With the increased incidence of obesity, nonalcoholic fatty liver disease (NAFLD) has become a major global health concern. The pathogenesis of NAFLD has not yet been fully elucidated, and as few efficient pharmaceutical treatments are available for the condition, economic and medical burdens are heavy. Hepatic steatosis, as a precursor of NAFLD, plays a vital role in the pathological process of NAFLD. Hepatic steatosis is a consequence of lipid acquisition (i.e. free fatty acid uptake and de novo lipogenesis) exceeding lipid disposal (i.e. fatty acid oxidation and export as very-low-density lipoproteins). Therefore, restoring lipid homeostasis in the liver is an important therapeutic strategy of NAFLD. Farnesoid X receptor (FXR) is a major member of the ligand-activated nuclear receptor superfamily. Previous reviews have shown that FXR is a multipurpose receptor that plays an important role in regulating bile acid homeostasis, glucose and lipid metabolism, intestinal bacterial growth, and hepatic regeneration. This review focuses on the role of FXR in individual pathways that contribute to hepatic steatosis; it further demonstrates the molecular function of FXR in the pathogenesis of NAFLD.

Information transmission between primary tumor cells and immunocytes or stromal cells in distal organs is a critical factor in the formation of pre-metastatic niche (PMN). Understanding this mechanism is essential for developing effective therapeutic strategy against tumor metastasis. Our study aims to prove the hypothesis that circ-0034880-enriched tumor-derived extracellular vesicles (TEVs) mediate the formation of PMN and colorectal cancer liver metastasis (CRLM), and targeting circ-0034880-enriched TEVs might be an effective therapeutic strategy against PMN formation and CRLM. We utilized qPCR and FISH to measure circRNAs expression levels in human CRC plasma, primary CRC tissues, and liver metastatic tissues. Additionally, we employed immunofluorescence, RNA sequencing, and in vivo experiments to assess the effect mechanism of circ-0034880-enriched TEVs on PMN formation and CRC metastasis. DARTS, CETSA and computational docking modeling were applied to explore the pharmacological effects of Ginsenoside Rb1 in impeding PMN formation. We found that circ-0034880 was highly enriched in plasma extracellular vesicles (EVs) derived from CRC patients and closely associated with CRLM. Functionally, circ-0034880-enriched TEVs entered the liver tissues and were absorbed by macrophages in the liver through bloodstream. Mechanically, TEVs-released circ-0034880 enhanced the activation of SPP1^highCD206⁺ pro-tumor macrophages, reshaping the metastasis-supportive host stromal microenvironment and promoting overt metastasis. Importantly, our mechanistic findings led us to discover that the natural product Ginsenoside Rb1 impeded the activation of SPP1^highCD206⁺ pro-tumor macrophages by reducing circ-0034880 biogenesis, thereby suppressing PMN formation and inhibiting CRLM. Circ-0034880-enriched TEVs facilitate strong interaction between primary tumor cells and SPP1^highCD206⁺ pro-tumor macrophages, promoting PMN formation and CRLM. These findings suggest the potential of using Ginsenoside Rb1 as an alternative therapeutic agent to reshape PMN formation and prevent CRLM.

Our previous studies found that salidroside can effectively treat non-alcoholic steatohepatitis (NASH). Here, we discuss the mechanism of salidroside in the treatment of NASH with a focus on the gut microbiota-bile acid-farnesoid X receptor axis. A NASH mouse model was created by providing mice with a high-fat diet (HFD) for 14 weeks. Mice were randomly divided into the HFD group, HFD + salidroside treatment group, and HFD + obeticholic acid treatment group (n = 8 in each group) and were intragastrically administered corresponding drugs for 4 weeks. Hematoxylin-eosin staining was performed to evaluate the histopathological changes associated with the various treatments. In addition, liver triglyceride (TG) content, serum alanine aminotransferase (ALT) activity, serum inflammatory factors, gut microbiota diversity, and the bile acid profile were evaluated. Western blotting and RT-PCR were performed to detect the expressions of FXR and fibroblast growth factor 15 (FGF15). The HFD group displayed obvious signs of hepatic steatosis. The liver TG, serum ALT, and IL-1a, IL-12, MCP-1, KC, MIP-1a, and MIP-1β were significantly higher in the HFD group than the control group (P < 0.01). Intestinal bacteria and bile acid profiles changed significantly in the HFD group (P < 0.05). Further, the expressions of FXR and FGF15 decreased significantly in the HFD group (P < 0.05). After treatment with salidroside, liver steatosis, TG content, and serum inflammatory factors significantly improved and HFD-induced intestinal bacteria, bile acid disorder, and FXR deficiency were significantly alleviated (P < 0.05). Salidroside can improve NASH via the gut microbiota-bile acid-FXR axis.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition observed globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Currently, the US Food and Drug Administration (FDA) has not approved any drugs for the treatment of NAFLD. NAFLD is characterized by histopathological abnormalities in the liver, such as lipid accumulation, steatosis, hepatic balloon degeneration, and inflammation. Dysbiosis of the gut microbiota and its metabolites significantly contribute to the initiation and advancement of NAFLD. Bacteroides, a potential probiotic, has shown strong potential in preventing the onset and progression of NAFLD. However, the precise mechanism by which Bacteroides treats NAFLD remains uncertain. In this review, we explore the current understanding of the role of Bacteroides and its metabolites in the treatment of NAFLD, focusing on their ability to reduce liver inflammation, mitigate hepatic steatosis, and enhance intestinal barrier function. Additionally, we summarize how Bacteroides alleviates pathological changes by restoring the metabolism, improving insulin resistance, regulating cytokines, and promoting tight-junctions. A deeper comprehension of the mechanisms through which Bacteroides is involved in the pathogenesis of NAFLD should aid the development of innovative drugs targeting NAFLD.

Background: Gypenosides (Gyp) are the main ingredient of the Chinese medicine, Gynostemma pentaphyllum. They are widely used in Asia as a hepatoprotective agent. Here, we elucidated the mechanism of Gyp in non-alcoholic steatohepatitis (NASH) with a focus on farnesoid X receptor (FXR)-mediated bile acid and lipid metabolic pathways. Methods: NASH was induced in mice by high-fat diet (HFD) feeding, while mice in the control group were given a normal diet. At the end of week 10, HFD-fed mice were randomly divided into HFD, HFD plus Gyp, and HFD plus obeticholic acid (OCA, FXR agonist) groups and were given the corresponding treatments for 4 weeks. Next, we analyzed the histopathological changes as well as the liver triglyceride (TG) level and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG), fasting insulin (FINS), TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels as well as the bile acid profile. We carried out RT-PCR and western blotting to detect HFD-induced alterations in gene/protein expression related to bile acid and lipid metabolism. Results: The HFD group had histopathological signs of hepatic steatosis and vacuolar degeneration. The liver TG and serum ALT, AST, FBG, FINS, TC, and LDL-C levels as well as the total bile acid level were significantly higher in the HFD group than in the control group (P < 0.01). In addition, we observed significant changes in the expression of proteins involved in bile acid or lipid metabolism (P < 0.05). Upon treatment with Gyp or OCA, signs of hepatic steatosis and alterations in different biochemical parameters were significantly improved (P < 0.05). Further, HFD-induced alterations in the expression genes involved in bile acid and lipid metabolism, such as CYP7A1, BSEP, SREBP1, and FASN, were significantly alleviated. Conclusions: Gyp can improve liver lipid and bile acid metabolism in a mouse model of NASH, and these effects may be related to activation of the FXR signaling pathway.

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