Search Results (366)

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing health concern worldwide. Human cell-based in vitro culture models that retain disease-relevant phenotypic pathways and responses to assess the efficacy and liability of new therapeutics are needed. Obeticholic Acid (OCA), a Farnesoid X Receptor agonist, has been identified for MAFLD treatment, and clinically shown to have anti-inflammatory and anti-fibrotic effects. In this study, healthy and disease-origin primary human hepatocytes (PHHs) were cultured in TruVivo^®, an all-human hepatic system for 14 days and treated with OCA to determine its’ effects on lipogenic, inflammatory, and fibrogenic pathways. Decreases in lipogenesis and triglyceride levels were measured in OCA treated healthy and diseased PHHs. Significant decreases in CYP3A4 activity and gene expression were quantified. Macrophage marker expression, pro-inflammatory cytokines and fibrotic markers were lowered in OCA treated diseased PHHs. CYP7A1 gene expression decreased, while BSEP gene expression increased in OCA treated healthy and diseased PHHs. Overall, OCA treatment reduced lipogenic, inflammatory, and fibrogenic markers in diseased PHHs. Differences in the potency and efficacy of OCA against different disease-relevant pathways were observed in healthy and diseased PHHs indicating divergence of key regulatory mechanisms between healthy versus diseased phenotypes. Full article

Objective: Yinchenhao decoction (YCHD), a classical herbal formula comprising Artemisia capillaris, Gardenia jasminoides, and Rheum palmatum, has been clinically used for over 1000 years to treat cholestasis. However, its mechanism of action remains undefined. This study aimed to elucidate YCHD’s therapeutic mechanisms against cholestasis, with a focus on the gut microbiota-mediated regulation of the farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) pathway. Methods: An alpha-naphthyl isothiocyanate (ANIT)-induced cholestasis mouse model was established. Mice received YCHD (3/9 g/kg) for 7 days. 16S rRNA sequencing, targeted LC/MS (bile acid (BA) quantification), untargeted GC/MS (fecal metabolite detection), qPCR/Western blot (FXR pathway analysis), fecal microbiota transplantation (FMT), and antibiotic depletion were employed to dissect the gut–liver axis interactions. Results: YCHD alleviated cholestatic liver injury by reducing serum biomarkers, restoring BA homeostasis via FXR-FGF15 activation, and suppressing hepatic Cyp7a1-mediated BA synthesis. It remodeled gut microbiota, enriched FXR-activating secondary BAs (CDCA, DCA, CA), and restored the intestinal barrier integrity. Antibiotic cocktail abolished YCHD’s efficacy, while FMT from YCHD-treated mice enhanced its therapeutic effects, confirming microbiota dependency. Conclusions: YCHD mitigates cholestasis through gut microbiota-driven FXR activation and direct hepatobiliary regulation. These findings bridge traditional medicine and modern pharmacology, highlighting microbiome modulation as a therapeutic strategy for cholestatic liver diseases. Full article

Bile acids (BAs), essential for lipid metabolism and fat-soluble vitamin absorption, also act as signaling molecules that regulate immune homeostasis. This review focuses on the roles of four key BA-activated receptors, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1), liver X receptors (LXRs), and vitamin D receptor (VDR), in modulating the functions of monocytes-macrophages, and dendritic cells (DCs). The biological synthesis, transport, and metabolism of BAs were discussed and highlighted the feedback mechanisms regulating the synthesis and enterohepatic circulation of BAs. Each receptor’s role in shaping immune responses is detailed, including their function in inflammation, apoptosis, phagocytosis, and pathogen clearance. FXR and GPBAR1 activation generally exhibits anti-inflammatory effects, while LXR and VDR modulate a more nuanced interplay between immune responses and lipid homeostasis. We also explored the cross-talk between BA-activated receptors and Toll-like receptors, providing a comprehensive understanding of the complex interplay between BA signaling and innate immunity. This review culminates by highlighting the therapeutic potential of targeting these receptors for the treatment of inflammatory and autoimmune diseases. Full article

Peroxisome proliferator-activated receptor α (PPARα, encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are the two prominent nutrient-sensing nuclear receptors essential for maintaining hepatic metabolism during fasting and fed states, respectively. These nuclear receptors comprehensively regulate the transcription of numerous genes involved in fatty acid oxidation (FAO), ketogenesis, bile acid (BA) biosynthesis, and other metabolic processes critical for liver energy homeostasis. These receptors have been shown to have opposite impacts on autophagy, which is triggered by PPARα activation but inhibited by FXR activation. Recent studies have further revealed that liver-specific genetic ablation of key autophagic genes tremendously impairs the activation of these nuclear receptors, thereby profoundly affecting hepatic metabolism in both fasting and feeding states. This review explores the roles and mechanisms of PPARα and FXR in regulating liver metabolism and autophagy, highlighting the necessity of basal autophagic activity in ensuring the proper signaling of these nutrient-sensing nuclear receptors. Finally, we examine the potential therapeutic strategies that leverage the interplay between PPARα, FXR, and autophagy for the treatment of metabolic liver disorders. We also delve into the clinical implications of this complex relationship, emphasizing its significance for translational medicine and future therapeutic interventions. Full article

Humans are continuously exposed to blue light from sunlight, computers, and smartphones. While blue light has been reported to affect living organisms, its role in fat synthesis and weight changes remains unclear. In this study, we investigated the effects of prolonged blue light exposure on weight changes in mice and the protective role of tranexamic acid (TA). Mice were exposed daily to blue light from a light-emitting diode for five months. Blue light exposure led to increased fat mass and body weight. The expression of the clock genes arnt-like 1 (Bmal1) and Clock was reduced in the brain and muscle of exposed mice. In addition, reduced Sirt1 and increased mammalian target of rapamycin complex 1 (mTORC1)/sterol regulatory element-binding protein 1 (SREBP1) were observed. The levels of liver X receptor a and liver kinase B1/5′AMP-activated protein kinase a1, both involved in SREBP1-mediated lipogenesis, were also elevated. TA treatment prevented the blue light-induced suppression of Bmal1/Clock and modulated the subsequent series of signal transduction. These findings suggest that prolonged blue light exposure suppresses the clock gene Bmal1/Clock, reduces Sirt1, and activates lipogenic pathways, contributing to weight gain. TA appears to regulate clock gene expression and mitigate blue light-induced weight gain. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a global health burden, however, therapeutic advancements remain hindered by incomplete insights on mechanisms and suboptimal clinical interventions. This review focused on the transcription factors (TFs) associated with the gut–liver axis, emphasizing their roles as molecular interpreters of systemic crosstalk in MAFLD. We delineate how TF networks integrate metabolic, immune, and gut microbial signals to manage hepatic steatosis, inflammation, and fibrosis. For instance, metabolic TFs such as peroxisome proliferator-activated receptor α (PPARα) and farnesoid X receptor (FXR) are responsible for regulating lipid oxidation and bile acid homeostasis, while immune-related TFs like signal transducer and activator of transcription 3 (STAT3) modulate inflammatory cascades involving immune cells. Emerging evidence highlights microbiota-responsive TFs, like hypoxia-inducible factor 2α (HIF2α) and aryl hydrocarbon receptor (AHR), linking microbial metabolite signaling to hepatic metabolic reprogramming. Critically, TF-centric therapeutic strategies, including selective TF-agonists, small molecules targeted to degrade TF, and microbiota modulation, hold considerable promise for treating MAFLD. By synthesizing these insights, this review underscores the necessity to dissect TF-mediated interorgan communication and proposes a roadmap for translating mechanism discoveries into precision therapies. Future research should prioritize the use of multi-omics approaches to map TF interactions and validate their clinical relevance to MAFLD. Full article

Bile acids (BAs) are synthesized in the liver from cholesterol and are subsequently conjugated with glycine and taurine. In the intestine, bile acids undergo various modifications, such as deconjugation, dehydrogenation, oxidation, and epimerization by the gut microbiota. These bile acids are absorbed in the intestine and transported to the liver as well as the systemic circulation. BAs can activate many types of receptors, including nuclear receptors and cell surface receptors. By activating these receptors, BAs can exert various effects on the metabolic, immune, and nervous systems. Recently, the detailed structure of TGR5, the major plasma membrane receptor for BAs, was elucidated, revealing a putative second BA binding site along with the orthosteric binding site. Furthermore, BAs act as ligands for bitter taste receptors and the Leukemia inhibitory factor receptor. In addition, the Mas-related, G-protein-coupled receptor X4 interacts with receptor activity-modifying proteins. Thus, a variety of cell surface receptors are associated with BAs, and BAs are thought to have very complex activities. This review focuses on recent advances regarding cell surface receptors for bile acids and the biological actions they mediate. Full article

Background/Objectives: Abnormal bile acid (BA) pool may play an important role in inducing liver damage in sepsis. Farnesoid X receptor (FXR) is a main negative feedback regulator of BA metabolism. This study aims to explore the protective effect and mechanism of the FXR agonist obeticholic acid (OCA) on liver dysfunction when sepsis occurs. Methods: A rat model of sepsis was induced by cecal ligation and puncture (CLP) for 24 h. Systematic inflammation, tissue injury, hepatic FXR, and BA transporter expression were investigated in the CLP rats and sham-operated control rats with and without OCA pre-treatment (10 mg/kg, gavage) at 2 h before operation. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay was performed to access BA composition in the rats’ serum and livers. The injury and inflammatory effects of the elevated unconjugated BAs found in the CLP rats was further verified in a hepatic cell line BRL-3A in vitro. Results: Hepatic FXR was repressed in CLP rats, whereas OCA upregulated liver FXR and hepatic BA transporter expression, reduced total serum BA concentration, ameliorated the elevation of serum levels of IL-1β and IL-6, and improved liver and ileal tissue injuries. OCA administration reduced the elevated unconjugated BAs in both serum and liver, and effectively inhibited increases in cholic acid (CA), deoxycholic acid (DCA), and 7-ketoDCA concentrations in CLP rat livers. These BA fractions promoted the release of aspartate aminotransferase (AST) from BRL-3A cells and increased IL-6, CXCL2, and monocyte chemoattractant protein-1 (MCP-1) expression in the cells, along with enhanced transcription factor nuclear factor-κB activation. Conclusions: Liver inflammation and dysfunction during sepsis is attributable to significant changes in bile acid composition in the blood and liver. FXR activation reduces systemic inflammation and liver dysfunction by regulating bile acid homeostasis, especially inflammatory unconjugated bile acid components. Full article

Depression, a highly prevalent mental disorder worldwide, arises from multifaceted interactions involving neurotransmitter imbalances, inflammatory responses, and gut–brain axis dysregulation. Emerging evidence highlights the pivotal role of bile acids (BAs) and their receptors, including farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), and liver X receptors (LXRs) in depression pathogenesis through modulation of neuroinflammation, gut microbiota homeostasis, and neural plasticity. Clinical investigations demonstrated altered BA profiles in depressed patients, characterized by decreased primary BAs (e.g., chenodeoxycholic acid (CDCA)) and elevated secondary BAs (e.g., lithocholic acid (LCA)), correlating with symptom severity. Preclinical studies revealed that BAs ameliorate depressive-like behaviors via dual mechanisms: direct CNS receptor activation and indirect gut–brain signaling, regulating neuroinflammation, oxidative stress, and BDNF/CREB pathways. However, clinical translation faces challenges including species-specific BA metabolism, receptor signaling complexity, and pharmacological barriers (e.g., limited blood–brain barrier permeability). While FXR/TGR5 agonists exhibit neuroprotective and anti-inflammatory potential, their adverse effects (pruritus, dyslipidemia) require thorough safety evaluation. Future research should integrate multiomics approaches and interdisciplinary strategies to develop personalized BA-targeted therapies, advancing novel treatment paradigms for depression. Full article

Hepatoblastoma (HB) is the most common pediatric primary liver tumor. About 20% of affected children have pulmonary metastasis at presentation. Survival rates for these children are dismal, not exceeding 25%. To study this subset of patients, we sequenced a metastatic HB cell line, HLM_2, and identified downregulation of the Liver X Receptor (LXR)/Retinoid X Receptor (RXR) pathway. LXR/RXRs function as transcriptional regulators that influence genes implicated in HB development, including the Wnt/β-catenin signaling pathway. We assessed the effects of a novel LXR/RXR agonist, UAB116, on metastatic HB, hypothesizing that this compound would affect genes governing the Wnt/β-catenin pathway, decreasing the metastatic phenotype of HLM_2 metastatic HB cells. We evaluated its effects on viability, proliferation, stemness, clonogenicity, and motility, and performed RNA sequencing to study differential gene regulation. Treatment with UAB116 for 72 h decreased HLM_2 proliferation, stemness, clonogenicity, and invasion. RNA sequencing identified an eight-fold increase in TRIM29, a gene known to inhibit β-catenin, in cells treated with UAB116. Administration of the LXR/RXR agonist, UAB116, reduces proliferation, stemness, and invasiveness of metastatic HB cells, potentially by upregulation of TRIM29, a known modulator of the Wnt/β-catenin pathway, providing support for further exploration of LXR/RXR agonism as a therapeutic strategy for metastatic HB. Full article

Yaks are an important livestock species on the Tibetan Plateau, but traditional grazing practices cause a sharp drop in their weight during winter, leading to grassland degradation due to overgrazing. Although off-site fattening can improve performance and protect ecology, it often leads to a negative energy balance, liver metabolism disorders, and immune impairment due to stress. However, the effects of rumen-protected glucose (RPG) and rumen-protected taurine (RPT) on yak liver health are not yet clear. The purpose of this study was to evaluate the effects of dietary RPG and RPT levels on the growth performance, serum biochemical parameters, liver antioxidant capacity, and immunity of yaks. Twenty-eight healthy yaks weighing 170 ± 10.4 kg were randomly divided into four treatments: LGLT (RPG: 1%—low RPG [LG]; RPT: 5 g/d—low RPT [LT]), LGHT (RPG: 1%—low RPG [LG]; RPT: 20 g/d—high RPT [HT]), HGLT (RPG: 3%—high RPG [HG]; RPT: 5 g/d—low RPT [LT]), and HGHT (RPG: 3%—high RPG [HG]; RPT: 20 g/d—high RPT [HT]). The results showed that compared with the LTHT treatment group, the HGHT group upregulated the serum concentrations of glucose (p = 0.004) and Interleukin-10 (p = 0.03), the relative mRNA expression of small heterodimer partners (p = 0.01), and the sterol 12-alpha-hydroxylase (p < 0.001), while reducing the serum concentration of gamma-glutamyl transferase (p = 0.048). The serum concentration of hepatic protein carbonyl (p = 0.005) and malondialdehyde (p = 0.03) was lower in the LGHT and HGHT treatment groups than in the LGLT and HGLT groups. The relative mRNA expression of Toll-like receptor 4 (p = 0.02), Interleukin-8 (p < 0.01), and Interleukin-1β (p < 0.01) was lower in the LGHT and HGHT groups than in the LGLT and HGLT groups. Tumor necrosis factor expression was lower (p = 0.04) and glucose transporter 2 expression was higher (p < 0.01) in the HGHT group compared to other treatment groups. The expression of glucokinase, glycogen synthase, pyruvate kinase, and farnesoid X receptor was higher in the HGLT treatment group than in other treatments (p < 0.01). In conclusion, dietary supplementation with 3% PRG and 5 g/d PRT can enhance liver antioxidant capacity and immune function, reduce lipid peroxidation, and promote glucose and bile acid metabolism in yaks. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem and the discovery of drugs is challenging. In this study, we aimed to investigate the effects of intestinal activation of the liver X receptor (LXR)α on MASH. Methods: An intestinal-specific LXRα activation model in mice was established and subjected to MASH development by combining a Western diet and carbon tetrachloride. Lipid metabolism, reverse cholesterol transport (RCT), steatosis, inflammation, and fibrosis were evaluated. In vitro models of steatosis and fibrosis were used to explore the role of scavenger receptor class B type 1 (SRB1). Results: We found that the intestinal activation of LXRα improved several MASLD features, including levels of triglycerides, RCT, steatosis, systemic and hepatic inflammatory profiles, and liver fibrosis. These effects were associated with increased high-density lipoprotein (HDL) levels and hepatic SRB1 expression. In vitro depletion of SRB1 hampered the beneficial effects of HDL on steatosis and fibrogenesis in liver cells by altering the activation of both peroxisome proliferator-activated receptors γ and small mothers against decapentaplegic homolog protein (SMAD)2/3 proteins. Conclusions: Our findings showed that the intestinal activation of LXRα and a parallel induction of hepatic SRB1 are protective against inflammation, steatosis, and advanced liver fibrosis in MASLD. Full article

Hypercholesterolemia causes atherosclerosis by inducing immune cell migration and chronic inflammation in arterial walls. Recent single-cell analyses reveal the presence of lipid-enriched foamy macrophages, as well as other macrophage subtypes, neutrophils, T cells, and B cells, in atherosclerotic plaques in both animal models and humans. These cells interact with each other and other cells, including non-immune cells such as endothelial cells and smooth muscle cells. They thereby regulate metabolic, inflammatory, phagocytic, and cell death processes, thus affecting the progression and stability of atherosclerotic plaques. The nuclear receptors liver X receptor (LXR)α and LXRβ are transcription factors that are activated by oxysterols and regulate lipid metabolism and immune responses. LXRs regulate cholesterol homeostasis by controlling cholesterol’s transport, absorption, synthesis, and breakdown in the liver and intestine. LXRs are also highly expressed in tissue-resident and monocyte-derived macrophages and other immune cells, including both myeloid cells and lymphocytes, and they regulate both innate and adaptive immune responses. Interestingly, LXRs have immunosuppressive and immunoregulatory functions that are cell-type-dependent. In animal models of atherosclerosis, LXRs have been shown to be involved in both progression and regression phases. The pharmacological activation of LXR enhances cholesterol efflux from macrophages and promotes atherosclerosis progression. Deleting LXR in immune cells, especially myeloid cells, accelerates atherosclerosis by increasing monocyte migration, macrophage proliferation and activation, and neutrophil extracellular traps (NETs); furthermore, the deletion of hematopoietic LXRs impairs the regression of atherosclerotic plaques. Therefore, LXRs in immune cells may be a potent therapeutic target for atherosclerosis. Full article

Antimony and copper can contaminate vegetables and enter the human body through the digestive tract, inducing severe and extensive biotoxicity. However, the role of bile acids (BAs) in the pathogenesis of liver inflammation by antimony or copper has not been elucidated. Our results indicated that antimony and/or copper induced liver inflammation, causing the disruption of gut microbiota, with the down-regulation of probiotics and up-regulation of harmful bacteria closely correlated to liver inflammation. Targeted metabolomics of BAs showed that antimony and/or copper significantly up-regulated the levels of taurine-β-muricholic acid (T-β-MCA) in serum and liver, which was due to the reduction of Lactobacillus spp. A farnesoid X receptor (FXR) antagonist, T-β-MCA inhibited the FXR-SHP pathway in liver and FXR-FGF15 pathway in ileum, thereby promoting the transcription of cholesterol 7-alpha hydroxylase (CYP7A1) and increasing total bile acid concentrations, ultimately leading to liver inflammation. These findings provide new insights into the underlying mechanisms of antimony- and/or copper-induced liver inflammation. Full article