Faculty Collaboration Database

Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008 Feb;134(2):556-67

Date

02/05/2008

Pubmed ID

18242221

DOI

10.1053/j.gastro.2007.11.037

Scopus ID

2-s2.0-38649096259 (requires institutional sign-in at Scopus site)   502 Citations

Abstract

BACKGROUND & AIMS: Liver X receptor (LXR) is known to promote hepatic lipogenesis by activating the lipogenic transcriptional factor sterol regulatory element-binding protein (Srebp). Pregnane X receptor (PXR), a previously known "xenobiotic receptor," could mediate a Srebp-independent lipogenic pathway by activating the free fatty acid uptake transporter Cd36. The goal of this study is to investigate further the role of Cd36 in hepatic steatosis.

METHODS: Wild-type, LXR transgenic, PXR transgenic, and Cd36 null mice were used to study the regulation of Cd36 and other hepatic lipogenic genes and the implication of this regulation in hepatic steatosis. Promoter sequences of Cd36 and peroxisome proliferator-activated receptor (PPAR) gamma were cloned, and their respective regulation by LXR and PXR was investigated by combinations of receptor-DNA binding and reporter gene assays.

RESULTS: We showed that genetic (transgene) or pharmacologic (ligands) activation of LXR induced Cd36. Promoter analysis established Cd36 as a novel transcription target of LXRalpha. Moreover, the hepatic steatosis induced by LXR agonists was largely abolished in Cd36 null mice. We also showed that PPARgamma, a positive regulator of Cd36, is a transcriptional target of PXR, suggesting that PXR can regulate Cd36 directly or through its activation of PPARgamma. Interestingly, both LXR-mediated Cd36 regulation and PXR-mediated PPARgamma regulation are liver specific.

CONCLUSIONS: We conclude that Cd36 is a shared target of LXR, PXR, and PPARgamma. The network of CD36 regulation by LXR, PXR, and PPARgamma establishes this free fatty acid transporter as a common target of orphan nuclear receptors in their mediation of lipid homeostasis.

Author List

Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
CD36 Antigens
DNA-Binding Proteins
Fatty Liver
Female
Gene Expression Regulation
Homeostasis
Lipid Metabolism
Liver
Liver X Receptors
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molecular Sequence Data
Orphan Nuclear Receptors
PPAR gamma
Promoter Regions, Genetic
Receptors, Cytoplasmic and Nuclear
Receptors, Steroid