DIETARY-FAT INCREASES HIGH-DENSITY-LIPOPROTEIN (HDL) LEVELS BOTH BY INCREASING THE TRANSPORT RATES AND DECREASING THE FRACTIONAL CATABOLIC RATES OF HDL CHOLESTEROL ESTER AND APOLIPOPROTEIN (APO) A-I - PRESENTATION OF A NEW ANIMAL-MODEL AND MECHANISTIC STUDIES IN HUMAN APO A-I TRANSGENIC AND CONTROL MICE

In humans, diets high in saturated fat and cholesterol raise HDL-chole sterol (HDL-C) levels. To explore the mechanism, we have devised a mou se model that mimics the human situation. In this model, HuAITg and co ntrol mice were studied on low fat (9% cal)-low cholesterol (57 mg/1,0 00 kcal) (chow) and high fat (41% cal)-high cholesterol (437 mg/1,000 kcal) (milk-fat based) diets. The mice responded to increased dietary fat by increasing both HDL-C and apo A-I levels, with a greater increa se in HDL-C levels. This was compatible with an increase in HDL size o bserved by nondenaturing gradient gel electrophoresis. Turnover studie s with doubly labeled HDL showed that dietary fat both increased the t ransport rate (TR) and decreased the fractional catabolic rate of HDL cholesterol ester (CE) and apo A-I, with the largest effect on HDL CE TR. The latter suggested that dietary fat increases reverse cholestero l transport through the HDL pathway, perhaps as an adaptation to the m etabolic load of a high fat diet. The increase in apo A-I TR by dietar y fat was confirmed by experiments showing increased apo A-I secretion from primary hepatocytes isolated from animals on the high fat diet. The increased apo A-I production was not associated with any increase in hepatic or intestinal apo A-I mRNA, suggesting that the mechanism o f the dietary fat effect was posttranscriptional, involving either inc reased translatability of the apo A-I mRNA or less intracellular apo A -I degradation. The dietary fat-induced decrease in HDL CE and apo A-I fractional catabolic rate may have been caused by the increase in HDL particle size, as was suggested by our previous studies in humans. In summary, a mouse model has been developed and experiments performed t o better understand the paradoxical HDL-raising effect of a high fat d iet.