Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway  

作　　者：Ji Wang Meng-yu Zhong Yun-xia Liu Jia-yu Yu Yi-bin Wang Xue-jiao Zhang Hai-peng Sun 

机构地区：[1]Department of Clinical Laboratory,The Second People’s Hospital of Hefei/Hefei Hospital Affiliated to Anhui Medical University,Hefei,230011,China [2]NHC Key Laboratory of Hormones and Development,Tianjin Key Laboratory of Metabolic Diseases,Chu Hsien-I Memorial Hospital&Tianjin Institute of Endocrinology,Tianjin Medical University,Tianjin,300134,China [3]Department of Pathophysiology,Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China [4]The Signature Research Program in Cardiovascular and Metabolic Disorders,Duke-NUS Medical School,Singapore,169857,Singapore

出　　处：《Acta Pharmacologica Sinica》2025年第3期662-671,共10页中国药理学报(英文版)

基　　金：supported by the National Key Research and Development Program of China(2019YFA0802503);the National Natural Science Foundation of China(92057107,31900819,32200965);Doctoral Degree Special Foundation of The Second People’s Hospital of Hefei(2020bszx07);Collaborative Innovation Program of Shanghai Municipal Health Commission(2020CXJQ01);Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-032A);Natural Science Foundation of Tianjin City(22JCQNJC01330);Scientific Research Funding of Tianjin Medical University Chu Hsien-I Memorial Hospital(ZXY-ZDSYSZD2021-2).

摘　　要：Branched-chain amino acids(BCAAs)including leucine,isoleucine and valine have been linked with metabolic and cardiovascular diseases.BCAAs homeostasis is tightly controlled by their catabolic pathway.BCKA dehydrogenase(BCKD)complex is the rate-limiting step for BCAA catabolism.Mitochondrial phosphatase 2C(PP2Cm)dephosphorylates the BCKD E1alpha subunit and activates BCKD complex.Deficiency of PP2Cm impairs BCAA catabolism,leading to higher plasma BCAA concentrations.Emerging evidence shows that bile acids are key regulators of glucose,lipid and energy metabolism.In this study,we investigated whether a direct link existed between BCAAs and bile acids metabolism.Wild-type mice were fed with normal-BCAA or high-BCAA diet,while PP2Cm deficiency mice were fed with normal chow for 14 weeks.The mice were fasted for 6 h before tissue harvest to exclude metabolic changes due to immediate food intake.We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow.These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase(CYP7A1),the rate-limiting enzyme of bile acid synthesis in liver,and 7α-hydroxy-4-cholesten-3-one(C4),a freely diffusible metabolite downstream of CYP7A1 in plasma.BCAAs induced Cyp7a1 expression in cultured hepatocytes.In mouse liver and cultured hepatocytes,we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21(FGF21)expression and ERK signaling pathway.Direct inhibition of ERK by U0126(800 nM)markedly induced Cyp7a1 expression in cultured hepatocytes.Moreover,the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes.Collectively,this study demonstrates a direct link between BCAAs and bile acid synthesis.BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway.BCAA

关 键 词：BCAAs bile acid CYP7A1 FGF21 ERK metabolic disorders 

分 类 号：R363[医药卫生—病理学]