EHDPHP may cause strong hepatic toxicities, which may be pounded by its hydroxylated metabolites.

Obesity is characterized by abnormal adipose tissue development and disrupted energy metabolism, involving multiple factors. Oxytocin receptor (OXTR) influences social behaviors, mammary gland development and reproduction. In this study, a transgenic mouse model with universal OXTR overexpression under the β-actin promoter (++Oxtr) was employed. Both ++Oxtr males and females exhibited a lean phenotype with reduced fat accumulation, despite unchanged food consumption. OXTR overexpression enhanced energy expenditure, adaptive thermogenesis and glucose tolerance. Morphologically, OXTR overexpression induced adipose tissue browning, marked by increased cell density and smaller adipocytes. Gene expression analysis revealed elevated levels of Brown Adipose Tissue (BAT) markers, fatty acid transport proteins and glucose transporters in adipose tissues. High OXTR ameliorated high-fat diet (HFD)-induced obesity with improvement of metabolic parameters. Mechanistically, OXTR overexpression led to an activation of PPAR signaling, increased energy expenditure, reduced fat deposition and promoted weight loss. These findings identify OXTR as a critical regulator of energy metabolism and thermogenesis. The ability of OXTR to enhance adaptive thermogenesis and energy metabolism suggests it may serve as a novel therapeutic target for metabolic disorders.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a major class of contaminants in recent years. Pregnant women are more susceptible to the influence of these compounds, which could heighten the risk of developing gestational diabetes mellitus (GDM). This study aims to conduct an updated systematic review and meta-analysis to determine the correlation between PFAS exposure during pregnancy and the risk of developing GDM and delve into their dose-response relationship.

Pubmed, EMBASE, Web of Science, and Cochrane Library databases were searched. Data were statistically analyzed using Stata 15.0. Fixed-effects (FEM) or random-effects (REM) models were used to combine STD mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) according to heterogeneity. Dose-response meta-analyses were performed when applicable.

A total of 12 papers were included in this study. Meta-analysis results indicated significantly higher levels of PFOA, PFBS, and PFUnDA in GDM patients compared to healthy pregnant women. Pregnant women exposed to high levels of PFOA and PFBS had a significantly increased risk of developing GDM, with ORs of 1.513 and 1.436, respectively. Dose-response analyses indicated that for each 1 ng/ml increase in PFOA and PFBS exposure, the risk of GDM increased by 0.3% and 11.7%, respectively. In contrast, no significant associations were observed between high exposure to other PFAS compounds, such as PFNA, PFHxS, and PFOS, and the development of GDM. Subgroup analyses suggested that PFOA, PFBS, and PFOS levels were higher in GDM patients from China compared to those from Western countries. The differences in PFOA and PFOS levels between GDM and normal pregnant women were more pronounced during late pregnancy.

Exposure to PFOA, PFBS, and PFUnDA during pregnancy is associated with an increased risk of GDM. Given the elevated risk, particularly in the Chinese population, it is crucial to reduce exposure to these substances, especially from the preconception period onward.

Cardiac lipotoxicity, characterized by excessive lipid accumulation in the cardiac tissue, is a critical contributor to the pathogenesis of diabetic heart. Recent research has highlighted the key mechanisms underlying lipotoxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and cell apoptosis, which ultimately impair the cardiac function. Various therapeutic interventions have been developed to target these pathways, mitigate lipotoxicity, and improve cardiovascular outcomes in diabetic patients. Given the global escalation in the prevalence of diabetes and the urgent demand for effective therapeutic approaches, this review focuses on how targeting cardiac lipotoxicity may be a promising avenue for treating diabetes.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the prevailing chronic liver disease in the pediatric population due to the global obesity pandemic. Evidence shows that prenatal and postnatal exposure to maternal abnormalities leads to a higher risk of pediatric NAFLD through persistent alterations in developmental programming. Gestational diabetes mellitus (GDM) is a hyperglycemic syndrome which has become the most prevalent complication in pregnant women. An increasing number of both epidemiologic investigations and animal model studies have validated adverse and long-term outcomes in offspring following GDM exposure in utero. Similarly, GDM is considered a crucial risk factor for pediatric NAFLD. This review aimed to summarize currently published studies concerning the inductive roles of GDM in offspring NAFLD development during childhood and adolescence. Dysregulations in hepatic lipid metabolism and gut microbiota in offspring, as well as dysfunctions in the placenta are potential factors in the pathogenesis of GDM-associated pediatric NAFLD. In addition, potentially effective interventions for GDM-associated offspring NAFLD are also discussed in this review. However, most of these therapeutic approaches still require further clinical research for validation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, and increasing evidence suggests that exposure to environmental pollutants is associated with the increased incidence of MASLD. The farnesoid X receptor (FXR) plays an important role in the development of MASLD by regulating bile acids (BAs) and lipid metabolism. However, whether FXR-active pollutants are the environmental drivers of MASLD remains unclear.

