PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricks.
PXR was isolated as a "xenobiotic receptor" that regulates drug-metabolizing enzymes and transporters, whereas LXR is known to promote hepatic lipogenesis by activating the lipogenic transcriptional factor sterol regulatory element-binding protein (SREBP). We have recently shown that PXR can mediate a SREBP-independent lipogenic pathway by activating the free fatty acid (FFA) uptake transporter CD36, PPARgamma, and several accessory lipogenic enzymes, such as stearoyl CoA desaturase-1 (SCD-1) and long-chain free fatty acid elongase (FAE). More recently, we found activation of LXR also induced the expression of CD36. Promoter analysis established CD36 as a novel transcriptional target of LXRalpha. Moreover, the steatotic effect of LXR agonists was largely abolished in CD36 null mice, suggesting an essential role for CD36 and FFA uptake in LXR-mediated steatosis. We also showed that PPARgamma, a positive regulator of CD36, is also a transcriptional target of PXR. Thus, PXR can regulate CD36 directly or through its activation of PPARgamma. Interestingly, PXR- and LXR-mediated CD36 activation and PXR-mediated PPARgamma activation are all liver-specific. We conclude that CD36 is a shared target of LXR, PXR, and PPARgamma. The network of CD36 regulation controlled by LXR, PXR, and PPARgamma establishes this FFA transporter as a common target of orphan nuclear receptors in their mediation of hepatic steatosis. It is hoped that the nuclear receptor-mediated CD36 regulation may offer novel targets for the therapeutic management of alcoholic and nonalcoholic steatosis.
Lee
Jung Hoon
JH
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Zhou
Jie
J
Xie
Wen
W
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*
D018955:CD36 Antigens; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid