Gypenosides Altered Hepatic Bile Acids Homeostasis in Mice Treated with High Fat Diet

Abstract

Gypenosides extracted from Gynostemma pentaphyllum (Thunb.) Makino have significant role in reducing serum lipid level and treating fatty liver diseases, however, without clear mechanism. As gypenosides share the similar core structures with bile acids (the endogenous ligands of nuclear receptor FXR), we hypothesize that gypenosides may improve hypercholesterolemia via FXR-mediated bile acids signaling. The present study was designed to validate the role of gypenosides in reducing levels of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), as well as in regulating bile acids homeostasis and related gene expression levels. The C57BL/6 male mice were divided into four groups. Mice in groups ND and HFD were fed with normal diet and high fat diet for 38 weeks, respectively. In groups HFD+GP and HFD+ST, mice were fed with high fat diet for 38 weeks and treated with gypenosides and simvastatin (positive control) from weeks 16 to 38, respectively. Serum TC and LDL-C levels were assayed by commercially available kits. Expression levels of genes were tested by the quantitative real-time PCR. The LC-MS/MS was applied to quantify major bile acids in mice livers. Our results showed that gypenosides significantly decreased serum TC and LDL-C levels. The gene expression level of Shp was downregulated while the levels of Cyp7a1, Cyp8b1, Fxr, Lrh1, Jnk1/2, and Erk1/2 were upregulated by gypenosides. Indicated by LC-MS/MS technology, gypenosides increased the hepatic levels of several free bile acids and most taurine-conjugated bile acids while decreasing glycine-conjugated bile acids levels. In addition, gypenosides decreased the CA/CDCA ratio. Gypenosides may improve the abnormal lipid profile of HFD-fed mice via two pathways: (1) enhancing the bile acids biosynthesis from cholesterol; (2) decreasing the CA/CDCA ratio which is positively related to cholesterol absorption.

Gypenosides regulate farnesoid X receptor-mediated bile acid and lipid metabolism in a mouse model of non-alcoholic steatohepatitis

“…Moreover, we observed that Gyp treatment could significantly reduce the TBA content as well as the aMCA, TaMCA, βMCA, TβMCA TCDCA, CA, GCDCA, GCA and TCA content and significantly increased the alloLCA and βCDCA content in liver tissues from NASH mice, and thus, it promoted hepatic bile acid homeostasis. In agreement, previous research demonstrated that Gyp can alter the liver bile acid homeostasis induced by a HFD [41]. Also, Gyp treatment successfully regulated the adipose thermogenesis and gut microbiota, which were reduced in the process of gaining weight [42].…”

High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice

“…Our study shows that high fat diet mice were inhibited expression of Cyp8b1 and Cyp7a1. Cholesterol catabolism into bile acids was inhibited, which caused the cholesterol elevated cholesterol [39].…”

Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis

“…An increased concentration of the primary bile BAs CA and CDCA [44], with a consequent increase of their ratio, has been evaluated as a marker of intrahepatic cholestasis of pregnancy [45] and progressive familial intrahepatic cholestasis [46]. More recently, changes have been observed in animal models and patients affected by NAFLD and NASH [47,48]. Coherently, we also observed a significant increase of the CDCA drop of CA plasma concentration in rats fed with a Western diet, but there was a significant drop of CA, leading to a decrease of the CA:CDCA ratio.…”