This study aimed to determine whether FXR-active pollutants exist in the environment and evaluate their ability to trigger MASLD development in mice.

An FXR protein affinity pull-down assay and nontargeted mass spectrometry (MS) analysis were used to identify environmental FXR ligands in sewage sludge. A homogeneous time-resolved fluorescence coactivator recruitment assay and cell-based dual-luciferase reporter assay were used to determine the FXR activities of the identified pollutants. Targeted analysis of BAs, MS imaging, lipidomic analysis, 16S rRNA sequencing, and quantitative polymerase chain reaction were conducted to assess the ability of FXR-active pollutants to induce metabolic disorders of BAs and lipids and to contribute to MASLD development in C57BL/6N mice.

We identified 19 compounds in the sewage sludge that had FXR-antagonistic activity, and triphenyl phosphate (TPHP) was the FXR antagonist with the highest efficacy. Mice exposed to either 10 or 50 mg / kg TPHP for 30 d had higher levels of conjugated primary BAs in enterohepatic circulation, and the BA pool showed FXR antagonistic activities. The exposed mice also had greater lipogenesis (more Oil Red O staining and high triglyceride levels) in liver.

Nineteen FXR-antagonistic pollutants were identified in sewage sludge. FXR inhibition by the strongest antagonist TPHP may have a role in promoting MASLD development in mice by inducing a positive feedback loop between the FXR and BAs. https://doi.org/10.1289/EHP15435.

Regulatory T cells (Tregs) mediate tissue homeostasis and repair. The function of the interleukin-7 receptor α (IL-7Rα) in nonlymphoid tissue Tregs is still unknown, although low expression of IL-7Rα is a widely accepted marker for Tregs. Here, we show that IL-33R (ST2)-expressing Tregs in the visceral adipose tissue (VAT) express the IL-7Rα at high levels. Treg-specific IL-7Rα-deficient mice exhibited reduced adipose ST2+ Tregs and impaired glucose tolerance, whereas IL-7Rα was dispensable for Tregs in lymphoid tissues. Mice deficient in thymic stromal lymphopoietin (TSLP), an additional ligand for IL-7Rα, displayed a modest decrease in adipose ST2+ Tregs and a reduced accumulation of adipose eosinophils, accompanied by slightly impaired glucose tolerance. In the VAT, mesothelial cells expressed IL-7, whereas adipose stem cells and folate receptor β-expressing tissue-resident macrophages expressed TSLP. Thus, this study indicates the significance of IL-7Rα signaling in the maintenance of VAT Tregs and glucose homeostasis, revealing a novel role for IL-7 and TSLP in immunometabolism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, with a prevalence as high as 32.4%. MASLD encompasses a spectrum of liver pathologies, ranging from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and, in some cases, progression to end-stage liver disease (cirrhosis and hepatocellular carcinoma). A comprehensive understanding of the pathogenesis of this highly prevalent liver disease may facilitate the identification of novel targets for the development of improved therapies. E3 ubiquitin ligases and deubiquitinases (DUBs) are key regulatory components of the ubiquitin‒proteasome system (UPS), which plays a pivotal role in maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression of E3 ligases and DUBs is involved in the progression of MASLD. Here, we review abnormalities in E3 ligases and DUBs by (1) discussing their targets, mechanisms, and functions in MASLD; (2) summarizing pharmacological interventions targeting these enzymes in preclinical and clinical studies; and (3) addressing challenges and future therapeutic strategies. This review synthesizes current evidence to highlight the development of novel therapeutic strategies based on the UPS for MASLD and progressive liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a clinical-pathological syndrome primarily characterized by excessive accumulation of fat in hepatocytes, independent of alcohol consumption and other well-established hepatotoxic agents. Mitochondrial dysfunction is widely acknowledged as a pivotal factor in the pathogenesis of various diseases, including cardiovascular diseases, cancer, neurodegenerative disorders, and metabolic diseases such as obesity and obesity-associated MAFLD. Mitochondria are dynamic cellular organelles capable of modifying their functions and structures to accommodate the metabolic demands of cells. In the context of MAFLD, the excess production of reactive oxygen species induces oxidative stress, leading to mitochondrial dysfunction, which subsequently promotes metabolic disorders, fat accumulation, and the infiltration of inflammatory cells in liver and adipose tissue. This review aims to systematically analyze the role of mitochondria-targeted therapies in MAFLD, evaluate current therapeutic strategies, and explore future directions in this rapidly evolving field. We specifically focus on the molecular mechanisms underlying mitochondrial dysfunction, emerging therapeutic approaches, and their clinical implications. This is of significant importance for the development of new therapeutic approaches for these metabolic disorders.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Oxidative stress is believed to play an important role in the development of MASH. Small aminothiol compounds such as cysteamine and its oxidized precursor, cystamine, are known pleiotropic compounds that exhibit relatively potent antioxidant and other effects. Herein, we evaluate the efficacy of cystamine, as well as two deuterated derivatives, in a choline-deficient, L-amino acid-defined, high-fat-diet (CDAA-HFD) mouse model of rapidly progressing liver fibrosis. Compared to control mice, daily oral administration of isotopically reinforced cystamine derivatives (200 mg/kg) led to a significant reduction of liver fibrosis and inflammation as well as oxidative stress. Moreover, the efficacy of treatment appeared to increase with the deuteration state of cystamine, with the tetradeuterated derivative, d 4 -cystamine, being the most effective. These results indicate that deuterated cystamine derivatives hold promise as potential candidates for the treatment of MASH.

