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Hepatocyte peroxisome proliferator-activated receptor alpha regulates bile acid synthesis and transport

文献类型：期刊论文

作者Xie, Cen1,2; Takahashi, Shogo1,3; Brocker, Chad N.1; He, Shijun2; Chen, Li2,4; Xie, Guomin5; Jang, Katrina1; Gao, Xiaoxia1; Krausz, Kristopher W.1; Qu, Aijuan5
刊名BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
出版日期2019-10-01
期号10页码:1396-1411
ISSN号1388-1981
关键词Peroxisome proliferator-activated receptor alpha Wy-14,643 Bile acid homeostasis Farnesoid X receptor Metabolomics
DOI10.1016/j.bbalip.2019.05.014
通讯作者Xie, Cen(xiecen@simm.ac.cn) ; Gonzalez, Frank J.(gonzalef@mail.nih.gov)
英文摘要Peroxisome proliferator-activated receptor alpha (PPAR alpha) controls lipid homeostasis through regulation of lipid transport and catabolism. PPAR alpha activators are clinically used for hyperlipidemia treatment. The role of PPAR alpha in bile acid (BA) homeostasis is beginning to emerge. Herein, Ppara-null and hepatocyte-specific Ppara-null (Ppara(Delta Hep)) as well as the respective wild-type mice were treated with the potent PPARa agonist Wy-14,643 (Wy) and global metabolomics performed to clarify the role of hepatocyte PPAR alpha in the regulation of BA homeostasis. Levels of all serum BAs were markedly elevated in Wy-treated wild-type mice but not in Ppara-null and Ppara(Delta Hep) mice. Gene expression analysis showed that PPAR alpha activation (1) down-regulated the expression of sodium-taurocholate acid transporting polypeptide and organic ion transporting polypeptide 1 and 4, responsible for the uptake of BAs into the liver; (2) decreased the expression of bile salt export pump transporting BA from hepatocytes into the bile canaliculus; (3) upregulated the expression of multidrug resistance-associated protein 3 and 4 transporting BA from hepatocytes into the portal vein. Moreover, there was a notable increase in the compositions of serum, hepatic and biliary cholic acid and taurocholic acid following Wy treatment, which correlated with the upregulated expression of the Cyp8b1 gene encoding sterol 12 alpha-hydroxylase. The effects of Wy were identical between the Ppara(Delta Hep) and Ppara-null mice. Hepatocyte PPAR alpha controlled BA synthesis and transport not only via direct transcriptional regulation but also via crosstalk with hepatic farnesoid X receptor signaling. These findings underscore a key role for hepatocyte PPAR alpha in the control of BA homeostasis.
WOS关键词FARNESOID-X RECEPTOR ; NECROSIS-FACTOR-ALPHA ; PPAR-ALPHA ; CHOLESTEROL 7-ALPHA-HYDROXYLASE ; LIPID-METABOLISM ; HUMANIZED MOUSE ; DOWN-REGULATION ; EXPRESSION ; GENE ; MICE
资助项目National Cancer Institute Intramural Research Program[NIH R01 AG049493] ; National Cancer Institute Intramural Research Program[NIH R01 DK116567] ; Postdoctoral Research Associate Training (PRAT) program through the National Institute of General Medical Sciences, National Institutes of Health ; Shanxi University
WOS研究方向Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
语种英语
出版者ELSEVIER
WOS记录号WOS:000480664300012
源URL[http://119.78.100.183/handle/2S10ELR8/288960]  
专题新药研究国家重点实验室
通讯作者Xie, Cen; Gonzalez, Frank J.
作者单位1.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Washington, DC USA
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Capital Med Univ, Sch Basic Med Sci, Key Lab Remodeling Related Cardiovasc Dis, Dept Physiol & Pathophysiol,Minist Educ, Beijing 100069, Peoples R China
推荐引用方式
GB/T 7714		 Xie, Cen,Takahashi, Shogo,Brocker, Chad N.,et al. Hepatocyte peroxisome proliferator-activated receptor alpha regulates bile acid synthesis and transport[J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS,2019(10):1396-1411.
APA Xie, Cen.,Takahashi, Shogo.,Brocker, Chad N..,He, Shijun.,Chen, Li.,...&Gonzalez, Frank J..(2019).Hepatocyte peroxisome proliferator-activated receptor alpha regulates bile acid synthesis and transport.BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS(10),1396-1411.
MLA Xie, Cen,et al."Hepatocyte peroxisome proliferator-activated receptor alpha regulates bile acid synthesis and transport".BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS .10(2019):1396-1411.

入库方式： OAI收割

来源：上海药物研究所

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