TY - JOUR T1 - Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway JF - Molecular Pharmacology JO - Mol Pharmacol SP - 110 LP - 122 DO - 10.1124/mol.116.106617 VL - 91 IS - 2 AU - Runbin Sun AU - Na Yang AU - Bo Kong AU - Bei Cao AU - Dong Feng AU - Xiaoyi Yu AU - Chun Ge AU - Jingqiu Huang AU - Jianliang Shen AU - Pei Wang AU - Siqi Feng AU - Fei Fei AU - Jiahua Guo AU - Jun He AU - Nan Aa AU - Qiang Chen AU - Yang Pan AU - Justin D. Schumacher AU - Chung S. Yang AU - Grace L. Guo AU - Jiye Aa AU - Guangji Wang Y1 - 2017/02/01 UR - http://molpharm.aspetjournals.org/content/91/2/110.abstract N2 - 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. ER -