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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.

SUBMITTER: Gibbons GF

PROVIDER: S-EPMC1147331 | biostudies-other | 1986 Nov

REPOSITORIES: biostudies-other

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Project description:ObjectiveAn increased ω6/ω3-polyunsaturated fatty acid ratio in the current Western diet is regarded as a critical epigenetic nutritional factor in the pathogenesis of several human lifestyle diseases, metabolic syndrome, cardiovascular disease, the central nervous system and the female and male reproductive systems. The impact of nutrient ω3-and ω6-PUFAs in the pathogenesis of dyslipoproteinemia and atherosclerosis has been a topic of intense efforts for several decades. Cellular homeostasis of the ω3-and ω6- PUFA pool is maintained by the synthesis of ω3-and ω6-PUFAs from essential fatty acids (EFA) (linoleic and α-linolenic acid) and their dietary supply. In this study, we used the auxotrophic Δ6-fatty acid desaturase- (FADS2) deficient mouse (fads2-/-), an unbiased model congenial for stringent feeding experiments, to investigate the molecular basis of the proposed protective role of dietary ω3-and ω6-PUFAs (Western diet) in the pathogenesis of multifactorial dyslipoproteinemia and atherosclerosis. We focused on the metabolic axis-liver endoplasmic reticulum (ER), serum lipoprotein system (Lp) and aorta vessel wall. Furthermore, we addressed the impact of the inactivated fads2-locus with inactivated PUFA synthesis on the development and progression of extended atherosclerosis in two different mouse mutants with disrupted cholesterol homeostasis, using the apoe-/- and ldlr-/- mutants and the fads2-/- x apoe-/- and fads2-/- x ldlr-/- double mutants.MethodsCohorts of +/+ and fads2-/- mice underwent two long-term dietary regimens: a) a PUFA-free standard chow diet containing only EFAs, essential for viability, and b) a high fat/high cholesterol (HFHC) diet, a mimicry of the human atherogenic "Western" diet. c) To study the molecular impact of PUFA synthesis deficiency on the development and progression of atherosclerosis in the hypercholesterolemic apoe-/- and ldlr-/- mouse models fed PUFA-free regular and sustained HFHC diets, we generated the fads2-/- x apoe-/- and the fads2-/- x ldlr-/- double knockout mutants. We assessed essential molecular, biochemical and cell biological links between the diet-induced modified lipidomes of the membrane systems of the endoplasmic reticulum/Golgi complex, the site of lipid synthesis, the PL monolayer and neutral lipid core of LD and serum-Lp profiles and cellular reactions in the aortic wall.Resultsω3-and ω6-PUFA synthesis deficiency in the fads2-/- mouse causes a) hypocholesterolemia and hypotriglyceridemia, b) dyslipoproteinemia with a shift of high-density lipoprotein (HDL) to very low-density lipoprotein (VLDL)-enriched Lp-pattern and c) altered liver lipid droplet structures. d) Long-term HFHC diet does not trigger atherosclerotic plaque formation in the aortic arc, the thoracic and abdominal aorta of PUFA-deficient fads2-/- mice. Inactivation of the fads2-/- locus, abolishing systemic PUFA synthesis in the fads2-/- x apoe-/- and fads2-/- x ldlr-/- double knockout mouse lines.ConclusionsDeficiency of ω3-and ω6-PUFA in the fads2-/- mutant perturbs liver lipid metabolism, causes hypocholesterolemia and hypotriglyceridemia and renders the fads2-/- mutant resistant to sustained atherogenic HFHC diet. Neither PUFA-free regular nor long-term HFHC-diet impacts the apoe- and LDL-receptor deficiency-provoked hypercholesterolemia and atherosclerotic plaque formation, size and distribution in the aorta. Our study strongly suggests that the absence of PUFAs as highly vulnerable chemical targets of autoxidation attenuates inflammatory responses and the formation of atherosclerotic lesions. The cumulative data and insight into the molecular basis of the pleiotropic functions of PUFAs challenge a differentiated view of PUFAs as culprits or benefactors during a lifespan, pivotal for legitimate dietary recommendations.

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

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