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  • The review Bile acid receptor link nutrient sensing to

    2019-06-11

    The review “Bile Nanaomycin A receptor link nutrient sensing to metabolic regulation” by Li and Li is focused on bile acid receptors in the regulation of hepatic glucose and lipid metabolism and inflammation. Cholestasis and NAFLD are inflammatory liver diseases. Triglycerides are non-toxic, but accumulation of free fatty acids can stimulate inflammatory cytokine production and hepatic insulin resistance. Activation of FXR is known to inhibit lipogenesis and gluconeogenesis in hepatocytes. This review also includes the recent finding that bile acids regulate autophagy in hepatocytes. Autophagy is induced during starvation to provide nutrients such as amino acids and fatty acids for energy metabolism. Autophagy is regulated by mechanistic target of rapamycin (mTOR) signaling and cAMP-activated protein kinase (AMPK) signaling in response to nutrient availability and growth hormone signaling. Autophagy transports stored lipids to the lysosomes for hydrolysis (lipophagy) and thus, inhibition of autophagy increases triglyceride storage in lipid droplets. Bile acids inhibit hepatic autophagic flux in cultured hepatocytes and in knockout mice an increased bile acid pool inhibits autophagy. A recent study reports that autophagy in hepatocytes is inhibited by free cholesterol and increasing bile acid synthesis reduces free cholesterol and results in stimulation of autophagy, and bile acids induce hepatic autophagy via a CYP7A1-AKT-mTOR pathway in mice. Thus, Nanaomycin A the control of bile acid homeostasis and autophagy is important in preventing cholestasis and NAFLD. The review entitled “New insights into the role of genes in cholesterol–supersaturated bile” by Wang et al. provides a historical summary of cholesterol gallstone disease genetics and treatment. Gallstone disease has high prevalence worldwide. The authors describe that in a Chinese medical record for “therapeutic interventions of gallstone stone disease was found in Treatise on Properties of Drugs (c. 643 CE or earlier) written by an ancient Chinese Doctor Zhen Quan (c. 540 to 643 CE)”. The Chinese have used bear bile to treat digestive disease for a thousand years. UDCA is a major component of bear bile. In this review, the authors describe the history of cholesterol and bile acid research. Heinrich Wieland and Adolf Windaus were awarded Nobel Prizes in Chemistry in 1927 and 1928, respectively, for their discovery of the structure of bile acid. The authors also describe the physical chemistry of the super saturation of cholesterol in gallstone formation, and identification of the mouse gene as one of many gallstone disease genes. The pathogenesis of cholesterol gallstone disease is described in detail. An original research article “Transgenic overexpression of steroid sulfatase alleviated cholestasis” describes the role of steroid sulfatase in maintaining oxysterol homeostasis and protection against bile acid-induced cholestasis. In liver, cholesterol is oxidized to oxysterols. Many intermediates in the bile acid synthesis pathways are oxysterol. Oxysterols are potent agonists of liver X receptor (LXR), which is known to induce mouse LXR (but not human CYP7A1) to stimulate bile acid synthesis and lipogenesis in mice. These oxidized cholesterol metabolites are toxic and conjugated to sulfate by sulfotransferases, whereas steroid sulfatase catalyzes the reverse reaction. Sulfated-oxysterols are antagonists of LXR. Interestingly, liver-specific transgenic mice are protected from lithocholic acid-induced cholestasis.
    Introduction
    Bile acid metabolism
    Bile acid receptors in metabolic regulation Bile acids regulate hepatic metabolism via activation of FXR and TGR5. These two bile acid-activated receptors are highly expressed in the gastrointestinal tract and play critical roles in the regulation of liver metabolism and homeostasis. The gut microbiota controls the release of gut hormones/peptides, such as peptide YY and glucagon-like peptide-1 (GLP-1). These hormones regulate insulin secretion from pancreatic β-cells and, in turn, glucose homeostasis. The gut microbiota also causes low-grade inflammation and initiates obesity and insulin resistance. Dysbiosis has been associated with inflammatory bowel diseases, obesity, and type 2 diabetes as well as non-alcoholic fatty liver disease, cirrhosis, and liver cancer.