PMID- 12730331
OWN - NLM
STAT- MEDLINE
DCOM- 20040617
LR  - 20220208
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 17
IP  - 7
DP  - 2003 Jul
TI  - 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.
PG  - 1240-54
AB  - 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.
FAU - Yoshikawa, Tomohiro
AU  - Yoshikawa T
AD  - Department of Metabolic Diseases, Graduate School of Agricultural and Life 
      Sciences, University of Tokyo, Bunkyo-ku, Japan.
FAU - Ide, Tomohiro
AU  - Ide T
FAU - Shimano, Hitoshi
AU  - Shimano H
FAU - Yahagi, Naoya
AU  - Yahagi N
FAU - Amemiya-Kudo, Michiyo
AU  - Amemiya-Kudo M
FAU - Matsuzaka, Takashi
AU  - Matsuzaka T
FAU - Yatoh, Shigeru
AU  - Yatoh S
FAU - Kitamine, Tetsuya
AU  - Kitamine T
FAU - Okazaki, Hiroaki
AU  - Okazaki H
FAU - Tamura, Yoshiaki
AU  - Tamura Y
FAU - Sekiya, Motohiro
AU  - Sekiya M
FAU - Takahashi, Akimitsu
AU  - Takahashi A
FAU - Hasty, Alyssa H
AU  - Hasty AH
FAU - Sato, Ryuichiro
AU  - Sato R
FAU - Sone, Hirohito
AU  - Sone H
FAU - Osuga, Jun-Ichi
AU  - Osuga J
FAU - Ishibashi, Shun
AU  - Ishibashi S
FAU - Yamada, Nobuhiro
AU  - Yamada N
LA  - eng
PT  - Comment
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030501
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Fatty Acids)
RN  - 0 (Hydrocarbons, Fluorinated)
RN  - 0 (Liver X Receptors)
RN  - 0 (Orphan Nuclear Receptors)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (SREBF1 protein, human)
RN  - 0 (Srebf1 protein, mouse)
RN  - 0 (Srebf1 protein, rat)
RN  - 0 (Sterol Regulatory Element Binding Protein 1)
RN  - 0 (Sulfonamides)
RN  - 0 (T0901317)
RN  - 0 (Transcription Factors)
RN  - 86C4MRT55A (pirinixic acid)
SB  - IM
CON - Mol Endocrinol. 2003 Jul;17(7):1255-67. PMID: 12730332
MH  - Animals
MH  - Anticholesteremic Agents/pharmacology
MH  - CCAAT-Enhancer-Binding Proteins/drug effects/genetics/*metabolism
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/drug effects/genetics/*metabolism
MH  - Fatty Acids/*metabolism
MH  - Gene Expression Regulation
MH  - Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Hydrocarbons, Fluorinated
MH  - Liver/drug effects/metabolism
MH  - Liver X Receptors
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nutritional Physiological Phenomena
MH  - Orphan Nuclear Receptors
MH  - *Promoter Regions, Genetic/drug effects
MH  - Pyrimidines/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Cytoplasmic and Nuclear/agonists/genetics/*metabolism
MH  - Receptors, Retinoic Acid/drug effects/metabolism
MH  - Response Elements/genetics
MH  - Retinoid X Receptors
MH  - Signal Transduction
MH  - Sterol Regulatory Element Binding Protein 1
MH  - Sulfonamides
MH  - Transcription Factors/agonists/drug effects/genetics/*metabolism
EDAT- 2003/05/06 05:00
MHDA- 2004/06/18 05:00
CRDT- 2003/05/06 05:00
PHST- 2003/05/06 05:00 [pubmed]
PHST- 2004/06/18 05:00 [medline]
PHST- 2003/05/06 05:00 [entrez]
AID - me.2002-0190 [pii]
AID - 10.1210/me.2002-0190 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2003 Jul;17(7):1240-54. doi: 10.1210/me.2002-0190. Epub 2003 May 
      1.