| First Author | Shimano H | Year | 1997 |
| Journal | J Clin Invest | Volume | 100 |
| Issue | 8 | Pages | 2115-24 |
| PubMed ID | 9329978 | Mgi Jnum | J:43570 |
| Mgi Id | MGI:1098057 | Doi | 10.1172/JCI119746 |
| Citation | Shimano H, et al. (1997) Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene [see comments]. J Clin Invest 100(8):2115-24 |
| abstractText | 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 [H-3]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. |
