Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease.
alcoholic liver disease (ALD); bacterial translocation; Bile acid; binding protein; farnesoid X receptor (FXR); farnesoid-x-receptor; fatty liver; glucagon-like peptide-1; growth-factor 19; gut microbiota; microbiota; molecular-cloning; non-alcoholic steatohepatitis (NASH); non-alcoholic steatohepatitis (NASH); nuclear receptor; solute transporter-alpha
Bile acids are synthesized from cholesterol only in hepatocytes. Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine. Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor TGR5. FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis. In addition, bile acid-activated cellular signaling pathways regulate metabolic homeostasis, immunity, and cell proliferation in various metabolically active organs. In the small and large intestine, gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects. In turn, bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity. Currently, bile acid-based therapies including systemic and intestine-restricted FXR agonists, TGR5 agonists, fibroblast growth factor 19 analogue, intestine FXR antagonists, and intestine apical sodium-bile acid transporter (ASBT) inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis (NASH). These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest. More recently, human and experimental alcoholic liver disease (ALD) has been associated with disrupted bile acid homeostasis. In additional, new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.
Li Tiangang; Chiang John Y L
Hepatobiliary surgery and nutrition
2020
2020-04
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journalArticle
<a href="http://doi.org/10.21037/hbsn.2019.09.03" target="_blank" rel="noreferrer noopener">10.21037/hbsn.2019.09.03</a>
The Ras-related protein AGS1/RASD1 suppresses cell growth
activation; AGS1; apoptosis; binding protein; Biochemistry & Molecular Biology; cancer; Cell Biology; coupled receptors; Dexras1; Dexras1; G protein; gene; Genetics &; Heredity; hormone; identification; Integration; Oncology; RASD1; signal-transduction
AGS1/RASD1 is a Ras-related protein identified as a dexamethasone-inducible cDNA and as a signal regulator in various functional and protein-interaction screens. As an initial approach to define the role of AGS1/RASD1 as a Ras-family member, we determined its influence on cell growth/survival. In clonogenic assays with NIH-3T3 murine fibroblast cells, the MCF-7 human breast cancer cell line and the human lung adenocarcinoma cell line A549, AGS1/RASD1 markedly diminished the number of G418-resistant colonies, whereas the Ras subgroup member K-Ras was without effect. A549 cell infection with adenovirus engineered to express AGS1/RASD1 (Ad.AGS1) inhibited log phase growth in vitro and increased the percentage of cells undergoing apoptosis. The anti-growth action was also observed in vivo as the expression of AGS1/RASD1 inhibited the subcutaneous tumor growth of A549 cells in athymic nude mice. These data indicate that AGS1/RASD1, a member of the Ras superfamily of small G-proteins that often promotes cell growth and tumor expansion, plays an active role in preventing aberrant cell growth.
Vaidyanathan G; Cismowski M J; Wang G S; Vincent T S; Brown K D; Lanier S M
Oncogene
2004
2004-07
Journal Article
<a href="http://doi.org/10.1038/sj.onc.1207774" target="_blank" rel="noreferrer noopener">10.1038/sj.onc.1207774</a>