CHOLESTEROL FEEDING REDUCES NUCLEAR FORMS OF STEROL REGULATORY ELEMENT-BINDING PROTEINS IN HAMSTER LIVER

Cholesterol feeding reduces the mRNAs encoding multiple enzymes in the cholesterol biosynthetic pathway and the low density lipoprotein rece ptor in livers of hamsters, Here we show that cholesterol feeding also reduces the levels of the nuclear NH2-terminal domains of sterol regu latory element binding proteins (SREBPs), which activate transcription of sterol-regulated genes, We show that livers of hamsters, like thos e of mice and humans, predominantly produce SREBP-2 and the 1c isoform of SREBP-1, Both are produced as membrane-bound precursors that must be proteolyzed to release the transcriptionally active NH2-terminal do mains, Diets containing 0.1% to 1.0% cholesterol decreased the amount of nuclear SREBP-1c without affecting the amount of the membrane precu rsor or its mRNA, suggesting that cholesterol inhibits the proteolytic processing of SREBP-1 in liver as it does in cultured cells, Choleste rol also appeared to reduce the proteolytic processing of SREBP-2. In addition, at high levels of dietary cholesterol the mRNA encoding SREB P-2 declined and the amount of the precursor also fell, suggesting tha t cholesterol accumulation also may inhibit transcription of the SREBP -2 gene, The high-cholesterol diets reduced the amount of low density lipoprotein receptor mRNA by 30% and produced a more profound 70-90% r eduction in mRNAs encoding 3-hydroxy-3-methylglutaryl CoA synthase and reductase, Treatment with lovastatin and Colestipol, which increases hepatic demands for cholesterol, increased the amount of SREBP-2 mRNA as well as the precursor and nuclear forms of the protein, This treatm ent caused a reciprocal decline in SREBP-1c mRNA and protein, Consider ed together, these data suggest that SREBPs play important roles in co ntrolling transcription of sterol-regulated genes in liver, as they do in cultured cells.