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