High-fat diet (HFD) induces negative effects on the activity of interscapular brown adipose tissue (iBAT) and systemic energy metabolism. Irisin, a small hormonal agent known to modulate metabolism has been used for intervening HFD-induced obesity. However, its mechanism of action on iBAT function remains to be fully elucidated. This study sought to investigate whether irisin intervention could restore the thermogenic function of iBAT in mice with HFD-induced obesity, thereby regulating systemic metabolism.

Magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) were used to monitor changes of thermogenic capacity of iBAT and systemic metabolism in mice with HFD-induced obesity and iBAT deficiency during 2-week or 4-week irisin intervention. Pathological and molecular biology analyses were performed on tissue and blood samples.

Prolonged HFD feeding in mice induced obesity and impaired the thermogenic capacity of iBAT. MRI results showed that irisin intervention for 4-week reduced lipid content in iBAT, increased uncoupling protein 1 (UCP 1) expression and enhanced glucose analogue uptake capacity. These improvements of functions in iBAT activity were accompanied by an improvement in systemic metabolism. The positive effects of irisin appears to be dependent on the length of intervention time. When iBAT was removed, the beneficial effects of irisin were partially suppressed, suggesting that irisin regulates metabolism through the restoration of the thermogenic function of iBAT.

HFD results in reduced thermogenic capacity of iBAT, while irisin intervention can effectively restore iBAT function, leading to improvement in overall glucose and lipid metabolism.

Screening environmental pollutants that are harmful to the cardiometabolic status and understanding their key toxic pathways are crucial for effective clinical intervention. Based on exposure data of 46 chemicals in a nationally representative 13,286 people, logistic regression and mixture modeling were used to preliminarily identify environmental pollutants with significant impacts on 12 indicators for cardiometabolic disorders. A total of 15 chemicals were found to be associated with the integrated latent class, among which four chemicals (perfluorononanoic acid [PFNA], perfluorooctanoic acid [PFOA], thiocyanate, and thallium) also contributed significantly to the mixture effect. We constructed the adverse outcome pathways (AOPs) for nine significant toxicants in both models of individual chemicals and the mixture for each cardiometabolic disorder. Notably, fluoroalkyl substances affect multiple aspects of hyperlipidemia by activating PPARα. We performed molecular docking and in vitro experiments to verify and supplement the toxicological mechanism of PFNA. Through binding to PPARα, PFNA increased the levels of downstream molecules including CD36 (fatty acid transfer), ACSL1 (fatty acid activation), and CPT1a (intracellular transfer for β-oxidation) and ultimately promoted the accumulation of triglycerides and lipid droplets in HepG2 cells. These markers, together with key events for other metabolic phenotypes, may be potential targets for scientific research or clinical treatment.

Nanopolystyrene (NP) and phoxim (PHO) are pervasive environmental contaminants that pose a significant threat to the health of aquatic organisms, prompting widespread concern among researchers and the public alike. The hepatopancreas play important roles in the Chinese mitten crab (Eriocheir sinensis), such as digestion, absorption and detoxification. This study assessed the hepatopancreatic toxicity caused by the exposure of Eriocheir sinensis to environmentally relevant concentrations of NP and/or PHO. After a 21-day exposure period, NP (1.0 × 1010 particles/L) and PHO (24 μg/L) exposure resulted in reduced number of blister-like, resorptive, and fibrillar cells and an elevation in lipid droplets within the hepatopancreas compared to the control group. Furthermore, trypsin and lipase activity decreased, amylase activity increased, and a significantly decrease in the expression of digestion-related genes, including CHT, CarL, and CarB, suggested impairment in both digestive and metabolic functions. The marked upregulation of key genes, including PPARγ, GYK, PEPCK, and SCD, as well as key metabolites such as 4-methylzymosterol-carboxylate, zymosterone, lathosterol, 7-dehydro-desmosterol, vitamin D2, 24-methylene-cycloartanol, 5-dehydroepisterol, and sitosterol in the lipid metabolic pathway, showed that the peroxisome proliferator-activated receptor (PPAR) and steroid biosynthesis signaling pathways were highly affected by exposure to NP and/or PHO. These findings indicated that exposure to NP and/or PHO might adversely affect the hepatopancreatic physiological homeostasis in E. sinensis by causing tissue damage and interfering with digestive and metabolic functions. Our results provide ecotoxicological insights into the effects of nanopolystyrene and/or phoxim exposure on the digestive function of Eriocheir sinensis.

Atherosclerosis is a chronic and complex disease caused by lipid disorder, inflammation, and other factors. It is closely related to cardiovascular diseases, the chief cause of death globally. Peroxisome proliferator-activated receptors (PPARs) are valuable anti-atherosclerosis targets that showcase multiple roles at different pathological stages of atherosclerosis and for cell types at different tissue sites.

Considering the spatial and temporal characteristics of the pathological evolution of atherosclerosis, the roles and pharmacological and clinical studies of PPARs were summarized systematically and updated under different pathological stages and in different vascular cells of atherosclerosis. Moreover, selective PPAR modulators and PPAR-pan agonists can exert their synergistic effects meanwhile reducing the side effects, thereby providing novel insight into future drug development for precise spatial-temporal therapeutic strategy of anti-atherosclerosis targeting PPARs.

Concepts of Review: Based on the spatial and temporal characteristics of atherosclerosis, we have proposed the importance of stage- and cell type-dependent precision therapy. Initially, PPARs improve endothelial cells' dysfunction by inhibiting inflammation and oxidative stress and then regulate macrophages' lipid metabolism and polarization to improve fatty streak. Finally, PPARs reduce fibrous cap formation by suppressing the proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, research on the cell type-specific mechanisms of PPARs can provide the foundation for space-time drug treatment. Moreover, pharmacological studies have demonstrated that several drugs or compounds can exert their effects by the activation of PPARs. Selective PPAR modulators (that specifically activate gene subsets of PPARs) can exert tissue and cell-specific effects. Furthermore, the dual- or pan-PPAR agonist could perform a better role in balancing efficacy and side effects. Therefore, research on cells/tissue-specific activation of PPARs and PPAR-pan agonists can provide the basis for precision therapy and drug development of PPARs.

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.

Puerarin is a crucial constituent separated from the Chinese herbaceous plant, Pueraria lobata (Willd.) Ohwi, which exhibits multiple biological activities. Previous studies have indicated that puerarin has a function to alleviate renal damage in animal models of diabetic nephropathy (DN). However, there is still a dearth of systematic preclinical studies.

This study was designed to assess the effectiveness of puerarin on DN through meta-analysis. Furthermore, it aimed to reveal the underlying mechanisms of puerarin's efficacy in treating DN.

The animal studies were retrieved from 5 electronic databases. In total, 26 studies were included in our analysis. STATA 18.0 software was employed to evaluate crucial parameters, including fasting blood glucose (FBG), serum creatinine (SCr), blood urea nitrogen (BUN), proteinuria, oxidative stress, inflammatory responses, and lipid metabolism.

