Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter.
In an attempt to identify transcription factors which activate sterol-regulatory element-binding protein 1c (SREBP-1c) transcription, we screened an expression cDNA library from adipose tissue of SREBP-1 knockout mice using a reporter gene containing the 2.6-kb mouse SREBP-1 gene promoter. We cloned and identified the oxysterol receptors liver X receptor (LXRalpha) and LXRbeta as strong activators of the mouse SREBP-1c promoter. In the transfection studies, expression of either LXRalpha or -beta activated the SREBP-1c promoter-luciferase gene in a dose-dependent manner. Deletion and mutation studies, as well as gel mobility shift assays, located an LXR response element complex consisting of two new LXR-binding motifs which showed high similarity to an LXR response element recently found in the ABC1 gene promoter, a reverse cholesterol transporter. Addition of an LXR ligand, 22(R)-hydroxycholesterol, increased the promoter activity. Coexpression of retinoid X receptor (RXR), a heterodimeric partner, and its ligand 9-cis-retinoic acid also synergistically activated the SREBP-1c promoter. In HepG2 cells, SREBP-1c mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR-RXR activation can induce endogenous SREBP-1c expression. The activation of SREBP-1c by LXR is associated with a slight increase in nuclear SREBP-1c, resulting in activation of the gene for fatty acid synthase, one of its downstream genes, as measured by the luciferase assay. These data demonstrate that LXR-RXR can modify the expression of genes for lipogenic enzymes by regulating SREBP-1c expression, providing a novel link between fatty acid and cholesterol metabolism.
Yoshikawa
T
T
Department of Metabolic Diseases, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Shimano
H
H
Amemiya-Kudo
M
M
Yahagi
N
N
Hasty
A H
AH
Matsuzaka
T
T
Okazaki
H
H
Tamura
Y
Y
Iizuka
Y
Y
Ohashi
K
K
Osuga
J
J
Harada
K
K
Gotoda
T
T
Kimura
S
S
Ishibashi
S
S
Yamada
N
N
D000077556:Alitretinoin; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; C003585:22-hydroxycholesterol; D000077556:Alitretinoin; D014212:Tretinoin; C007997:25-hydroxycholesterol; D002784:Cholesterol