Effect of NK-104, a new synthetic HMG-CoA reductase inhibitor, on triglyceride secretion and fatty acid oxidation in rat liver.
For the investigation of the mechanism responsible for the hypotriglyceridemic effect of NK-104, a new synthetic inhibitor of HMG-CoA reductase, the rate-limiting enzyme for cholesterol synthesis, isolated rat liver was perfused with or without NK-104 in the presence of exogenous [1-(14)C]oleic acid substrate. Addition of NK-104 tended to increase the ketone body production while it caused a significant decrease in the secretion rate of triglyceride by the perfused liver without affecting uptake of exogenous [1-(14)C]oleic acid. The inhibitor also significantly decreased hepatic triglyceride concentration. The altered triglyceride secretion was accompanied by a concomitant decreased incorporation of exogenous [1-(14)C]oleate into triglyceride. The conversion of exogenous [1-(14)C]oleic acid substrate indicated an inverse relationship between the pathways of oxidation and esterification. No effect of NK-104 on hepatic secretion of cholesterol was observed. These results suggest that NK-104 exerts its hypotriglyceridemic action, primarily by diverting the exogenous free fatty acid to the pathways of oxidation at the expense of esterification.
Yamamoto
K
K
Department of Internal Medicine, Saga Medical University School of Medicine, Japan.
Todaka
N
N
Goto
H
H
Jayasooriya
A P
AP
Sakono
M
M
Ogawa
Y
Y
Fukuda
N
N
D000818:Animals; D001667:Binding, Competitive; D005227:Fatty Acids / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D017035:Pravastatin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism*
D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D014280:Triglycerides; D019821:Simvastatin; D017035:Pravastatin; C108475:pitavastatin