The results indicate that puerarin significantly improves FBG, SCr, BUN, proteinuria, and kidney index (KI). Additionally, puerarin enhances indicators of oxidative stress including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), while reduces inflammatory indicators like interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α). Moreover, puerarin lowers triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) levels.

In conclusion, puerarin has the effect of improving renal function in DN animals possibly through antioxidative, anti-inflammatory, and the regulation of renal lipid accumulation, which offers preclinical support for its possible therapeutic use in the management of DN.

A large body of evidence has shown that modulation of the nuclear receptors peroxisome proliferator-activated receptors (PPARs), the liver X receptors (LXRs), the proprotein convertase subtilisin/kexin type 9 (PCSK9) and inflammatory processes by natural compounds has hypolipidemic and anti-atherosclerotic effects. These beneficial outcomes are certainly related to the crucial function of these targets in maintaining cholesterol homeostasis and regulating systemic inflammation. Currently, the therapeutic scenario for cardiovascular diseases (CVD) offers a plethora of widely validated and functional pharmacological treatments to improve the health status of patients. However, patients are increasingly sceptical of pharmacological treatments which are often associated with moderate to severe side effects. The aim of our review is to provide a collection of the most recent scientific evidence on the most common phytochemicals, used for centuries in the Mediterranean diet and traditional chinese medicine that act on these key regulators of cholesterol homeostasis and systemic inflammation, which could constitute important tools for CVD management.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health problem linked to obesity, insulin resistance, and dyslipidemia. MASLD often leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, therapeutic options are limited, emphasizing the need for novel, targeted pharmacological interventions. Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, offers a promising approach by specifically enhancing hepatic metabolism while minimizing systemic effects. Clinical trials have demonstrated its capacity to reduce hepatic triglyceride accumulation and improve lipid profiles. Early- and advanced-phase studies, including the MAESTRO program, highlight significant reductions in hepatic fat content and favorable impacts on noninvasive biomarkers of fibrosis with minimal side effects. This review highlights evidence from pivotal studies, explores resmetirom's mechanism of action, and compares its efficacy and safety with other emerging therapeutic agents. While resmetirom marks a breakthrough in non-cirrhotic MASH management, further long-term studies are essential to fully evaluate its clinical benefits and potential regulatory approval for broader use in MASLD and MASH.

Chromium is an essential trace mineral in insulin-mediated glucose metabolism, potentially affecting protein synthesis and improving performance and meat quality. This study aimed to assess the impact of chromium on performance, carcass characteristics, meat quality, and the gene expression in the skeletal muscle of lambs fed a high-concentrate diet. Sixteen just just-weaned Dorper × Santa Inês crossbred lambs, weighing 24.95 ± 1.97 kg, were allocated into a control group, a basal diet without chromium in the diet supplementation (CTL) or chromium supplementation (Cr3.0), with the addition of 3.0 mg of chromium per kg of dry matter (Cr3.0DM). The animals were housed in individual pens and fed a diet comprising 6% forage and 94% concentrate for 60 days. We evaluated average daily gain (ADG), dry matter intake (DMI), feed efficiency (FE), carcass characteristics, meat quality, and muscle transcriptome. Chromium supplementation increased ADG (P = 0.048) and tended to improve FE (P = 0.08). Further, chromium supplementation increased kidney, pelvic, and heart fat (P ≤ 0.05). In meat, a reduction in cooking losses and an increase in shear force were observed in the meat of lambs treated with chromium-treated lambs (P ≤ 0.05). Transcriptome analysis revealed 21 differentially expressed genes, with 9 downregulated genes, including COX6C, TMED5, ODC1, HNRNPA1, and 12 upregulated genes, such as RPL39, RPL35A, RPS25, NSA2, RRM2, GCNT1, associated with pathways of ribosome biogenesis, protein synthesis, collagen remodeling, and fat metabolism. In conclusion, dietary chromium supplementation at 3.0 mg/kg DM can improve performance and efficiency without affecting carcass characteristics. In meat, chromium reduced cooking losses, potentially increasing its juiciness, but reduced its juiciness-related tenderness, negatively impacting the tenderness of the meat.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the leading chronic liver disease globally, and there are no approved pharmacotherapies to treat this disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) has been found to be related to insulin resistance and lipid accumulation. However, the role and mechanism of Enpp1 in the development of MAFLD remain unknown.

