REGULATION OF STEROL REGULATORY ELEMENT-BINDING PROTEINS IN LIVERS OFFASTED AND REFED MICE

Hepatic lipid synthesis is known to be regulated by food consumption. In rodents fasting decreases the synthesis of cholesterol as well as f atty acids. Refeeding a high carbohydrate/low fat diet enhances fatty acid synthesis by 5- to 20-fold above the fed state, whereas cholester ol synthesis returns only to the prefasted level. Sterol regulatory el ement binding proteins (SREBPs) are transcription factors that regulat e genes involved in cholesterol and fatty acid synthesis. Here, we sho w that fasting markedly reduces the amounts of SREBP-1 and -2 in mouse liver nuclei, with corresponding decreases in the mRNAs for SREBP-act ivated target genes. Refeeding a high carbohydrate/low fat diet result ed in a 4- to 5-fold increase of nuclear SREBP-1 above nonfasted level s, whereas nuclear SREBP-2 protein returned only to the nonfasted leve l, The hepatic mRNAs for fatty acid biosynthetic enzymes increased 5- to 10-fold above nonfasted levels, a pattern that paralleled the chang es in nuclear SREBP-1. The hepatic mRNAs for enzymes involved in chole sterol synthesis returned to the nonfasted level, closely following th e pattern of nuclear SREBP-2 regulation. Transgenic mice that overprod uce nuclear SREBP-1c failed to show the normal decrease in hepatic mRN A levels for cholesterol and fatty acid synthetic enzymes upon fasting , We conclude that SREBPs are regulated by food consumption in the mou se liver and that the decline in nuclear SREBP-1c upon fasting may exp lain in part the decrease in mRNAs encoding enzymes of the fatty acid biosynthetic pathway.