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Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c.

Two treatments, fasting/refeeding and administration of liver X receptor (LXR) agonists, elevate the mRNA for sterol regulatory element-binding protein-1c (SREBP-1c) and enhance lipid synthesis in liver. These treatments do not affect the mRNA for SREBP-1a, an alternative transcript from the same gene. Through homologous recombination, we eliminated the exon encoding SREBP-1c from the mouse genome, leaving the SREBP-1a transcript intact. On a normal diet, livers of SREBP-1c(-/-) mice manifested reductions in multiple mRNAs encoding enzymes of fatty acid and triglyceride synthesis, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In contrast, SREBP-1c(-/-) livers showed a compensatory increase in hepatic SREBP-2 mRNA, accompanied by increased mRNA levels for cholesterol biosynthetic enzymes. In fasted/refed animals, ACC and FAS mRNAs rose, but not to the same extent as in wild-type livers. The refeeding-induced increase in SREBP-1c(-/-) mice was greater than in mice lacking SREBP cleavage-activating protein (SCAP), in which all nuclear SREBPs are absent. Thus, SREBP-2 and/or SREBP-1a can substitute partially for SREBP-1c in permitting an insulin-mediated increase in ACC and FAS mRNAs. In contrast, mRNAs for several other lipogenic enzymes (glucose-6-phosphate dehydrogenase, malic enzyme, glycerol-3-phosphate acyltransferase, and stearoyl-CoA desaturase-1) showed a complete failure of the normal inductive response to refeeding, indicating specific reliance on SREBP-1c. Moreover, these mRNAs, as well as multiple other lipogenic mRNAs, showed a markedly blunted response to the LXR agonist T090137, indicating an essential role of SREBP-1c in the LXR response.

Pubmed ID: 11782483


  • Liang G
  • Yang J
  • Horton JD
  • Hammer RE
  • Goldstein JL
  • Brown MS


The Journal of biological chemistry

Publication Data

March 15, 2002

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL20948

Mesh Terms

  • Acetyl-CoA Carboxylase
  • Adipocytes
  • Animals
  • Anticholesteremic Agents
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Fasting
  • Fatty Acid Synthases
  • Hydrocarbons, Fluorinated
  • Intracellular Signaling Peptides and Proteins
  • Lipids
  • Liver
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Orphan Nuclear Receptors
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Sulfonamides
  • Transcription Factors