Gastroenterology

Gastroenterology

Volume 134, Issue 2, February 2008, Pages 556-567.e1
Gastroenterology

Basic–Liver, Pancreas, and Biliary Tract
Hepatic Fatty Acid Transporter Cd36 Is a Common Target of LXR, PXR, and PPARγ in Promoting Steatosis

https://doi.org/10.1053/j.gastro.2007.11.037Get rights and content

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) γ 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 LXRα. Moreover, the hepatic steatosis induced by LXR agonists was largely abolished in Cd36 null mice. We also showed that PPARγ, a positive regulator of Cd36, is a transcriptional target of PXR, suggesting that PXR can regulate Cd36 directly or through its activation of PPARγ. Interestingly, both LXR-mediated Cd36 regulation and PXR-mediated PPARγ regulation are liver specific. Conclusions: We conclude that Cd36 is a shared target of LXR, PXR, and PPARγ. The network of CD36 regulation by LXR, PXR, and PPARγ establishes this free fatty acid transporter as a common target of orphan nuclear receptors in their mediation of lipid homeostasis.

Section snippets

Animals and Drugs

FABP-VP-hPXR transgenic,27 FABP-VP-LXR transgenic,28 PXR null mice, and Cd36 null mice22 have been previously described. VP-LXR/VP-PXR double transgenic mice were created by crossbreeding. Transgenic mice are in mixed background of C57BL/6J and SvJ129, and Cd36 null mice are in sixth generation of backcross to C57BL/6J mice. Background and age (8–10 weeks old)-matched littermate controls were used for all experiments. Wild-type CD-1 female mice purchased from Charles River (Wilmington, MA) were

Activation of LXR Induced the Expression of Cd36 in a Liver-Specific Manner

We have recently created transgenic mice that express the activated LXRα (VP-LXR) or PXR (VP-PXR) in the liver and intestine under the control of the rat liver fatty acid-binding protein promoter.26, 27, 28 VP-LXR and VP-PXR were created by fusing the VP16 activation domain of the herpes simplex virus to the amino terminal of mouse LXRα and human PXR, respectively. Our recent study showed that PXR promotes an Srebp-independent lipogenic pathway by activating Cd36, as well as PPARγ, Fae, and

Discussion

In this study, we established Cd36 as a novel LXR target gene. Activation of LXR and PXR in transgenic mice cooperated to promote hepatic steatosis, which is characterized by a marked accumulation of triglycerides. The effects of LXR, PXR, and PPARγ converge on the activation of Cd36. This network of Cd36 regulation and associated steatosis, summarized in Figure 7, appeared to be liver specific.

One of the most interesting findings in this study is the previously unrecognized role of Cd36 in

References (47)

  • M. Febbraio et al.

    A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism

    J Biol Chem

    (1999)
  • S.O. Rahaman et al.

    A CD36-dependent signaling cascade is necessary for macrophage foam cell formation

    Cell Metab

    (2006)
  • P. Tontonoz et al.

    PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL

    Cell

    (1998)
  • J. Zhou et al.

    A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway

    J Biol Chem

    (2006)
  • T. Matsuzaka et al.

    Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs

    J Lipid Res

    (2002)
  • J.R. Goudriaan et al.

    CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice

    J Lipid Res

    (2003)
  • F. Nassir et al.

    CD36 is important for fatty acid and cholesterol uptake by the proximal but not distal intestine

    J Biol Chem

    (2007)
  • S.A. Kliewer et al.

    An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway

    Cell

    (1998)
  • E.A. Podrez et al.

    A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions

    J Biol Chem

    (2002)
  • K. Motojima et al.

    Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor α and γ activators in a tissue- and inducer-specific manner

    J Biol Chem

    (1998)
  • A. Chawla et al.

    A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenes

    Mol Cell

    (2001)
  • S. Hummasti et al.

    Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target

    J Lipid Res

    (2004)
  • J.J. Repa et al.

    Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ

    Genes Dev

    (2000)
  • Cited by (493)

    View all citing articles on Scopus

    Supported in part by NIH grants CA107011 ES012479, and ES014626 (to W.X.); NIH contract N01-DK-7-0004/HHSN267200700004C through which normal human hepatocytes were obtained through the Liver Tissue Procurement and Distribution System, Pittsburgh, Pennsylvania; and Chinese Government Research Grant 2004AA221060 (to Y.Z.)

    View full text