Bisphenol A exposure disrupts the circadian clock system and impairs glycolipid metabolic function in mice liver.

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are characterized by disrupted bile acid (BA) homeostasis and subsequent liver injury. Emerging evidence indicates that circadian rhythms significantly influence liver metabolism and the pathogenesis of liver diseases. CD36 has been identified as a regulator of the hepatic circadian clock and metabolic processes; however, the specific mechanisms by which CD36 links circadian rhythms to cholestatic liver disease remain unclear. In this study, we employed bile duct ligation (BDL) mice and liver-specific CD36 knockout (CD36 LKO) mice to examine the role of CD36 in BA metabolism and circadian gene expression. BDL mice presented disrupted rhythms in both liver clock and BA metabolism, accompanied by increased diurnal expression of CD36. Conversely, in the context of BDL, CD36 LKO reduced cholestatic liver injury, improved BA metabolism, and restored diurnal variation of BA levels. Transcriptomic analysis revealed that BA metabolism genes were regulated by CD36, particularly those involved in synthesis, which displayed diurnal variation. Targeted inhibition of CD36 expression effectively mitigated liver injury and inflammation in BDL mice by restoring the rhythmicity of HMGCR/CYP7A1 and normalizing the BA pool size. These findings suggest that CD36 plays a pro-cholestatic role through its regulation of rhythmic BA synthesis and that its inhibition may represent a promising therapeutic strategy for cholestatic liver diseases.

Although physiological adaptations to high altitude are well-studied, the synergistic mechanisms linking foraging strategies to internal metabolism remain unclear. To investigate how dietary shifts are associated with molecular variation in plateau pikas (Ochotona curzoniae) along an altitudinal gradient, we integrated dietary analysis with liver transcriptomics and metabolomics. Results revealed a significant dietary differentiation in plateau pikas along the altitudinal gradient, shifting from a selective foraging strategy on diverse forbs at low altitudes to a tolerance foraging strategy centered on hardy sedges (Carex) and toxic locoweeds (Oxytropis) at high altitudes. Dietary differentiation along the altitudinal gradient was associated with coordinated changes in liver metabolism: low-altitude populations were enriched in metabolites related to biotic stress responses, whereas high-altitude populations showed increased accumulation of antioxidant compounds consistent with adaptation to intense abiotic stress. Transcriptomic analysis unveiled the molecular basis for this adaptation: the livers of high-altitude pikas exhibited significant upregulation of genes related to xenobiotic detoxification and energy metabolism regulation; in contrast, low-altitude populations upregulated pathways associated with cell growth and immune response. This study reveals a tightly coupled diet-gene-metabolism axis in plateau pikas. The shift in foraging strategy from selective to tolerance is a key driver of the functional shift in liver metabolism, redirecting the physiological focus from coping with biotic stress at low altitudes to counteracting abiotic stress at high altitudes. Our study highlights the importance of integrating ecological and molecular data to better understand how environmental gradients shape organismal physiology in natural populations.

Hepatocrinology is an emerging interdisciplinary field that examines the bidirectional interactions between the liver and the endocrine system, emphasizing how hepatic dysfunction influences hormonal regulation and how endocrine disorders, in turn, shape liver metabolism, inflammation, and disease progression. This review summarizes current theoretical frameworks, including hepato-endocrine axes, hepatokine signaling, and multi-organ communication models, highlighting the liver's role as a central endocrine hub. Key hepatic hormones, transport proteins, and hepatokines such as fetuin-A, fibroblast growth factor 21, and selenoprotein P are discussed in relation to metabolic disorders including metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, polycystic ovary syndrome, diabetes, and advanced chronic liver disease. The review further explores hormonal axes involving the thyroid, pancreas, adrenal glands, parathyroids, and gonads, illustrating their complex interplay with hepatic physiology. Current challenges, such as limited long-term studies and therapeutic controversies, are examined alongside emerging directions involving hepatokine-targeted therapies, precision medicine, and microbiome-driven modulation. Understanding these interconnected pathways is essential for improving diagnostic accuracy, risk stratification, and therapeutic strategies in hepato-endocrine disorders.

Endurance exercise elicits temporal and sexual dimorphic multi-omics remodeling of liver metabolism revealed by MoTrPAC.

The in vivo micronucleus (MN) assay is used for evaluation of chromosomal aberration induced by chemicals, and the liver MN assay can detect genotoxic compounds which require metabolic activation to induce micronucleus formation. However, species differences in liver metabolism are known, and therefore results obtained from mouse and rat liver MN assays may not always be directly extrapolated to humans. Chimeric mouse with human hepatocytes (the PXB-mouse®) is expected to be used in genotoxicity studies as an animal model of metabolic reactions in humans. To date, the use of the liver MN assay with PXB-mice has been reported, but its application has been limited to compounds that do not require metabolic activation to induce chromosomal aberrations. In this study, we used the liver MN assay in PXB-mice to evaluate diethylnitrosamine (DEN) and N-nitrosodimethylamine (NDMA), both of which require metabolic activation to induce chromosomal aberrations. After repeated administration of DEN for 14 days or NDMA for 28 days, statistically significant increases in micronucleus frequency were observed. From the results of this examination, it was demonstrated that the liver MN assay using PXB-mice can detect the genotoxicity of compounds that require metabolic activation to exert genotoxicity. Although some issues remain, such as the presence of residual mouse hepatocytes, the liver MN assay using PXB-mice is expected to provide supportive information for more accurate evaluation of chemical genotoxicity in humans.

Glucokinase activity suppresses hepatic cholesterol synthesis and triglyceride accumulation: A new model for the effects of the GKRP P466L common human variant.

Cancer cells require large quantities of glucose to ensure sufficient ATP production through glycolysis, and the liver may facilitate this glucose supply. A high-fat low-carbohydrate ketogenic diet (KD) could represent a strategy to reduce tumor growth. However, the molecular effects of carbohydrate restriction mediated by the KD and its hepatic impact remain poorly understood. To address this question, 6-week-old FVB/N-Tg(MMTV-PyVT)634Mul/J mice, which develop spontaneous mammary tumors, were fed a standard chow diet (SD group) or a KD diet (KD group) until reaching the age of 12 weeks. The effects of carbohydrate restriction were assessed by plasma analyses, as well as histological staining, RT-qPCR and Western Blotting in tumors and liver. We found that carbohydrate restriction reduced tumor growth by 46% and was associated with decreased expression of pro-tumorigenic factors (Ang2, Hgf, Mki67). Moreover, a decrease of metabolic enzymes (Pfk, Bdh1, Scot1) highlighted the lack of metabolic flexibility of the tumor cells and underscored their strong dependency on glucose. Conversely, the liver exhibited a strong adaptive response with enhanced ketogenesis and gluconeogenesis, evidenced by elevated blood glucose and upregulation of Pepck, Foxo1, and CREB. A high-fat, low-carbohydrate diet exerts a dual metabolic effect: it suppresses tumor progression through local metabolic reprogramming but simultaneously enhances hepatic glucose production. This highlights the pivotal role of systemic glucose availability in tumorigenesis and underscores the need to consider liver metabolism when designing dietary interventions for cancer therapy.

Kaiyujiangzhuo formula alleviates glycolipid metabolic disorders by improving arginine metabolism and inhibiting the ERK-mediated PPARγ-Ser273 phosphorylation.

ObjectiveTo explore the effects and mechanisms of metandienone abuse on hepatotoxicity.MethodsHepG2 cells were treated with 1 μg/mL metandienone for 24 h. Cell viability and apoptosis were detected via Cell Counting Kit-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, respectively. Cellular morphology was assessed via transmission electron microscopy. Genetic changes were analyzed using transcriptome sequencing. Meanwhile, metandienone (0.1 mg·g−1·d−1) was administered via gavage to mice for 14 days. Liver pathology was examined via hematoxylin and eosin, periodic acid–Schiff, and transmission electron microscopy. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total cholesterol, triglyceride, lactate dehydrogenase, and creatine kinase were measured.ResultsCell Counting Kit-8 assay confirmed that cell viability decreased to 88.01% after 24 h of metandienone treatment. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that the apoptosis rate increased to 25.08%, compared with 4.94% in the NC group. RNA transcriptome data showed that the expression levels of 221 genes in the metandienone group altered significantly; these genes were closely related to liver metabolism, oxidative stress, inflammatory response, and immune regulation. Meanwhile, exposure to metandienone-induced liver injury was characterized by hepatocyte steatosis and inflammation, accompanied by significant increases in serum alanine aminotransferase and aspartate aminotransferase.ConclusionThe abuse of anabolic hormones leads to liver function damage, and the mechanism may be related to inflammatory responses and metabolism.

