Inhibition of squalene synthase upregulates PCSK9 expression in rat liver.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol metabolism by enhancing the degradation of the LDL receptor protein in the liver. It has previously been shown that administration of zaragozic acid A (ZA), a potent inhibitor of squalene synthase, also significantly increases the rate of degradation of hepatic LDL receptor protein. Thus, we decided to determine whether ZA administration might act to up regulate hepatic expression of the rat PCSK9 gene. Administration of ZA resulted in increased PCSK9 mRNA and protein levels in rat liver surprisingly in concert with an increase in hepatic LDL receptor mRNA levels, LDL receptor protein turnover, and decreased serum cholesterol levels. These observations suggest an involvement of PCSK9 in hepatic LDL receptor protein degradation and perhaps, in increasing the rate of LDL receptor cycling resulting in lower serum cholesterol levels in response to cholesterol biosynthesis inhibitors.
Department of Molecular Medicine, School of Basic Biomedical Sciences, University of South Florida, College of Medicine, Tampa, FL 33612, USA.
Mohini
M
Bedi
Melissa
M
Niesen
Dayami
D
Lopez
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014233:Tricarboxylic Acids / Q000008:administration & dosage*; D015854:Up-Regulation / Q000187:drug effects
D019086:Bridged Bicyclo Compounds, Heterocyclic; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D013186:Farnesyl-Diphosphate Farnesyltransferase