The NH2-terminal domain of sterol-regulatory element binding protein-1a (SREBP-1a) activates transcription of genes encoding enzymes of cholesterol and fatty acid biosynthesis in cultured cells. These transgenic mice overexpress a truncated version of human SREBP-1a that includes the NH2-terminal domain but lacks the membrane attachment site. Expression is driven by the rat phosphoenolpyruvate carboxykinase (Pck1, also called Pepck) promoter, which gives high level expression in liver. When placed on a low carbohydrate/high protein diet to induce the Pck1 promoter the transgenic mice develop progressive and massive enlargement of the liver due to the engorgement of hepatocytes with cholesterol and triglycerides. The mRNAs encoding 3-hydroxy-3-methylglutaryl CoA (HMG CoA) synthase, HMG CoA reductase, squalene synthase, acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase-1 are elevated, as is the LDL receptor mRNA. The rates of cholesterol and fatty acid synthesis in liver is elevated 5- and 25-fold, respectively. Plasma lipid levels are not elevated. The amount of white adipose tissue decreases progressively as the liver enlarges. (Shimano H, et al., J Clin Invest. 1996, 98:1575)
