Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via Gαi-protein-coupled receptors and the AKT pathway

被引：60

作者：

Cao, Risheng ^{[1
]}

Cronk, Zhumei Xu ^{[3
]}

Zha, Weibin ^{[1
]}

Sun, Lixin ^{[1
]}

Wang, Xuan ^{[1
]}

Fang, Youwen ^{[1
]}

Studer, Elaine ^{[1
]}

Zhou, Huiping ^{[1
,2
]}

Pandak, William M. ^{[2
,4
]}

Dent, Paul

Gil, Gregorio ^{[3
]}

Hylemon, Phillip B. ^{[1
,2
,4
]}

机构：

[1] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA

[3] Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA

[4] Virginia Commonwealth Univ, McGuire Vet Affairs Med Ctr, Richmond, VA 23298 USA

来源：

JOURNAL OF LIPID RESEARCH | 2010年 / 51卷 / 08期

基金：

美国国家卫生研究院;

关键词：

protein kinase C zeta; GW4064; chronic bile fistula rat; primary rat hepatocyte; serine/threonine kinase AKT (protein kinase B); ORPHAN NUCLEAR RECEPTOR; PRIMARY RAT HEPATOCYTES; GROWTH-FACTOR RECEPTOR; KINASE-C-ZETA; SIGNALING PATHWAYS; CHOLESTEROL; 7-ALPHA-HYDROXYLASE; TRANSCRIPTIONAL ACTIVITY; CARBOHYDRATE-METABOLISM; GLUCOSE-HOMEOSTASIS; CELLULAR FUNCTIONS;

D O I：

10.1194/jlr.M004929

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Bile acids are important regulatory molecules that can activate specific nuclear receptors and cell signaling pathways in the liver and gastrointestinal tract. In the current study, the chronic bile fistula (CBF) rat model and primary rat hepatocytes (PRH) were used to study the regulation of gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) and the gene encoding short heterodimeric partner (SHP) by taurocholate (TCA). The intestinal infusion of TCA into the CBF rat rapidly (1 h) activated the AKT (similar to 9-fold) and ERK1/2 (3- to 5-fold) signaling pathways, downregulated (similar to 50%, 30 min) the mRNA levels of PEPCK and G-6-Pase, and induced (14-fold in 3 h) SHP mRNA. TCA rapidly (similar to 50%, 1-2 h) downregulated PEPCK and G-6-Pase mRNA levels in PRH. The downregulation of these genes by TCA was blocked by pretreatment of PRH with pertussis toxin (PTX). In PRH, TCA plus insulin showed a significantly stronger inhibition of glucose secretion/synthesis from lactate and pyruvate than either alone. The induction of SHP mRNA in PRH was strongly blocked by inhibition of PI3 kinase or PKC zeta by specific chemical inhibitors or knockdown of PKC zeta by siRNA encoded by a recombinant lentivirus.jlr Activation of the insulin signaling pathway appears to be linked to the upregulation of farnesoid X receptor functional activity and SHP induction.-Cao, R., Z. X. Cronk, W. Zha, L. Sun, X. Wang, Y. Fang, E. Studer, H. Zhou, W. M. Pandak, P. Dent, G. Gil, and P. B. Hylemon. Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G alpha(i) protein coupled receptors and the AKT pathway. J. Lipid Res. 2010. 51: 2234-2244.

引用

页码：2234 / 2244

页数：11

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