Received for publication April 7, 2008.
Revised May 21, 2008.
Accepted for publication June 23, 2008.

Pharmacologic inhibition of site-1 protease activity inhibits SREBP processing and reduces lipogenic enzyme gene expression and lipid synthesis in cultured cells and experimental animals

Abstract

Sterol regulatory element-binding proteins (SREBPs) are major transcriptional regulators of cholesterol, fatty acid and glucose metabolism. Genetic disruption of SREBP activity reduces plasma and liver levels of cholesterol and triglycerides, as well as insulin-stimulated lipogenesis, suggesting that SREBP is a viable target for pharmacological intervention. The proprotein convertase SREBP site-1 protease (S1P) is an important post-transcriptional regulator of SREBP activation. This report demonstrates that 10 µM PF-429242, a recently described reversible, competitive aminopyrrolidineamide inhibitor of S1P, inhibits endogenous SREBP processing in Chinese hamster ovary cells. The same compound also down-regulates the signal from an SRE-luciferase reporter gene in HEK293 cells and the expression of endogenous SREBP target genes in cultured HepG2 cells. In HepG2 cells, PF-429242 inhibited cholesterol synthesis with an IC50 of 0.5 µM. In mice treated with PF-429242 for 24 h, the expression of hepatic SREBP target genes was suppressed, and the hepatic rates of cholesterol and fatty acid synthesis were reduced. Taken together, these data establish that small molecule S1P inhibitors are capable of reducing cholesterol and fatty acid synthesis in vivo, and therefore represent a potential new class of therapeutic agents for dyslipidemia and for a variety of cardiometabolic risk factors associated with diabetes, obesity and the metabolic syndrome.

Key words: SREBP, Site-1 protease, cholesterol synthesis, enzyme inhibition, fatty acid synthesis, metabolic regulation