Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene

J Clin Invest. 1997 Oct 15;100(8):2115-24. doi: 10.1172/JCI119746.


The synthesis of cholesterol and its uptake from plasma LDL are regulated by two membrane-bound transcription factors, designated sterol regulatory element binding protein-1 and -2 (SREBP-1 and SREBP-2). Here, we used the technique of homologous recombination to generate mice with disruptions in the gene encoding the two isoforms of SREBP-1, termed SREBP-1a and SREBP-1c. Heterozygous gene-disrupted mice were phenotypically normal, but 50- 85% of the homozygous (-/-) mice died in utero at embryonic day 11. The surviving -/- mice appeared normal at birth and throughout life. Their livers expressed no functional SREBP-1. There was a 1.5-fold upregulation of SREBP-2 at the level of mRNA and a two- to threefold increase in the amount of mature SREBP-2 in liver nuclei. Previous studies showed that SREBP-2 is much more potent than SREBP-1c, the predominant hepatic isoform of SREBP-1, in activating transcription of genes encoding enzymes of cholesterol synthesis. Consistent with this observation, the SREBP-1 -/- animals manifested elevated levels of mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase, farnesyl diphosphate synthase, and squalene synthase. Cholesterol synthesis, as measured by the incorporation of [3H]water, was elevated threefold in livers of the -/- mice, and hepatic cholesterol content was increased by 50%. Fatty acid synthesis was decreased in livers of the -/- mice. The amount of white adipose tissue was not significantly decreased, and the levels of mRNAs for lipogenic enzymes, adipocyte lipid binding protein, lipoprotein lipase, and leptin were normal in the -/- mice. We conclude from these studies that SREBP-2 can replace SREBP-1 in regulating cholesterol synthesis in livers of mice and that the higher potency of SREBP-2 relative to SREBP-1c leads to excessive hepatic cholesterol synthesis in these animals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipose Tissue / chemistry
  • Adrenal Glands / metabolism
  • Amino Acid Sequence
  • Animals
  • CCAAT-Enhancer-Binding Proteins*
  • Cells, Cultured
  • Cholesterol / biosynthesis*
  • Cloning, Molecular
  • Crosses, Genetic
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics*
  • Fatty Acids / biosynthesis
  • Female
  • Genetic Vectors
  • Homozygote
  • Humans
  • Kidney / cytology
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nuclear Proteins / genetics*
  • RNA, Messenger / analysis
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors / biosynthesis*


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Fatty Acids
  • Nuclear Proteins
  • RNA, Messenger
  • SREBF1 protein, human
  • SREBF2 protein, human
  • Srebf1 protein, mouse
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors
  • Cholesterol