Diurnal variations in the effects of an unsaturated-fat-containing diet on fatty acid and cholesterol synthesis in rat hepatocytes

Abstract

Rats were fed ad libitum on either a standard high-carbohydrate diet, or a standard diet supplemented with 15% corn oil. Hepatocytes were prepared either during the light phase (L2-hepatocytes) or during the dark phase (D6-hepatocytes) of the diurnal cycle. In hepatocytes from rats fed on the fat-containing diet, fatty acid synthesis (lipogenesis) was suppressed to a much greater extent at D6 than at L2. The magnitude of the increase in plasma-free fatty acid concentration was similar at the two times of day. The rate of cholesterol synthesis was also significantly suppressed in the D6- but not in the L2-hepatocytes. This differential inhibition resulted in the abolition of the normal diurnal rhythm of cholesterogenesis. The initial activity of 3-hydroxy-3-methylglutaryl-CoA reductase in hepatocytes was also suppressed by corn-oil feeding at D6 but not at L2. In D6-hepatocytes, the inhibitory effect of the high-fat diet on the conversion of lactate into cholesterol and fatty acids was greater than that on total carbon flux into these substances for all endogenous sources. Despite this, under these conditions a high concentration of lactate and pyruvate resulted in a several-fold stimulation of total carbon flux into fatty acids. In hepatocytes prepared at L2, fat-feeding had little effect on the degree of stimulation of lipogenesis by insulin or inhibition by glucagon. However, at D6, fat-feeding blunted the response of lipogenesis to both these hormones.