出版社：American Society for Biochemistry and Molecular Biology
摘要：Squalene synthase (SS) is the first committed enzyme for cholesterolbiosynthesis, located at a branch point in the mevalonate pathway.To examine the role of SS in the overall cholesterol metabolism,we transiently overexpressed mouse SS in the livers of miceusing adenovirus-mediated gene transfer. Overexpression of SSincreased de novo cholesterol biosynthesis with increased 3-hydroxy-3-methyglutaryl-CoA(HMG-CoA) reductase activity, in spite of the downregulationof its own mRNA expression. Furthermore, overexpression of SSincreased plasma concentrations of LDL, irrespective of thepresence of functional LDL receptor (LDLR). Thus, the hypercholesterolemiais primarily caused by increased hepatic production of cholesterol-richVLDL, as demonstrated by the increases in plasma cholesterollevels after intravenous injection of Triton WR1339. mRNA expressionof LDLR was decreased, suggesting that defective LDL clearancecontributed to the development of hypercholesterolemia. Curiously,the liver was enlarged, with a larger number of Ki-67-positivecells. These results demonstrate that transient upregulationof SS stimulates cholesterol biosynthesis as well as lipoproteinproduction, providing the first in vivo evidence that SS playsa regulatory role in cholesterol metabolism through modulationof HMG-CoA reductase activity and cholesterol biosynthesis.Supplementary key words lipoprotein • adenovirus • hyperlipoproteinemia • 3-hydroxy-3-methyglutaryl-CoA reductase • farnesyl diphosphate • mevalonate • hepatomegaly • cell proliferation • feedback regulation
Abbreviations: Ad-SS, recombinant adenovirus carrying SS cDNA under the control of cytomegalovirus promoter; apoB, apolipoprotein B; E, embryonic day; ER, endoplasmic reticulum; LDLR, LDL receptor; m.o.i., multiplicity of infection; SREBP, sterol-regulatory element binding protein; SS, squalene synthase; TC total cholesterol; TG, triglyceride; TUNEL, terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling
