A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway.
The pregnane X receptor (PXR) was isolated as a xenosensor regulating xenobiotic responses. In this study, we show that PXR plays an endobiotic role by impacting lipid homeostasis. Expression of an activated PXR in the livers of transgenic mice resulted in an increased hepatic deposit of triglycerides. This PXR-mediated lipid accumulation was independent of the activation of the lipogenic transcriptional factor SREBP-1c (sterol regulatory element-binding protein 1c) and its primary lipogenic target enzymes, including fatty-acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC-1). Instead, the lipid accumulation in transgenic mice was associated with an increased expression of the free fatty acid transporter CD36 and several accessory lipogenic enzymes, such as stearoyl-CoA desaturase-1 (SCD-1) and long chain free fatty acid elongase. Studies using transgenic and knock-out mice showed that PXR is both necessary and sufficient for Cd36 activation. Promoter analyses revealed a DR-3-type of PXR-response element in the mouse Cd36 promoter, establishing Cd36 as a direct transcriptional target of PXR. The hepatic lipid accumulation and Cd36 induction were also seen in the hPXR "humanized" mice treated with the hPXR agonist rifampicin. The activation of PXR was also associated with an inhibition of pro-beta-oxidative genes, such as peroxisome proliferator-activated receptor alpha (PPARalpha) and thiolase, and an up-regulation of PPARgamma, a positive regulator of CD36. The cross-regulation of CD36 by PXR and PPARgamma suggests that this fatty acid transporter may function as a common target of orphan nuclear receptors in their regulation of lipid homeostasis.
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jie
J
Zhou
Yonggong
Y
Zhai
Ying
Y
Mu
Haibiao
H
Gong
Hirdesh
H
Uppal
David
D
Toma
Songrong
S
Ren
Ronald M
RM
Evans
Wen
W
Xie
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000378:metabolism; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
D018955:CD36 Antigens; D005227:Fatty Acids; D047495:PPAR gamma; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D051780:Sterol Regulatory Element Binding Protein 1; D064429:Fatty Acid Synthases