Journal
MOLECULAR PHARMACEUTICS
Volume 5, Issue 1, Pages 60-66Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp700121u
Keywords
nuclear hormone receptor; gene regulation; steatosis; lipogenesis; transgenic mice
Funding
- NATIONAL CANCER INSTITUTE [R01CA107011] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES012479, R01ES014626] Funding Source: NIH RePORTER
- NCI NIH HHS [CA107011] Funding Source: Medline
- NIEHS NIH HHS [ES014626, ES012479] Funding Source: Medline
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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, PPAR gamma, 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 LXR alpha. 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 PPAR gamma, a positive regulator of CD36, is also a transcriptional target of PXR. Thus, PXR can regulate CD36 directly or through its activation of PPAR gamma. Interestingly, PXR- and LXR-mediated CD36 activation and PXR-mediated PPAR gamma activation are all liver-specific. We conclude that CD36 is a shared target of LXR, PXR, and PPAR gamma. The network of CD36 regulation controlled by LXR, PXR, and PPAR gamma 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.
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