ELEVATED LEVELS OF SREBP-2 AND CHOLESTEROL-SYNTHESIS IN LIVERS OF MICE HOMOZYGOUS FOR A TARGETED DISRUPTION OF THE SREBP-1 GENE

The synthesis of cholesterol and its uptake from plasma LDL are regula ted by two membrane-bound transcription factors, designated sterol reg ulatory element binding protein-1 and -2 (SREBP-1 and SREBP-2), Here, we used the technique of homologous recombination to generate mice wit h disruptions in the gene encoding the two isoforms of SREBP-1, termed SREBP-1a and SREBP-1c. Heterozygous gene-disrupted mice were phenotyp ically normal, but 50-85% of the homozygous (-/-) mice died in utero a t embryonic day 11, The surviving -/- mice appeared normal at birth an d 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 transcri ption of genes encoding enzymes of cholesterol synthesis, Consistent w ith this observation, the SREBP-1 -/- animals manifested elevated leve ls of mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A synthase and red uctase, farnesyl diphosphate synthase, and squalene synthase. Choleste rol synthesis, as measured by the incorporation of [H-3]water, was ele vated threefold in livers of the -/- mice, and hepatic cholesterol con tent was increased by 50%, Fatty acid synthesis was decreased in liver s of the -/- mice. The amount of white adipose tissue was not signific antly decreased, and the levels of mRNAs for lipogenic enzymes, adipoc yte lipid binding protein, lipoprotein lipase, and leptin were normal in the -/- mice, We conclude from these studies that SREBP-2 can repla ce SREBP-1 in regulating cholesterol synthesis in livers of mice and t hat the higher potency of SREBP-2, relative to SREBP-1c leads to exces sive hepatic cholesterol synthesis in these animals.