RNA helicase associated with AU-rich elements (RHAU) regulates hepatic glucose homeostasis via a novel microRNA-150-Notch3-peroxisome proliferator-activated receptor γ pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health issue, largely driven by high-sugar and high-fat diets (HSHF). In this study, enzymatically modified grass carp fish oil (MFO), rich in medium- and long-chain triglycerides composed of medium-chain and long-chain fatty acids, was developed to investigate its protective effect on HSHF-induced MASLD in C57BL/6 mice. MFO supplementation significantly alleviated obesity, hepatic steatosis, dyslipidemia, and improved liver function. It remodeled the gut microbiota, elevating beneficial bacterial genera, increasing fecal short-chain fatty acid (SCFA) levels, and strengthening intestinal barrier integrity. Lipidomics and transcriptomics revealed that MFO regulated hepatic glycerophospholipid metabolism and modulated key genes, including Mboat1, Lpin1, and Pnpla3. A system-level mechanism underlying MFO's metabolic benefits was elucidated through an integrated network that linked gut microbiota, SCFAs, lipid species, and host gene expression. MFO supplementation was a promising nutraceutical strategy for MASLD intervention, achieved through targeted modulation of a gut-liver axis.

Polycystic ovary syndrome (PCOS) is frequently accompanied by visceral obesity, insulin resistance, low-grade chronic inflammation, and metabolic syndrome (MetS). These alterations promote significant dysfunction in adipose tissue and liver metabolism through cytokine production. Growing evidence indicates that the interaction between hepatokines and adipokines plays a central role in the development of metabolic and hepatic abnormalities in women with PCOS. This narrative review was conducted to analyze the relationship between adipose tissue dysfunction and liver metabolic impairment in women with PCOS, emphasizing the involvement of hepatokines and adipokines in insulin resistance, inflammation, hepatic steatosis, hepatic fibrosis and MetS. From this perspective, contemporary clinical, biochemical, and molecular studies were reviewed to evaluate how adipocyte-derived factors and hepatocyte-derived cytokines influence metabolic homeostasis in the liver and adipose tissue in women with PCOS. Increased visceral adiposity in PCOS enhances the release of free fatty acids (FFAs) to the liver, resulting in hepatotoxicity, oxidative stress, and hepatic inflammation. Several hepatokines, including fetuin-A, angiopoietin-like protein 3 (ANGPTL3), selenoprotein P(Sep-P), and hepassocin (HPS), show abnormal circulating levels in PCOS and are strongly associated with insulin resistance, dyslipidemia, and progression to hepatic steatosis. In contrast, fibroblast growth factor 21 (FGF-21), follistatin, and interleukin (IL-6) may exert dual effects. Adipokines, such as resistin, visfatin, apelin, and retinol-binding protein 4 (RBP-4), contribute to chronic inflammation, impaired glucose metabolism, androgen excess, and hepatic steatosis and fibrosis. Some of these adipokines, such as leptin and vaspin, may exert both beneficial and detrimental effects, while others, including chemerin and omentin, appear to play predominantly beneficial roles in metabolism. Reduced adiponectin-to-leptin levels further aggravate metabolic dysfunction. These changes indicate that adipose tissue-liver crosstalk is a key mechanism linking PCOS and MetS. Overall, metabolic disturbances in PCOS are strongly mediated by dysregulated communication between adipose tissue and the liver. Altered hepatokine and adipokine profiles contribute to insulin resistance, liver dysfunction, hypertension and the development of MetS in women with PCOS. Understanding these intricate interactions may support the early identification of high-risk patients and the development of targeted therapeutic strategies.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with type 2 diabetes mellitus, which is characterized by hepatic steatosis. Vanadium compounds have the potential to prevent hyperlipidemia. However, whether vanadium compound supplementation could rescue hepatic steatosis in NAFLD remains uncertain. We sought to investigate the molecular mechanisms by which vanadium(IV)-chlorodipicolinate (VOdipic-Cl) ameliorated hepatic steatosis in obesity. The therapeutic effect of VOdipic-Cl was evaluated using high-fat diet (HFD)-induced C57BL/6 mice and palmitic acid/oleic acid (PO)-treated L02 hepatocytes, respectively. Lipidomic analysis, RNA-sequencing (RNA-seq), Western blotting, and molecular dynamics simulation were employed to elucidate the molecular mechanism of VOdipic-Cl in regulating lipid metabolism in liver and hepatocytes. VOdipic-Cl treatment effectively reduced hepatic lipid accumulation and improved hepatic function in HFD-fed mice. Lipidomic analysis showed that the primary differential lipid metabolites were mainly associated with glycerophospholipid metabolism pathway. Transcriptomic analysis revealed that adenosine monophosphate-activated protein kinase (AMPK) signaling pathway was involved in the regulation of hepatic lipid metabolism by VOdipic-Cl treatment. Moreover, VOdipic-Cl-induced AMPK activation significantly restored hepatic mitochondrial homeostasis and reduced lipid accumulation through upregulating transcription factor peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and carnitine palmitoyltransferase 1 (CPT1) in hepatocytes, respectively. Our findings suggest that VOdipic-Cl triggers the activation of AMPK, leading to the upregulation of PGC-1α and CPT1 expression, ultimately improving mitochondrial homeostasis and decreasing lipid accumulation. Collectively, these molecular cascades contribute to the ameliorating effect of VOdipic-Cl on HFD-induced hepatic steatosis. This study also provides evidence supporting the potential utilization of VOdipic-Cl for the treatment of NAFLD.

