Inhibition of fatty acid synthesis decreases very low density lipoprotein secretion in the hamster.
The hamster was developed as a model to study very low density lipoprotein (VLDL) metabolism, since, as is the case in humans, the hamster liver was found to synthesize apoB-100 and not apoB-48. The effect of inhibiting fatty acid synthesis on the hepatic secretion of VLDL triglyceride (TG) and apolipoprotein (apo) B-100 in this model was then investigated. In an in vivo study, hamsters were fed a chow diet containing 0.15% TOFA (5-tetradecyloxy-2-furancarboxylic acid), an inhibitor of acetyl-CoA carboxylase. After 6 days of treatment, plasma triglyceride and cholesterol levels were decreased by 30.2% and 11.6%, respectively. When the secretion of VLDL-TG by the liver was measured in vivo after injection of Triton WR 1339, TOFA treatment was found to decrease VLDL-TG secretion by 40%. In subsequent in vitro studies utilizing cultured primary hamster hepatocytes, incubation with 20 microM TOFA for 4 h resulted in 98% and 76% inhibition in fatty acid and triglyceride synthesis, respectively; VLDL-TG secretion was decreased by 90%. When hepatocytes were pulsed with [3H]leucine, incubation with TOFA resulted in a 50% decrease in the incorporation of radiolabel into secreted VLDL apoB-100. The results of this study indicate that inhibition of intracellular triglyceride synthesis decreases the secretion of VLDL-TG and apoB-100, and does not result in the secretion of a dense, triglyceride-depleted lipoprotein.
Arbeeny
C M
CM
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.
Meyers
D S
DS
Bergquist
K E
KE
Gregg
R E
RE
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D005227:Fatty Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D005663:Furans / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism
D005227:Fatty Acids; D005663:Furans; D000960:Hypolipidemic Agents; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C014289:5-(tetradecyloxy)-2-furancarboxylic acid