%0 Journal Article %A Runbin Sun %A Na Yang %A Bo Kong %A Bei Cao %A Dong Feng %A Xiaoyi Yu %A Chun Ge %A Jingqiu Huang %A Jianliang Shen %A Pei Wang %A Siqi Feng %A Fei Fei %A Jiahua Guo %A Jun He %A Nan Aa %A Qiang Chen %A Yang Pan %A Justin D. Schumacher %A Chung S. Yang %A Grace L. Guo %A Jiye Aa %A Guangji Wang %T Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway %D 2016 %R 10.1124/mol.116.106617 %J Molecular Pharmacology %P mol.116.106617 %X Previous studies suggest that the lipid-lowering effect of BBR involves actions on the LDL receptor and the AMPK 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 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, significantly increased the levels of tauro-conjugated bile acids, especially taurocholic acid, 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 the lipid lowering effect of BBR maybe primarily exert in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, for the first time, we provide evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which leads to the suppression of hepatic expression of CD36 to result in reduced uptake of long-chain fatty acids in the liver. %U https://molpharm.aspetjournals.org/content/molpharm/early/2016/12/08/mol.116.106617.full.pdf