Enhancement of fatty acid and cholesterol synthesis accompanied by enhanced biliary but not very-low-density lipoprotein lipid secretion following sustained pravastatin blockade of hydroxymethyl glutaryl coenzyme A reductase in rat liver.
A 3-week treatment of rats with pravastatin (PV) augmented biliary cholesterol and phospholipid output 3.6- and 2.2-fold over controls, while bile acid (BA) output and kinetics were unchanged. No major changes were detected in hepatic and serum cholesterol concentrations despite the PV inhibitory property on hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase. To evaluate the mechanisms of this adaptive phenomenon, several parameters of hepatic lipid homeostasis were assessed. Biliary cholesterol changes could not be attributed to an increased influx of lipoprotein cholesterol to the liver and bile. Hepatic low-density lipoprotein (LDL) receptor content, as inferred from Western blot analysis, was unchanged, as was the biliary excretion of labeled cholesterol derived from chylomicron remnants. In vivo 3H2O-incorporation studies showed an 80% increase in hepatic cholesterol synthesis, evidence for bypass of the PV block. Remarkably, fatty acid synthesis was also stimulated twofold, providing substrate for hepatic triglycerides, which were slightly enhanced. However, serum triglycerides decreased 52% associated with a 22% decrease in hepatic very-low-density lipoprotein (VLDL) secretion. Thus, the biochemical adaptation following PV treatment produces complex alterations in hepatic lipid metabolism. An enhanced supply of newly synthesized cholesterol and fatty acids in association with a limited VLDL secretion rate augments the biliary lipid secretion pathway in this experimental model.
Carrella
M
M
Cattedra di Gastroenterologia, Facolta' di Medicina e Chirurgia, Universita' degli Studi di Udine, Italy.
Fong
L G
LG
Loguercio
C
C
Del Piano
C
C
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D005227:Fatty Acids / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D002784:Cholesterol; D017035:Pravastatin