Lupeol improves bile acid metabolism and metabolic dysfunction-associated steatotic liver disease in mice via FXR signaling pathway and gut-liver axis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has a multifactorial and complex pathogenesis. Notably, the disorder of Bile acid (BA) metabolism and lipid metabolism-induced lipotoxicity are the main risk factors of MASLD. Lupeol, traditional regional medicine from Xinjiang, has a long history of use for its anti-inflammatory, anti-tumor, and immune-modulating properties. Recent research suggests its potential as a therapeutic option for MASLD due to its proposed binding capacity to the nuclear BA receptor, Farnesoid X receptor (FXR), hence could represent a therapeutic option for MASLD. In this study, a natural triterpenoid drug lupeol improved BA metabolism and MASLD in mice through the FXR signaling pathway and the gut-liver axis. Furthermore, lupeol effectively restored gut healthiness and improved intestinal immunity, barrier integrity, and inflammation, as indicated by the reconstructed gut flora. Compared with fenofibrate (Feno), lupeol treatment significantly reduced weight gain, fat deposition, and liver injury, decreased serum total cholesterol (TC) and triglyceride (TG) levels, and alleviated hepatic steatosis and liver inflammation. BA analysis showed that lupeol treatment accelerated BA efflux and decreased uptake of BA by increasing hepatic FXR and bile salt export pump (BSEP) expression. Gut microbiota alterations could be related to enhanced fecal BA excretion in lupeol-treated mice. Therefore, consumption of lupeol may prevent HFD-induced MASLD and BA accumulation, possibly via the FXR signaling pathway and regulating the gut microbiota.

Qin D ，Pan P ，Lyu B ，Chen W ，Gao Y ... -  《-》

Mitigation of high-fat diet-induced hepatic steatosis by thyme (Thymus quinquecostatus Celak) polyphenol-rich extract (TPE): insights into gut microbiota modulation and bile acid metabolism.

Sheng X ，Zhan P ，Wang P ，He W ，Tian H ... -  《-》

Silymarin targets the FXR protein through microbial metabolite 7-keto-deoxycholic acid to treat MASLD in obese mice.

Silymarin is recognized for its excellent hepato-protective properties. Recent clinical studies have examined the effects of silymarin on metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the necessity of further exploration into optimal dosages, active components, and mechanisms of action. This study assessed the anti-inflammatory activity of the principal constituents of silymarin at the cellular level. The therapeutic effects of varying silymarin doses and components on MASLD in mouse models induced by a high-fat diet (HFD) were also examined. These findings indicate the superior efficacy of 80 mg kg-1 silymarin in mitigating liver steatosis and reducing lipid accumulation compared to 30 mg kg-1 silymarin or a combination of silybin and isosilybin A. The mechanism of silymarin involves regulating gut microbiota homeostasis and influencing the TLR4/NF-κB signalling pathway through LPS. Bile acid-targeted metabolomics analysis revealed that silymarin significantly decreases the HFD-induced increase in 7-keto-deoxycholic acid (7-KDCA). Further investigations suggested that 7-KDCA as an antagonist targeted farnesoid X receptor (FXR) and that both silybin and isosilybin A could directly interact with FXR. These findings elucidate that 80 mg kg-1 of silymarin can exert therapeutic effects on MASLD mice and offer novel insights into the mechanism of silymarin in treating MASLD. Especially, it was found that silymarin could regulate bile acid metabolism, reduce the concentration of 7-KDCA, and thus perform negative feedback regulation on FXR.

Yi M ，Manzoor M ，Yang M ，Zhang H ，Wang L ，Zhao L ，Xiang L ，Qi J ... -  《-》

Dan-shen Yin promotes bile acid metabolism and excretion to prevent atherosclerosis via activating FXR/BSEP signaling pathway.

Dan-shen Yin (DSY), a traditional prescription, has been demonstrated to be effective in decreasing hyperlipidemia and preventing atherosclerosis (AS), but its mechanism remains unknown. We hypothesized that DSY activates farnesoid X receptor (FXR) to promote bile acid metabolism and excretion, thereby alleviating AS. This study was designed to explore whether DSY reduces liver lipid accumulation and prevents AS by activating FXR and increasing cholesterol metabolism and bile acid excretion. The comprehensive chemical characterization of DSY was analyzed by UHPLC-MS/MS. The AS models of ApoE-/- mice and SD rats was established by high-fat diet and high-fat diet combined with intraperitoneal injection of vitamin D3, respectively. The aortic plaque and pathological changes were used to evaluate AS. Lipid levels, H&E staining and oil red O staining were used to evaluate liver lipid accumulation. The cholesterol metabolism and bile acid excretion were evaluated by enzyme-linked immunosorbent assay, UPLC-QQQ/MS. In vitro, the lipid and FXR/bile salt export pump (BSEP) levels were evaluated by oil red O staining, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. A total of 36 ingredients in DSY were identified by UPLC-MS/MS analysis. In vivo, high-dose DSY significantly inhibited aortic intimal thickening, improved arrangement disorder, tortuosity, and rupture of elastic fibers, decreased lipid levels, and reduced the number of fat vacuoles and lipid droplets in liver tissue in SD rats and ApoE-/- mice. Further studies found that high-dose DSY significantly reduced liver lipid and total bile acids levels, increased liver ursodeoxycholic acid (UDCA) and other non-conjugated bile acids levels, increased fecal total cholesterol (TC) levels, and augmented FXR, BSEP, cholesterol 7-alpha hydroxylase (CYP7A1), ATP binding cassette subfamily G5/G8 (ABCG5/8) expression levels, while decreasing ASBT expression levels. In vitro studies showed that DSY significantly reduced TC and TG levels, as well as lipid droplets, while also increasing the expression of ABCG5/8, FXR, and BSEP in both HepG2 and Nr1h4 knockdown HepG2 cells. This study demonstrated that DSY promotes bile acid metabolism and excretion to prevent AS by activating FXR. For the prevent of AS and drug discovery provided experimental basis.

Sheng Y ，Meng G ，Zhang M ，Chen X ，Chai X ，Yu H ，Han L ，Wang Q ，Wang Y ，Jiang M ... -  《-》

Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway.

Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXRint-/-) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXRint-/- mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver.

Sun R ，Yang N ，Kong B ，Cao B ，Feng D ，Yu X ，Ge C ，Huang J ，Shen J ，Wang P ，Feng S ，Fei F ，Guo J ，He J ，Aa N ，Chen Q ，Pan Y ，Schumacher JD ，Yang CS ，Guo GL ，Aa J ，Wang G ... -  《-》