Submitted on March 13, 2006
Revised on April 4, 2006
Accepted on April 10, 2006
Transgenic expression of CYP7a1 in LDL receptor deficient mice blocks diet-induced hypercholesterolemia
Eric P. Ratliff, Alejandra Gutierrez, and Roger A. Davis
Biology, San Diego State University, San Diego, CA 92182
Corresponding Author: rdavis{at}sunstroke.sdsu.edu
Constitutive expression of a CYP7A1 transgene in LDL receptor deficient mice blocked the ability of a cholesterol-enriched diet to increase plasma levels of apo B-containing lipoproteins. LDL receptor deficient mice expressing the CYP7A1 transgene exhibited a complete resistance to diet-induced hypercholesterolemia and to the accumulation of cholesterol in the liver. Hepatic mRNA expression of LXR-inducible ABCG5 and ABCG8, whose functional heterodimer facilitates biliary cholesterol excretion, were decreased in CYP7A1 transgenic, LDL receptor deficient mice fed a cholesterol-enriched diet. CYP7A1 transgenic, LDL receptor deficient mice fed the cholesterol-enriched diet exhibited decreased jejunal NPC1L1 mRNA expression, an important mediator of intestinal cholesterol absorption. Further studies showed that consuming a taurocholate-enriched diet also decreased NPC1L1 mRNA expression in an FXR independent manner. Reduced expression of NPC1L1 mRNA in LDL receptor deficient mice fed the cholesterol-enriched diet was associated with decreased cholesterol absorption (~20%, P<0.05). Enhanced conversion of cholesterol to bile acids, biliary bile acid excretion and fecal bile acid loss are responsible for the CYP7A1 transgene preventing the accumulation of excess cholesterol in liver and plasma of LDL receptor deficient mice fed a cholesterol-enriched diet. CYP7A1 is an effective therapeutic target to prevent diet-induced hypercholesterolemia.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