Hepatic amino acid metabolism in liver, cardiovascular, kidney and metabolic diseases.

Dietary supplementation with sodium butyrate or bovine colostrum modulates the gut–liver axis in weaned piglets. Sodium butyrate exerted beneficial effects on liver function and lipid parameters, while also inhibiting inflammation and promoting the maintenance of the intestinal barrier. A particularly pronounced effect was observed with bovine colostrum supplementation, which significantly increased average daily weight gain (p < 0.001). In addition, piglets receiving colostrum consumed more feed and exhibited a significantly lower feed conversion ratio (p = 0.002). Metabolic changes induced by sodium butyrate and bovine colostrum supplementation resulted in alterations in the hepatic fatty acid profile, including a reduction in n-3 polyunsaturated fatty acids and a decrease in collagen fiber content in the liver (p = 0.03). The nutritional interventions did not significantly affect microbial diversity indices; however, marked changes in volatile fatty acid concentrations were observed in the large intestine. These changes indicate enhanced microbial fermentation and increased nutrient absorption in the experimental groups. Significant increases were detected in acetic acid (p = 0.003) as well as in butyric, isobutyric, and valeric acids (p = 0.014, p = 0.024, and p = 0.038, respectively). Supplementation with sodium butyrate and dried bovine colostrum also led to increased hepatic concentrations of macro- and microelements in piglets from the experimental groups. Genomic analyses suggest that sodium butyrate modulates hepatic metabolic and inflammatory pathways by downregulating PPAR (peroxisome proliferator-activated receptor) and SIRT3 (sirtuin 3) expression and reducing TNF (tumor necrosis factor) gene expression, highlighting its potential role in regulating lipid metabolism, oxidative stress, and inflammation in a porcine model. Overall, the results indicate that both supplements may contribute to the modulation of gut microbial activity and liver metabolism in weaned piglets.

