Restoration of sterol-regulatory-element-binding protein-1c gene expression in HepG2 cells by peroxisome-proliferator-activated receptor-gamma co-activator-1alpha.
The expression of SREBP-1 (sterol-regulatory-element-binding protein-1) isoforms differs between tissues and cultured cell lines in that SREBP-1a is the major isoform in established cell lines, whereas SREBP-1c predominates in liver and most other human tissues. SREBP-1c is transcriptionally less active than SREBP-1a, but is a main mediator of hepatic insulin action and is selectively up-regulated by LXR (liver X receptor) agonists. LXR-mediated transactivation is co-activated by PGC-1alpha (peroxisome-proliferator-activated receptor-gamma co-activator-1alpha), which displays deficient expression in skeletal-muscle-derived cell lines. In the present paper, we show that PGC-1alpha expression is also deficient in HepG2 cells and in a human brown adipocyte cell line (PAZ6). In transient transfection studies, PGC-1alpha selectively amplified the LXR-mediated transcription from the human SREBP-1c promoter in HepG2 and PAZ6 cells via two LXR-response elements with extensive similarity to the respective murine sequence. Mutational analysis showed that the human LXR-response element-1 (hLXRE-1) was essential for co-activation of LXR-mediated SREBP-1c gene transcription by PGC-1alpha. Ectopic overexpression of PGC-1alpha in HepG2 cells enhanced basal SREBP-1c and, to a lesser extent, -1a mRNA expression, but only SREBP-1c expression was augmented further in an LXR/RXR (retinoic X receptor)-dependent fashion, thereby inducing mRNA abundance levels of SREBP-1c target genes, fatty acid synthase and acetyl-CoA carboxylase. These results indicate that PGC-1alpha contributes to the regulation of SREBP-1 gene expression, and can restore the SREBP-1 isoform expression pattern of HepG2 cells to that of human liver.
Oberkofler
Hannes
H
Department of Laboratory Medicine, Landeskliniken Salzburg, Muellner Hauptstrasse 48, A-5020, Salzburg, Austria. h.oberkofler@lks.at
Schraml
Elisabeth
E
Krempler
Franz
F
Patsch
Wolfgang
W
D000273:Adipose Tissue / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D000328:Adult; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017568:Rectus Abdominis / Q000737:chemistry / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors