Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling - PubMed (original) (raw)
Comment
. 2003 Jul;17(7):1240-54.
doi: 10.1210/me.2002-0190. Epub 2003 May 1.
Tomohiro Ide, Hitoshi Shimano, Naoya Yahagi, Michiyo Amemiya-Kudo, Takashi Matsuzaka, Shigeru Yatoh, Tetsuya Kitamine, Hiroaki Okazaki, Yoshiaki Tamura, Motohiro Sekiya, Akimitsu Takahashi, Alyssa H Hasty, Ryuichiro Sato, Hirohito Sone, Jun-Ichi Osuga, Shun Ishibashi, Nobuhiro Yamada
Affiliations
- PMID: 12730331
- DOI: 10.1210/me.2002-0190
Comment
Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling
Tomohiro Yoshikawa et al. Mol Endocrinol. 2003 Jul.
Abstract
Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors that form obligate heterodimers with retinoid X receptors (RXRs). These nuclear receptors play crucial roles in the regulation of fatty acid metabolism: LXRs activate expression of sterol regulatory element-binding protein 1c (SREBP-1c), a dominant lipogenic gene regulator, whereas PPARalpha promotes fatty acid beta-oxidation genes. In the current study, effects of PPARs on the LXR-SREBP-1c pathway were investigated. Luciferase assays in human embryonic kidney 293 cells showed that overexpression of PPARalpha and gamma dose-dependently inhibited SREBP-1c promoter activity induced by LXR. Deletion and mutation studies demonstrated that the two LXR response elements (LXREs) in the SREBP-1c promoter region are responsible for this inhibitory effect of PPARs. Gel shift assays indicated that PPARs reduce binding of LXR/RXR to LXRE. PPARalpha-selective agonist enhanced these inhibitory effects. Supplementation with RXR attenuated these inhibitions by PPARs in luciferase and gel shift assays, implicating receptor interaction among LXR, PPAR, and RXR as a plausible mechanism. Competition of PPARalpha ligand with LXR ligand was observed in LXR/RXR binding to LXRE in gel shift assay, in LXR/RXR formation in nuclear extracts by coimmunoprecipitation, and in gene expression of SREBP-1c by Northern blot analysis of rat primary hepatocytes and mouse liver RNA. These data suggest that PPARalpha activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPARalpha in hepatic lipid homeostasis.
Comment on
- Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling.
Ide T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Nakakuki M, Yatoh S, Iizuka Y, Tomita S, Ohashi K, Takahashi A, Sone H, Gotoda T, Osuga J, Ishibashi S, Yamada N. Ide T, et al. Mol Endocrinol. 2003 Jul;17(7):1255-67. doi: 10.1210/me.2002-0191. Epub 2003 May 1. Mol Endocrinol. 2003. PMID: 12730332
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources