title: Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Runbin
authors.initials: R
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Fei
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Jiahua
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Aa
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Schumacher
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China jiyea@cpu.edu.cn guangjiwang@hotmail.com.
authors.forename: Jiye
authors.initials: J
authors.lastname: Aa
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China (R.S., N.Y., D.F., X.Y., C.G., J.H., P.W., S.F., F.F. J.G., J.H., N.A., Q.C., J.A., G.W.); Department of Pharmacology and Toxicology (B.K., J.S., Y.P., J.D.S., G.L.G.), Department of Chemical Biology (C.S.Y.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Nanjing Drum Tower Hospital (B.C.), the Affiliated Hospital of Nanjing University Medical School, Nanjing, China jiyea@cpu.edu.cn guangjiwang@hotmail.com.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism*; D001599:Berberine / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005243:Feces / Q000737:chemistry; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008095:Lithocholic Acid / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013656:Taurocholic Acid / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001599:Berberine; D001647:Bile Acids and Salts; D018955:CD36 Antigens; D000960:Hypolipidemic Agents; D008095:Lithocholic Acid; D018160:Receptors, Cytoplasmic and Nuclear; D013656:Taurocholic Acid; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated