title: Human sterol regulatory element-binding protein 1a contributes significantly to hepatic lipogenic gene expression.
abstract: OBJECTIVE
  Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver.
  
  
  METHODS
  mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR.
  
  
  RESULTS
  In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down.
  
  
  CONCLUSIONS
  We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.
authors: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors: Andreas
authors: A
authors: Bitter
authors: Andreas K
authors: AK
authors: Nüssler
authors: Wolfgang E
authors: WE
authors: Thasler
authors: Kathrin
authors: K
authors: Klein
authors: Ulrich M
authors: UM
authors: Zanger
authors: Matthias
authors: M
authors: Schwab
authors: Oliver
authors: O
authors: Burk
mesh_terms: D018450:Disease Progression; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology; D059368:RNA Isoforms / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C570314:PF-429242; D011759:Pyrrolidines; D059368:RNA Isoforms; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1