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[PMID]: | 27932556 |
[Au] Autor: | Sun R; Yang N; Kong B; Cao B; Feng D; Yu X; Ge C; Huang J; Shen J; Wang P; Feng S; Fei F; Guo J; He J; Aa N; Chen Q; Pan Y; Schumacher JD; Yang CS; Guo GL; Aa J; Wang G |
[Ad] Endereço: | 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. |
[Ti] Título: | Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway. |
[So] Source: | Mol Pharmacol;91(2):110-122, 2017 Feb. | [Is] ISSN: | 1521-0111 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | 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 (FXR ) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXR 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. |
[Mh] Termos MeSH primário: |
Bactérias/metabolismo Berberina/administração & dosagem Berberina/farmacologia Ácidos e Sais Biliares/metabolismo Intestinos/metabolismo Metabolismo dos Lipídeos/efeitos dos fármacos Fígado/metabolismo Receptores Citoplasmáticos e Nucleares/metabolismo
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[Mh] Termos MeSH secundário: |
Animais Bactérias/efeitos dos fármacos Berberina/uso terapêutico Ácidos e Sais Biliares/sangue Peso Corporal/efeitos dos fármacos Antígenos CD36/genética Antígenos CD36/metabolismo Dieta Hiperlipídica Fezes/química Microbioma Gastrointestinal/efeitos dos fármacos Regulação da Expressão Gênica/efeitos dos fármacos Hipolipemiantes/farmacologia Hipolipemiantes/uso terapêutico Metabolismo dos Lipídeos/genética Ácido Litocólico/farmacologia Fígado/efeitos dos fármacos Masculino Camundongos Endogâmicos C57BL Obesidade/sangue Obesidade/tratamento farmacológico Obesidade/genética Obesidade/prevenção & controle Transdução de Sinais/efeitos dos fármacos Ácido Taurocólico/farmacologia Triglicerídeos/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Bile Acids and Salts); 0 (CD36 Antigens); 0 (Hypolipidemic Agents); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Triglycerides); 0 (farnesoid X-activated receptor); 0I8Y3P32UF (Berberine); 5E090O0G3Z (Taurocholic Acid); 5QU0I8393U (Lithocholic Acid) |
[Em] Mês de entrada: | 1705 |
[Cu] Atualização por classe: | 171116 |
[Lr] Data última revisão:
| 171116 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 161210 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1124/mol.116.106617 |
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