SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation

In liver, the synthesis of cholesterol and fatty acids increases in respons e to cholesterol deprivation and insulin elevation, respectively. This regu latory mechanism underlies the adaptation to cholesterol synthesis inhibito rs (statins) and high calorie diets (insulin). In nonhepatic cells, lipid s ynthesis is controlled by sterol regulatory element-binding proteins (SREBP s), membrane-bound transcription factors whose active domains are released proteolytically to enter the nucleus and activate genes involved in the syn thesis and uptake of cholesterol and fatty acids. SCAP (SREBP cleavage-acti vating protein) is a sterol-regulated escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of cleavage in the Golgi. Here, we produced a conditional deficiency of SCAP in mouse liver by genomic recombination mediated by inducible Cre recombina se. SCAP-deficient mice showed an 80% reduction in basal rates of cholester ol and fatty acid synthesis in liver, owing to decreases in mRNAs encoding multiple biosynthetic enzymes. Moreover, these mRNAs failed to increase nor mally in response to cholesterol deprivation produced by a cholesterol synt hesis inhibitor and to insulin elevation produced by a fasting-refeeding pr otocol. These data provide in vivo evidence that SCAP and the SREBPs are re quired for hepatic lipid synthesis under basal and adaptive conditions.