Here we discovered that Enpp1 is lowly expressed in the liver of MAFLD patients by clinical investigation. Knocking out Enpp1 in the liver of mice aggravated obesity, insulin resistance and hepatic steatosis, and these effects were reversed by liver-specific Enpp1 overexpression. Through transcriptomic data mining and experimental validation, we demonstrated that Enpp1 deficiency inhibited the expression of AMPK (energy receptor) and PPARα (nuclear transcription factor for lipid metabolism), thereby promoting the transcription of lipid synthesis factors and mediating the progression of MAFLD. Mechanistically, Enpp1 enhanced the activity of AMPK by increasing the AMP-to-ATP ratio, which in turn raised PPARα levels and promoted the transcription of its downstream lipid metabolism factors. Pharmacological inhibition of AMPK activity abolished the promoting effect of Enpp1 on PPARα protein expression.

This study indicate that Enpp1 can effectively ameliorate MAFLD through effects on AMPK/PPARα signaling pathway-mediated lipid metabolism, revealing the significance of Enpp1 as a promising therapeutic target against MAFLD.

The pathological mechanisms of Parkinson's disease (PD) is complex, and no definitive cure currently exists. This study identified Rutaecarpine (Rut), an alkaloid extracted from natural plants, as a potential therapeutic agent for PD. To elucidate its mechanisms of action and specific effects in PD, network pharmacology, molecular docking, and experimental validation methods were employed. Our findings demonstrated the efficacy of Rut in ameliorating PD symptoms. Network pharmacology analysis indicated that Rut exerts its therapeutic effects through the PPAR signaling pathway and the lipid pathway. Molecular docking results revealed that Rut forms stable protein-ligand complexes with PPARα and PPARγ. Animal experiments showed that Rut improved motor function in PD mice, protected dopaminergic neurons, ameliorated lipid metabolism disorders, and reduced neuroinflammation. This study identified the critical molecular mechanisms and therapeutic targets of Rut in the treatment of PD, providing a theoretical foundation for future investigations into the pharmacodynamics of Rut as a potential anti-PD agent.

Neurological disorders refer to the pathological changes of the nervous system involving multiple pathological mechanisms characterized by complex pathogenesis and poor prognosis. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor that is a member of the nuclear receptor superfamily. PPAR has attracted considerable attention in the past decades as one of the potential targets for the treatment of neurological disorders. Several in vivo and in vitro studies have confirmed that PPARs play a neuroprotective role by regulating multiple pathological mechanisms. Several selective PPAR ligands, such as thiazolidinediones and fibrates, have been approved as pharmacological agonists. Nevertheless, PPAR agonists cause a variety of adverse effects. Some natural PPAR agonists, including wogonin, bergenin, jujuboside A, asperosaponin VI, monascin, and magnolol, have been introduced as safe agonists, as evidenced by clinical or preclinical experiments. This review summarizes the effects of phytochemicals on PPAR receptors in treating various neurological disorders. Further, it summarizes recent advances in phytochemicals as potential, safe, and promising PPAR agonists to provide insights into understanding the PPAR-dependent and independent cascades mediated by phytochemicals. The phytochemicals exhibited potential for treating neurological disorders by inhibiting neuroinflammation, exerting anti-oxidative stress and anti-apoptotic activities, promoting autophagy, preventing demyelination, and reducing brain edema and neurotoxicity. This review presents data that will help clarify the potential mechanisms by which phytochemicals act as pharmacological agonists of PPARs in the treatment of neurological disorders. It also provides insights into developing new drugs, highlighting phytochemicals as potential, safe, and promising PPAR agonists. Additionally, this review aims to enhance understanding of both PPAR-dependent and independent pathways mediated by phytochemicals.

Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequently disrupts the binding of MDM2 to PPARα, therefore inhibiting MDM2-mediated PPARα ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS mutation or knock-in expression of PPARα P87A inhibited PPARα-mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK-Transferrin-PPARα axis could synergize with a well-established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPARα P87 hydroxylation is positively correlated with PPARα expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPARα through iron-dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.

The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking.

We explored the potential role of SLC25A47 through in vitro studies and using mice overexpressing and lacking SLC25A47.

SLC25A47 was identified as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomic analysis showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47.

Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding.