Previous studies have suggested that abnormal hepatobiliary system function may contribute to poor prognosis in patients with acute coronary syndrome (ACS) and that abnormal hepatobiliary system function may be associated with per- and polyfluoroalkyl substances (PFAS) exposure. However, there is limited evidence for this association in cardiovascular subpopulations, particularly in the ACS patients. Therefore, we performed this study to evaluate the association between plasma PFAS exposure and hepatobiliary system function biomarkers in patients with ACS. This study included 546 newly diagnosed ACS patients at the Second Hospital of Hebei Medical University, and data on 15 hepatobiliary system function biomarkers were obtained from medical records. Associations between single PFAS and hepatobiliary system function biomarkers were assessed using multiple linear regression models and restricted cubic spline model (RCS), and mixture effects were assessed using the Quantile g-computation model. The results showed that total bile acids (TBA) was negative associated with perfluorohexane sulfonic acid (PFHxS) (-7.69 %, 95 % CI: -12.15 %, -3.01 %). According to the RCS model, linear associations were found between TBA and PFHxS (P for overall = 0.003, P for non-linear = 0.234). We also have observed the association between between PFAS congeners and liver enzyme such as aspartate aminotransferase (AST) and α-l-Fucosidase (AFU), but it was not statistically significant after correction. In addition, Our results also revealed an association between prealbumin (PA) and PFAS congeners as well as mixtures. Our findings have provided a piece of epidemiological evidence on associations between PFAS congeners or mixture, and serum hepatobiliary system function biomarkers in ACS patients, which could be a basis for subsequent mechanism studies.

Metabolic reprogramming represents a hallmark of malignant tumors, manifested through progressive alterations in nutrient utilization patterns during oncogenesis. As fundamental constituents of biological membranes, essential components of signaling pathways, and critical energy substrates, lipids undergo comprehensive metabolic restructuring in neoplastic cells. This lipid remodeling confers enhanced adaptability to sustain uncontrolled proliferation while promoting aggressive migratory phenotypes. Farnesoid X receptor (FXR), a ligand‑activated nuclear receptor responsive to bile acid (BA) derivatives and cholesterol metabolites, orchestrates key aspects of lipid homeostasis. Its regulatory network encompasses cholesterol/BA metabolism, fatty acid (FA) metabolism and plasma lipoprotein trafficking pathways. Emerging evidence positions FXR as a pleiotropic modulator in oncogenesis, with dysregulated expression patterns documented across multiple tumor lineages and premalignant lesions. This mechanistic understanding has propelled FXR‑targeted therapeutics into the forefront of precision oncology development. The present review critically examines the FXR‑lipid axis in lipid‑enriched malignancies, with particular emphasis on its regulatory circuitry governing BA flux and FA turnover.

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors activated by various xenobiotics, drugs, hormones, and bile acids (BAs). Upon activation, these nuclear receptors play critical roles in regulating systemic energy homeostasis. However, precise mechanisms through which CAR and PXR influence systemic metabolism remain incompletely understood. Here, we investigated the impact of CAR and PXR on the liver-secreted hormone (i.e., hepatokine) expressions in response to BA stress, such as cholic acid (CA) feeding. Our analysis revealed that several BA-activated genes, including the well-known CAR/PXR target, aldo-keto reductase family 1, member B7 (Akr1b7), were commonly increased by CAR- and PXR-agonist treatments. Notably, we identified a gene cluster encoding new BA-regulated hepatokines, orosomucoids (ORMs), as direct transcriptional targets of CAR and PXR. The Orm1 and Orm2 expressions were completely abolished in the absence of both CAR and PXR following CA feeding. In addition, we found that Orm transcriptions are dynamically regulated under various metabolic conditions, proposing a potential contribution of CAR/PXR. In conclusion, our study demonstrated that BA stress activates CAR and PXR, which play a key role in regulating hepatokine expression, including ORMs. This suggests a potential link between hepatic BA signaling, CAR/PXR activity, and systemic metabolic effects.NEW & NOTEWORTHY Hepatic bile acid signaling plays a crucial role in coordinating systemic metabolism between the liver and other peripheral tissues. Our report demonstrates that, under bile acid-enriched conditions, activation of nuclear receptors CAR and PXR stimulate the expression of several putative hepatokines, including the orosomucoid gene family, which may exert regulatory effects in the liver and adipose tissue against metabolic disorders.

Fexaramine, a gut-restricted farnesoid X receptor (FXR) agonist, promotes glucose and lipid homeostasis, improves insulin sensitivity, promotes white adipose tissue browning, and stimulates nonshivering thermogenesis. Enhancement in energy expenditure due to an increase in amount of energy burned by brown and 'beige' adipocytes results in subsequent weight loss. Fexaramine is poorly absorbed into circulation when delivered orally, which limits systemic FXR activation and toxicity. An increase in β3-adrenoceptor signaling, activation of Takeda G protein-coupled receptor 5/glucagon-like peptide-1 (TGR5/GLP-1) signaling, and induction of fibroblast growth factor (FGF)-19/FGF-15 play crucial roles in fexaramine metabolic actions. Intestinal FXR activation is a promising, potentially safe approach for treating obesity and metabolic syndrome.

This study aimed to evaluate the effects of different bile acid levels in the diet on the growth performance, hepatic lipid metabolism, antioxidant capacity, and cecal microbiota of Danzhou chickens. 480 one-day-old male Danzhou chickens were randomly divided into four treatments and fed diets supplemented with 0, 200, 400, or 800 mg/kg bile acids. The trial lasted for 35 days. The results indicated that supplementing the diet with 400 mg/kg bile acids significantly increased average daily weight gain and reduced the feed conversion ratio (P < 0.05). Bile acid supplementation modulated serum lipid profiles, with 800 mg/kg increasing total bile acid levels, while 400 mg/kg reduced triglyceride and total cholesterol concentrations (P < 0.05). In the liver, 400 mg/kg bile acids increased total bile acid content, reduced triglycerides and total cholesterol accumulation, upregulated phospholipase C delta 1, acyl-CoA oxidase 1, and apolipoprotein A1 expression, and enhanced hepatic lipase and lipoprotein lipase activities (P < 0.05), indicating alleviated lipid deposition. All bile acids treatments improved antioxidant capacity by elevating total antioxidant capacity, catalase, superoxide dismutase, and glutathione peroxidase levels (P < 0.05) while reducing malondialdehyde (P < 0.05) in serum and liver, with optimal effects at 400 mg/kg. Bile acid supplementation increased levels of immunoglobulins (IgA and IgG) and the anti-inflammatory cytokine IL-10 (P < 0.05), while reducing levels of the pro-inflammatory cytokine IL-1β (P < 0.05). Morphological analysis of the intestine revealed that 400 mg/kg of bile acids significantly enhanced villus height and the villus height-to-crypt depth ratio (P < 0.05) in both the duodenum and ileum. Cecal microbiota analysis revealed that supplementation with 400 mg/kg bile acids increased microbial diversity and enriched Christensenellaceae_R-7_group and Weissella, whereas Barnesiellaceae_unclassified, Campylobacter, and Lactobacillus were predominant in the CON. In conclusion, the results suggest that dietary supplementation with 400 mg/kg of bile acids enhances antioxidant capacity and immune function in Danzhou chickens, potentially improving serum and hepatic lipid metabolism by modulating the cecal microbiota, thereby promoting growth performance.

Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of Bacteroidetes ovatus (B. ovatus), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by B. ovatus might be a promising strategy to activate NK cell cytotoxicity to treat HCC.

Seaweed-derived dietary fibre sodium alginate (SA) has been shown to present with health benefits in food-derived disease models. To determine whether SA improves the disease rather than merely suppressing its progression, we assessed its effects using farnesoid X receptor (FXR)-deficient mice to provide a model of advanced hyperlipidaemia. Fxr-null mice were fed with a 5% SA-supplemented diet for nine weeks and showed significant decreases in the levels of liver triglycerides (p < 0.05), total cholesterol (p < 0.05), serum low-density lipoprotein-cholesterol (p < 0.001). The expression levels of fatty acid-synthesizing genes (Fas and Scd1) and cholesterol-metabolizing genes (Hmgcr, Hmgcs, and Abca1), were significantly reduced. Furthermore, the SA supplementation has altered the gut microbiota and significantly increased the abundance of the genus Oscillospira (p < 0.001) and Parabacteroides (p < 0.01). These results suggest that SA improves lipid disruption and influences the composition of the gut microbiota in the Fxr-null mice.

High-fat diets (HFDs) can lead to excessive accumulation of lipids in the liver, leading to liver injury. Dietary zinc (Zn) has been shown to reduce HFD-induced lipid accumulation and improve lipid profiles in mammals, yet it remains unclear whether waterborne Zn maintains its lipid-lowering effects in osteichthyes.

This study aimed to elucidate the regulatory role of Zn in HFD-induced hepatic lipid accumulation in yellow catfish (Pelteobagrus fulvidraco) and its potential mechanisms.

Yellow catfish were fed a control diet (11.21% lipid concentration), HFD (16.10% lipid concentration), or HFD combined with waterborne Zn exposure (0.2 mg/L) for 8 wk. Various biochemical, genetic, histologic, and molecular techniques were conducted to evaluate hepatic lipid deposition and lipid metabolism and determine protein interactions between silent information regulator (SIRT) 1 and farnesoid X receptor (FXR), as well as protein-gene interactions between FXR and adipose triglyceride lipase (ATGL).

HFD feeding significantly increased liver fat content and induced hepatic damage in yellow catfish, but concurrent exposure to waterborne Zn alleviated these detrimental effects. Zn treatment increased mRNA and protein concentrations of SIRT1 (mean ± SEM; 97.19% ± 11.67% and 83.25% ± 28.60%, respectively) and FXR (163.90% ± 24.60% and 24.90% ± 11.12%, respectively) in yellow catfish liver (P < 0.05). Zn-activated FXR directly interacted with the promoter of ATGL, stimulating the expression of atgl (54.40% ± 16.33%; P < 0.05) and facilitating the hydrolysis of triglycerides and lipid droplets. Furthermore, Zn reduced the acetylation concentration of FXR by SIRT1 deacetylation of FXR protein K167.

The findings reveal that Zn protect against HFD-induced liver injury in yellow catfish by promoting the deacetylation of FXR protein K167 by SIRT1 and activating FXR, thereby promoting the transcriptional activation of ATGL to increase lipolysis.

Tri-ortho-cresyl phosphate (TOCP) is an environmental toxic pollutant, belonging to the chemical class of organophosphorus flame retardants and repressing hepatic membrane drug transporter expression. The present study investigated whether the liver canalicular bile salt efflux pump (BSEP) may also be targeted by TOCP. TOCP used at a non-cytotoxic concentration of 10 μM for 48 h was demonstrated to decrease BSEP mRNA expression in cultured hepatic HepaRG cells (by a 4.4-fold factor) and primary human hepatocytes (by a 2.5-fold factor). This effect was concentration-dependent (IC50 = 0.8 μM) and was associated with a significant reduction of canalicular taurocholate secretion in HepaRG cells. It was not impaired by TOCP metabolism inhibitors. TOCP also potently antagonized farnesoid-X-receptor (FXR) mediated-BSEP up-regulation. The specific FXR antagonist DY268 decreased constitutive BSEP expression in HepaRG cells, as TOCP, suggesting a major implication of FXR antagonism in TOCP effects towards BSEP. The TOCP-mediated BSEP repression was finally predicted to potentially occur in vivo in response to a neurotoxic dose or to acute or chronic safe doses of TOCP. Taken together, these data demonstrate that the major bile salt transporter BSEP is a target for TOCP, which may support deleterious hepatotoxic effects of this chemical.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule.

Recent studies have indicated that Lactococcus petauri LZys1 (L. petauri LZys1), isolated from healthy human feces, exhibits a promising probiotic profile in vitro. However, its impact on the physiological status of the host in vivo remains uncertain. The objective of our study was to investigate the effects and mechanisms of orally administering L. petauri LZys1 on gut microbiota and liver function in mice. We administered L. petauri LZys1 through daily oral gavage to C57BL/6 male mice. Subsequently, we analyzed changes in gut microbiota composition using 16S rRNA sequencing and quantified alterations in hepatic-intestinal bile acid (BA) profile. Serum biochemical parameters were assessed to evaluate liver function. Our findings revealed that L. petauri LZys1 led to an increase in body weight, liver mass, and serum aminotransferase levels. Oral administration altered the gut microbiota composition, resulting in reduced diversity and abundance of intestinal bacteria. Additionally, the profiles of BAs were suppressed across organs, associated with the downregulation of the ileum's farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15) signaling pathway. The decrease in circulating FGF15 mediated the downregulation of hepatic fibroblast growth factor receptor 4 (FGFR4)/FXR, disrupting BA metabolism and fatty acid oxidation. Our findings suggest that L. petauri LZys1 may impact liver function by influencing the gut microbiota-mediated ileal FXR-FGF15 axis and inhibiting hepatic bile acid metabolism.

This work elucidated the impact of L. petauri LZys1 on host gut microbiota metabolism and hepatic physiological metabolism. We observed that L. petauri LZys1 administration induced liver weight gain and biochemical parameters changes, in addition to a altered gut microbiota and suppressed bile acid (BA) profiles. Furthermore, we propose that changes in liver status are related to the enterohepatic farnesoid X receptor-fibroblast growth factor axis, which alters bile acid metabolism and disrupts liver function. The above findings suggest that attention should be paid to the effect of probiotics on liver function.

Disruption of bile acid (BA) metabolism causes various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains elusive. Here, we report that BA metabolism is directly controlled by a repressor function of YAP, which induces cholestasis by altering BA levels and composition via inhibiting the transcription activity of Fxr, a key physiological BA sensor. Elevated BA levels further activate hepatic YAP, resulting in a feedforward cycle leading to HCC. Mechanistically, Teads are found to bind Fxr in a DNA-binding-independent manner and recruit YAP to epigenetically suppress Fxr. Promoting BA excretion, or alleviating YAP repressor function by pharmacologically activating Fxr and inhibiting HDAC1, or overexpressing an Fxr target gene Bsep to promote BA exportation, alleviate cholestasis and HCC caused by YAP activation. Our results identify YAP's transcriptional repressor role in BA metabolism as a key driver of HCC and suggest its potential as a therapeutic target.

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.

The incidence of Barrett esophagus (BE) and gastroesophageal adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BAs) support fat digestion and undergo microbial metabolism in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. When activated, FXR can inhibit cancer-related processes, and thus, it is an appealing therapeutic target. Here, we assess the effect of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression.

L2-IL1B mice (mouse model of BE and GEAC) under different diets, and L2-IL1B-FXR KO-mice were characterized. L2-IL1B-derived organoids were exposed to different BAs and to the FXR agonist obeticholic acid (OCA). The BA profile in serum and stool of healthy controls and patients with BE and GEAC was assessed.

Here we show that a high-fat diet accelerated tumorigenesis in L2-IL1B mice while increasing BA levels and altering the composition of the gut microbiota. Although upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine BE organoids and L2-IL1B mice with OCA notably ameliorated the phenotype.

GEAC carcinogenesis appears to be partially driven via loss or inhibition of FXR on progenitor cells at the gastroesophageal junction. Considering that the resulting aggravation in the phenotype could be reversed with OCA treatment, we suggest that FXR agonists have great potential as a preventive strategy against GEAC progression.

Similarly to conventional steroids, bile acids function as signaling molecules, acting on a family of membrane and nuclear receptors. The best-characterized bile acid-regulated receptors are the farnesoid X receptor, activated by primary bile acids, and the G-protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), which is activated by secondary bile acids, such as lithocholic acid (LCA) and deoxycholic acid. Both the farnesoid X receptor and G-protein-coupled bile acid receptor 1 are expressed in cells of innate immunity, monocytes/macrophages, and natural killer cells. Their activation in these cells provides counter-regulatory signals that are inhibitory in nature and attenuate inflammation. In recent years, however, it has been increasingly appreciated that bile acids biotransformations by intestinal microbiota result in the formation of chemically different secondary bile acids that potently regulate adaptive immunity. The 3-oxoLCA and isoalloLCA, two LCA derivatives, bind receptors such as the retinoic acid receptor-related orphan receptor gamma t (RORγt) and the vitamin D receptor (VDR) that are expressed only by lymphoid cells, extending the regulatory role of bile acids to T cells, including T-helper 17 cells and type 3 innate lymphoid cells (ILC3). In this novel conceptual framework, bile acids have emerged as one of the main components of the postbiota, the waste array of chemical mediators generated by the intestinal microbiota. Deciphering the interaction of these mediators with the immune system in the intestine and liver is a novel and fascinating area of bile acid renaissance.

The liver is vital for metabolism, detoxification, storage, and secretion. Cholestasis, in which bile flow is hindered, can cause serious harm to the liver. This study examines the potential of ellagic acid to prevent cholestasis in male rats that has been caused by alpha-naphthyl isothiocyanate (ANIT).

Male rats were divided into four groups for an 8-day study. The control group received 5 % dimethyl sulfoxide (DMSO) orally for eight days and maize oil (1 mL/kg, orally) 48 h before sacrifice. The ANIT Group received 5 % DMSO orally for 8 days, the ANIT (100 mg/kg, orally) administered on the 6th day, 48 h before sacrifice. The low-Dose Ellagic Acid + ANIT Group was given ellagic acid (5 mg/kg, orally) for eight days, with ANIT (100 mg/kg, orally) on the 6th day, 48 h prior to sacrifice. The high-Dose Ellagic Acid + ANIT Group received ellagic acid (10 mg/kg, orally) for eight days, the ANIT (100 mg/kg, orally) on the 6th day, 48 h before sacrifice. Different biochemical and histopathological analyses were conducted to assess the protective effects of ellagic acid on ANIT-induced liver injury.

ANIT significantly elevated serum of liver enzymes. It caused severe bile duct inflammation and reduced bile salt export pump (BSEP) and Na+-taurocholate cotransporting polypeptide (NTCP) expression, indicating liver injury. Ellagic acid treatment mitigated these changes, improving biochemical parameters and reducing liver damage. ANIT-induced cholestasis results in bile acid accumulation due to decreased BSEP and NTCP expression linked to impaired farnesoid X receptor (FXR) signaling. Ellagic acid restored BSEP and NTCP levels via FXR activation, reducing bile acids and inflammatory markers IL-1β and TNF-α. Ellagic acid also enhanced SIRT1 activity, further improving FXR function and bile acid homeostasis.

Ellagic acid exhibits protective effects against cholestasis by enhancing the FXR signaling and ntcp and bsep expression with mitigating liver damage and inflammation.

The present study investigated the impact of butyrate glycerides (BG) on lipid metabolism, intestinal morphology, and microbiota of laying hens. Four hundred eighty 54-week-old Hy-line Brown laying hens were randomly selected and divided into five groups. The control group (ND) was fed a basal diet. Meanwhile, the remaining groups were given a basal supplemented with 0.5, 1, 2, and 4 g/kg of the product containing BG and were designated as BG-0.5, BG-1, BG-2, and BG-4 groups, respectively. The findings showed that: (1) BG supplementation significantly decreased (P < 0.001) the blood Glu levels (BG-0.5, BG-1, BG-2, and BG-4) and increased (P < 0.001) the serum HDL-C levels (BG-2, and BG-4). (2) The BG-2 and BG-4 groups showed an increase (P < 0.01) in abdominal lipid HSL activity. (3) The levels of hepatic TC and TG in all BG groups were significantly decreased (P < 0.05). (4) The addition of BG resulted in a significant reduction in the mRNA expression of the liver X receptor alpha (LXRα) (P < 0.05). (5) All BG groups presented a substantial reduction in duodenal crypt depth and a notable increase in the ratio of villus height to crypt depth (V/C) (P < 0.01). Additionally, all BG groups exhibited a significant increase in villus height in the ileum (P < 0.001). (6) Both the BG-1 and BG-4 groups exhibited a significant reduction in the amounts of n-butyric and n-glutaric acids in the cecum contents (P < 0.05). (7) The inclusion of BG did not substantially impact the diversity of cecal microbiota in laying hens. However, it dramatically boosted the proportion of the beneficial bacterium Alistipes (P < 0.05) and reduced the abundance of the harmful bacterium Verrucomicrobiota (P < 0.05). Overall, incorporating BG with glycerol monobutyrate as the diet's primary active component reduces fat accumulation in laying hens' blood and liver. It potentially regulates lipid metabolism via the PPARγ-LXRα-SREBP1c pathway. Additionally, BG has the potential to enhance the structure of the small intestine's mucous membrane and increase the presence of beneficial bacteria. Under the experimental conditions, late-laying hens supplemented with 4 g/kg BG performed best overall.

Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.

To evaluate the influence of late cholecystectomy following bariatric surgery on the postoperative evolution of weight loss and biochemical, metabolic, and micronutrient parameters.

A retrospective study that assessed 86 patients who underwent cholecystectomy after at least 18 months of bariatric surgery. The analyzed variables included demographic data, comorbidities, weight loss, and biochemical, metabolic, and micronutrient parameters.

Among the analyzed patients, 20 underwent gastric bypass (GB) and 66 underwent sleeve gastrectomy (SG). The GB group comprised 55% of women, with a mean age of 54.4 years and a mean preoperative body mass index (BMI) of 29.2 kg/m 2 . The mean time elapsed between GB and cholecystectomy was 118.3±43.9 months. The sample of SG comprised 83.3% of women, with a mean age of 41.1 years and a mean preoperative BMI of 28.7 kg/m 2 . The mean time elapsed between SG and cholecystectomy was 26.1±17.5 months. Both SG and GB groups showed a reduction in the mean BMI, but it was not statistically significant after cholecystectomy. In the metabolic, biochemical, and micronutrient evaluation, there was no statistically significant difference, except in the GB group, where an increase in vitamin D was observed after cholecystectomy with statistical significance.

Cholecystectomy does not negatively impact the clinical and anthropometric evolution of patients previously submitted to bariatric surgery.

Lipid droplets (LDs) are dynamic organelles essential for lipid storage and organismal survival. Studies have highlighted the importance of glial function in brain LD formation during aging; however, the genes and mechanisms involved remain elusive. Here, we found that Ugt35b, a member of the uridine diphosphate (UDP)-glycosyltransferases that catalyze the transfer of glycosyl groups to acceptors, is highly expressed in glia and crucial for Drosophila lifespan. By integrating multiomics data, we demonstrated that glial Ugt35b plays key roles in regulating glycerolipid and glycerophospholipid metabolism in the brain. Notably, we found that Ugt35b and Lsd-2 are co-expressed in glia and confirmed their protein interaction in vivo. Knockdown of Ugt35b significantly reduced LD formation by downregulating Lsd-2 expression, while overexpression of Lsd-2 partially rescued the shortened lifespan in glial Ugt35b RNAi flies. Our findings reveal the crucial role of glial Ugt35b in regulating LD formation to maintain brain lipid homeostasis and support Drosophila lifespan.

The effects of Enterococcus faecalis (E. faecalis) at a concentration of 1.0 × 108 CFU/mL on growth performance, hepatic lipid metabolism, and mRNA expression related to lipid metabolism, intestinal morphology, and intestinal flora were investigated in geese. A total of 60 male geese, aged 30 days and of similar weight, were randomly assigned to 2 groups. Each group was divided into six replicates, with five geese per replicate. During the 45-day experiment, the control group received a basal diet, while the experimental group was provided with the same basal diet supplemented with E. faecalis in drinking water at a concentration of 1.0 × 108 CFU/mL. E. faecalis significantly increased the half-eviscerated weight of geese and improved ileal intestinal morphology (p < 0.05). Serum triglyceride (TG) levels were significantly reduced on day 5, while serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased on day 25 (p < 0.05). By day 45, serum TG and free fatty acid (FFA) levels were also significantly reduced (p < 0.05). Additionally, E. faecalis significantly increased the HDL/LDL ratio and serum high-density lipoprotein cholesterol (HDL-C) levels (p < 0.05). Serum insulin levels were significantly elevated on day 25, and glucagon-like peptide-1 (GLP-1) levels were significantly increased on day 45 (p < 0.05). On day 25 of the trial, hepatic TG levels, FFA levels, and Oil Red O-stained areas in the liver were significantly reduced (p < 0.05), accompanied by significantly decreased mRNA expression of hepatic acetyl-CoA carboxylase (ACCA) (p < 0.05). Conversely, the mRNA expression levels of fatty acid synthase (FASN), farnesoid X receptor (FXR), sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor-α (PPARα) were significantly elevated (p < 0.05). A 16S rRNA diversity analysis of ileal contents on day 25 revealed significant differences in intestinal flora composition between the control and E. faecalis groups. The 16S rRNA data demonstrated a strong correlation between microbial communities and lipid-related physiological and biochemical indicators (p < 0.05). In conclusion, E. faecalis supplementation promoted fatty acid oxidation, reduced blood lipid levels, alleviated hepatic lipid accumulation, and improved ileal morphology and intestinal flora diversity, thereby enhancing growth performance and lipid metabolism in geese. These findings suggest that E. faecalis is a promising probiotic candidate for development as a feed additive.

The prevalence of obesity and osteoporosis (OP) represents a significant public health concern on a global scale. A substantial body of evidence indicates that there is a complex relationship between obesity and OP, with a correlation between the occurrence of OP and obesity. In recent years, sirtuins have emerged as a prominent area of interest in the fields of aging and endocrine metabolism. Among the various research avenues exploring the potential of sirtuins, the effects of these proteins on obesity and OP have garnered significant attention from numerous researchers. Sirtuins regulate energy balance and lipid balance, which in turn inhibit the process of adipogenesis. Additionally, sirtuins regulate the balance between osteogenic and osteoblastic activity, which protects against the development of OP. However, no study has yet provided a comprehensive discussion of the relationship between the three: sirtuins, obesity, and OP. This paper will therefore describe the relationship between sirtuins and obesity, the relationship between sirtuins and OP, and a discussion focusing on the possibility of treating OP caused by obesity by targeting sirtuins. This will be based on the common influences on the occurrence of obesity and OP (such as mesenchymal stem cells, gut microbiota, and insulin). Finally, the potential of SIRT1, an important member of sirtuins, in polyphenolic natural products for the treatment of obesity and OP will be presented. This will contribute to a better understanding of the interactions between sirtuins and obesity and bone, which will facilitate the development of new therapeutic strategies for obesity and OP in the future.

There is evidence of perturbed microbial and host processes in the gastrointestinal tract of individuals with functional gastrointestinal disorders (FGID) compared to healthy controls. The faecal metabolome provides insight into the metabolic processes localised to the intestinal tract, while the plasma metabolome highlights the overall perturbances of host and/or microbial responses. This study profiled the faecal (n = 221) and plasma (n = 206) metabolomes of individuals with functional constipation (FC), constipation-predominant irritable bowel syndrome (IBS-C), functional diarrhoea (FD), diarrhoea-predominant IBS (IBS-D) and healthy controls (identified using the Rome Criteria IV) using multimodal LC-MS technologies. Discriminant analysis separated patients with the 'all constipation' group (FC and IBS-C) from the healthy control group and 'all diarrhoea' group (FD and IBS-D) from the healthy control group in both sample types. In plasma, almost all multimodal metabolite analyses separated the 'all constipation' or 'all diarrhoea' group from the healthy controls, and the IBS-C or IBS-D group from the healthy control group. Plasma phospholipids and metabolites linked to several amino acid and nucleoside pathways differed (p < 0.05) between healthy controls and IBS-C. In contrast, metabolites involved in bile acid and amino acid metabolism were the key differentiating classes in the plasma of subjects with IBS-D from healthy controls. Faecal lipids, particularly ceramides, diglycerides, and triglycerides, varied (p < 0.05) between healthy controls and the 'all constipation' group and between healthy controls and 'all diarrhoea' group. The faecal and plasma metabolomes showed perturbations between constipation, diarrhoea and healthy control groups that may reflect processes and mechanisms linked to FGIDs.

Inflammation-induced cholestasis is a common problem in septic patients and results from cytokine-mediated inhibition of bile acid export including impaired expression of the bile salt export pump (BSEP) with a consecutive increase in intracellular bile acids mediating cell damage. The present study focuses on the mechanisms by which interleukin 1 β (IL-1β), as a critical mediator of sepsis-induced cholestasis, controls the expression of BSEP in hepatocytes. Notably, the treatment of hepatocytes with IL-1β leads to the upregulation of a broad chemokine pattern. Thereby, the IL-1β -induced expression of in particular the CXCR2 ligands CXCL1 and 2 is further enhanced by bile acids, whereas the FXR-mediated upregulation of BSEP induced by bile acids is inhibited by IL-1β. In this context, it is interesting to note that inhibitor studies indicate that IL-1β mediates its inhibitory effects on bile acid-induced expression of BSEP indirectly via CXCR2 ligands. Consistently, inhibition of CXCR2 with the inhibitor SB225002 significantly attenuated of the inhibitory effect of IL-1β on BSEP expression. These data suggest that part of the cholestasis-inducing effect of IL-1β is mediated via a CXCR2-dependent feedback mechanism.

Non-alcoholic fatty liver disease (NAFLD) begins with lipid accumulation and progresses toward inflammation and fibrosis. Nuclear receptors (NRs), like the Peroxisome Proliferator-Activated Receptors alpha and gamma (PPARα and PPARy), the Farnesoid X Receptor (FXR), and the Liver X receptor (LXR), regulate genes by heterodimerizing with Retinoid X receptor (RXR). These receptors are emerging targets for pharmaceutical intervention for metabolic diseases.

Bile acid (BA) signaling dysregulation is an important etiology for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). As diverse signaling molecules synthesized in the liver by pathways initiated with CYP7A1 and CYP27A1, BAs are endogenous modulators of farnesoid x receptor (FXR). FXR activation is crucial in maintaining BA homeostasis, regulating lipid metabolism, and suppressing inflammation. Additionally, BAs interact with membrane receptors and gut microbiota to regulate energy expenditure and intestinal health. Complex modulation of BAs in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs, especially during MASLD development. Previously, we determined that acute feeding of individual BAs differentially affects lipid, inflammation, and oxidative stress pathways in a low-BA mouse model, Cyp7a1/Cyp27a1 double knockout (DKO) mice. Currently, we investigated to what degree cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological concentrations impact MASLD development in DKO mice. The results showed that these 3 BAs varied in the ability to activate hepatic and intestinal FXR, disrupt lipid homeostasis, and modulate inflammation and fibrosis. Additionally, UDCA activated intestinal FXR in these low-BA mice. Significant alterations in lipid uptake and metabolism in DKO mice following CA and DCA feeding indicate differences in cholesterol and lipid handling across genotypes. Overall, the DKO were less susceptible to weight gain, but more susceptible to MASH diet induced inflammation and fibrosis on CA and DCA supplements, whereas WT mice were more vulnerable to CA-induced fibrosis on the control diet.

Mitochondria are the main source of energy for cellular activity. Their functional damage or deficiency leads to cellular deterioration, which in turn triggers autophagic reactions. Taking mitochondrial autophagy as a starting point, the present review explored the mechanisms of duodenal abnormalities in detail, including mucosal barrier damage, release of inflammatory factors, and disruption of intracellular signal transduction. We summarized the key roles of mitochondrial autophagy in the abnormal development of the duodenum and examined the in-depth physiological and pathological mechanisms involved, providing a comprehensive theoretical basis for understanding the pathogenesis of functional dyspepsia. At present, it has been confirmed that an increase in the eosinophil count and mast cell degranulation in the duodenum can trigger visceral hypersensitive reactions and cause gastrointestinal motility disorders. In the future, it is necessary to continue exploring the molecular mechanisms and signaling pathways of mitochondrial autophagy in duodenal abnormalities. A deeper understanding of mitochondrial autophagy provides important references for developing treatment strategies for functional dyspepsia, thereby improving clinical efficacy and patient quality of life.

Hepatic oxidative injury induced by free fatty acids (FFA) and metabolic disorders of bile acids (BA) increase the risk of metabolic diseases in dairy cows during perinatal period. However, the effects of FFA on BA metabolism remained poorly understood. In present study, high concentrations of FFA caused cell impairment, oxidative stress and BA overproduction. FFA treatment increased the expression of BA synthesis-related genes [cholesterol 7a-hydroxylase (CYP7A1), hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7, sterol 12α-hydroxylase, sterol 27-hydroxylase and oxysterol 7α-hydroxylase], whereas reduced BA exportation gene (ATP binding cassette subfamily C member 1) and inhibited farnesoid X receptor/small heterodimer partner (FXR/SHP) pathway in bovine hepatocytes. Knockdown of nuclear receptor subfamily 1 group H member 4 (NR1H4) worsened FFA-caused oxidative damage and BA production, whereas overexpression NR1H4 ameliorated FFA-induced BA production and cell oxidative damage. Besides, reducing BA synthesis through knockdown of CYP7A1 can alleviate oxidative stress and hepatocytes impairment caused by FFA. In summary, these data demonstrated that regulation of FXR/SHP-mediated BA metabolism may be a promising target in improving hepatic oxidative injury of dairy cows during high levels of FFA challenges.

Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal-mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.

Shengmai San Formula (SMS) is a traditional Chinese medicine (TCM) that has been used to treat wasting-thirst regarded as diabetes mellitus, which occurs disproportionately in obese patients. Therefore, we investigated whether SMS could be used to treat obesity, and explored possible mechanisms by which it might improve glucose and fat metabolism.

To investigate the effects of SMS on a high-fat diet (HFD)-induced obesity (DIO) model, we studied glucose metabolism via glucose tolerance testing (GTT) and insulin tolerance testing (ITT). Browning of white adipose tissue (WAT) was evaluated using H&E staining, along with browning-related gene and protein expression. Changes in bile acid (BA) levels in serum, liver, ileum, and inguinal white adipose tissue were detected by Ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). In addition, antimicrobial mixture (ABX) and fecal microbial transplantation (FMT) experiments were used to verify the role of gut flora in the effects produced by SMS on HFD-induced obesity model.

SMS ameliorated diet-induced dyslipidemia in a dose-dependent manner and reduced glucose intolerance and insulin resistance in DIO mice, helping to restore energy metabolism homeostasis. SMS significantly altered the structure of intestinal microbiome composition, decreasing the abundance of Lactobacillus carrying bile salt hydrolase (BSH) enzymes and thereby increasing the level of conjugated BAs in the blood, ileum, and iWAT. Increased TCA content promoted the secretion of Slit3 from M2 macrophages in iWAT, which activates the protein kinase A/calmodulin-dependent protein kinase II (PKA/CaMKII) signaling pathway in sympathetic neurons via the roundabouts receptor 1(ROBO1). This pathway promotes the synthesis and release of norepinephrine (NE), inducing cyclic adenosine monophosphate (cAMP) release in adipose tissue that activates the cyclic adenosine monophosphate/protein kinase A/phosphorylated hormone-sensitive lipase (cAMP/PKA/pHSL) pathway and enhances WAT browning. ABX treatment eliminated SMS effects on glucose and lipid metabolism in DIO mice, whereas glucose and lipid metabolism in obese mice improved following SMS-FMT and increased the level of serum bile acids.

SMS affects intestinal flora and bile acid composition in vivo and increased TCA promotes M2 macrophage polarization and Slit3 release in adipose tissue. This induces NE release and increases WAT browning in obese mice, which may be a mechanism by which SMS could be used to treat obesity.

Current treatment paradigms for metabolic dysfunction-associated steatohepatitis (MASH) are based primarily on dietary restrictions and the use of existing drugs, including anti-diabetic and anti-obesity medications. Given the limited number of approved drugs specifically for MASH, recent efforts have focused on promising strategies that specifically target hepatic lipid metabolism, inflammation, fibrosis, or a combination of these processes. In this review, we examined the pathophysiology underlying the development of MASH in relation to recent advances in effective MASH therapy. Particularly, we analyzed the effects of lipogenesis inhibitors, nuclear receptor agonists, glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, fibroblast growth factor mimetics, and combinatorial therapeutic approaches. We summarize these targets along with their preclinical and clinical candidates with the ultimate goal of optimizing the therapeutic prospects for MASH.

The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor signaling potentiates ethanol (EtOH)-induced hepatotoxicity in male mice, however, how PXR signaling modulates EtOH-induced hepatotoxicity in female mice is unknown. Wild type (WT) and Pxr-null mice received 5 % EtOH-containing diets or paired-fed control diets for 8 weeks followed by assessment of liver injury, EtOH elimination rates, histology, and changes in gene and protein expression; microarray and bioinformatic analyses were also employed to identify PXR targets in chronic EtOH-induced hepatotoxicity. In WT females, EtOH ingestion significantly increased serum ethanol and alanine aminotransferase (ALT) levels, hepatic Pxr mRNA, constitutive androstane receptor activation, Cyp2b10 mRNA and protein, oxidative stress, endoplasmic stress (phospho-elF2α) and pro-apoptotic (Bax) protein expression. Unexpectedly, EtOH-fed female Pxr-null mice displayed increased EtOH elimination and elevated levels of hepatic acetaldehyde detoxifying aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA and protein, EtOH-metabolizing alcohol dehydrogenase 1 (ADH1), and lipid suppressing microsomal triglyceride transport protein (MTP) protein, aldo-keto reductase 1b7 (Akr1b7) and Cyp2a5 mRNA, but suppressed CYP2B10 protein levels, with evidence of protection against chronic EtOH-induced oxidative stress and hepatotoxicity. While liver injury was not different between the two WT sexes, female sex may suppress EtOH-induced macrovesicular steatosis in the liver. Several genes and pathways important in retinol and steroid hormone biosynthesis, chemical carcinogenesis, and arachidonic acid metabolism were upregulated by EtOH in a PXR-dependent manner in both sexes. Together, these data establish that female Pxr-null mice are resistant to chronic EtOH-induced hepatotoxicity and unravel the PXR-dependent and -independent mechanisms that contribute to EtOH-induced hepatotoxicity.

Progressive familial intrahepatic cholestasis (PFIC) is a liver disease that occurs during childhood and requires liver transplantation. ABCB4 is localized along the canalicular membranes of hepatocytes, transports phosphatidylcholine into bile, and its mutation causes PFIC3. Abcb4 gene-deficient mice established as animal models of PFIC3 exhibit cholestasis-induced liver injury. However, their phenotypes are often milder than those of human PFIC3, partly because of the existence of large amounts of less toxic hydrophilic bile acids synthesized by the rodent-specific enzymes Cyp2c70 and Cyp2a12. Mice with double deletions of Cyp2c70/Cyp2a12 (CYPDKO mice) have a human-like hydrophobic bile acid composition. PFIC-related gene mutations were induced in CYPDKO mice to determine whether these triple-gene-deficient mice are a better model for PFIC. To establish a PFIC3 mouse model using CYPDKO mice, we induced abcb4 gene deletion in vivo using adeno-associated viruses expressing SaCas9 under the control of a liver-specific promoter and abcb4-target gRNAs. Compared to Abcb4-deficient wild-type mice, Abcb4-deficient CYPDKO mice showed more pronounced liver injury along with an elevation of inflammatory and fibrotic markers. The proliferation of intrahepatic bile ductal cells and hematopoietic cell infiltration were also observed. CYPDKO/abcb4-deficient mice show a predominance of taurine-conjugated chenodeoxycholic acid and lithocholic acid in the liver. In addition, phospholipid levels in the gallbladder bile were barely detectable. Mice with both human-like bile acid composition and Abcb4-defect exhibit severe cholestatic liver injury and are useful for studying human cholestatic diseases and developing new treatments.