Methamphetamine (METH) addiction causes serious psychiatric and neurological disorders, while the overall efficacy of current interventions remains unsatisfactory. Endurance exercise is one effective approach to facilitate drug abstinence and functional rehabilitation, although its exact mechanism has not been fully elucidated. In the current work, we successfully suppressed drug craving behaviors in METH addicts by 48 weeks of aerobic exercise, and a metabolomics study indicated the elevation of serum N-Acetylneuraminic acid (Neu5Ac) specifically in exercised individuals. Further studies in rodent models of METH exposure replicated both behavioral improvement and the increase of Neu5Ac levels in circulation and the striatum. More importantly, we demonstrated that exercise stimulated the hepatic tissues to synthesize Neu5Ac, which modulates synaptic protein in the striatum to alleviate METH-seeking behaviors. In sum, our results propose a liver-brain axis in which exercise reshapes liver metabolism to facilitate drug abstinence.

Background: Dietary crude protein (CP) acts as a key nutritional factor that affects the growth performance and liver metabolism of fattening Hu sheep, with metabolizable energy (ME) representing a major confounding factor in CP-related responses. To isolate the specific effects of CP on liver metabolism and minimize energy-protein interactions, we standardized dietary ME at 9.4 MJ/kg dry matter. Methods: We then established three isoenergetic CP concentrations: 11.07%, 13.07%, and 15.11%. A total of ninety 4-month-old male Hu sheep (with an initial body weight of 27.09 ± 1.83 kg) were allocated at random to three dietary treatment groups, each containing 30 animals distributed across three replicate pens, and fed pelleted total mixed rations (PTMRs) for 75 days under pen conditions in southern Xinjiang. Exploratory combined transcriptomic and metabolomic profiling of liver tissue was conducted to characterize how graded CP levels modulate growth traits and hepatic metabolic pathways, thereby identifying the appropriate dietary CP level for efficient and sustainable fattening of Hu sheep in this region. Result: Results indicated that animals fed the 15.11% CP diet showed a significantly higher average daily gain (ADG) and cumulative weight gain compared with those fed 11.07% or 13.07% CP (p < 0.05). Exploratory multi-omics enrichment analysis demonstrated significant overrepresentation (p < 0.05) of differentially expressed genes and metabolites in key biological pathways-including bile secretion, AMP-activated protein kinase (AMPK) signaling, steroid biosynthesis, peroxisome proliferator-activated receptor (PPAR) signaling, and oxidative stress-related and oxidative phosphorylation. Correlation analyses characterized two hub genes-ATP6AP1 and LOC101119853-that were significantly and negatively correlated with ADG (p < 0.05), whereas two metabolites-calcidiol and ADP-displayed significant positive relationships with ADG (p < 0.05). Pathway-level comparisons further demonstrated that both the 13.07% vs. 15.11% CP and the 11.07% vs. 15.11% CP contrasts yielded significant enrichment in AMPK signaling and steroid biosynthesis. Notably, calcidiol and ADP both declined numerically in the 13.07% vs. 15.11% CP comparison, whereas only ADP reached statistical significance in the 11.07% vs. 15.11% CP contrast. Conclusions: Collectively, under an ME level of 9.4 MJ/kg, a dietary CP concentration of 15.11% contributes to favorable growth of 4-month-old fattening Hu sheep housed in pens in southern Xinjiang. This level is associated with improved growth performance and coordinated regulation of central hepatic regulatory networks-particularly those involved in energy homeostasis and steroidogenesis-thereby supporting metabolic stability without compromising animal health or production efficiency. These findings provide a preliminary molecular basis for precision protein nutrition in Hu sheep feeding systems and offer translational insights for optimizing ruminant nutrition under arid and semi-arid environmental constraints. All correlations indicate potential associations, not causal relationships.

Liver Metabolism and Function.

ABSTRACTObjectivesPrior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions.MethodsMice with or without hepatocyte cyclin D1 (D1fl/flor D1ΔHep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. TheC. elegansmodel was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition.ResultsCyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1ΔHepmice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroidErcc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine ofCaenorhabditis elegans(which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting.ConclusionsCyclin D1 regulates nutrient-mediated physiology in the liver andC. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging.HighlightsCyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression.Acute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1.Hepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation.Cyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition inC. elegans.