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.

Abstract

IntroductionIn humans, diets high in saturated fat and cholesterol raise HDL-cholesterol (HDL-C) levels. To explore the mechanism, we have devised a mouse model that mimics the human situation. In this model, HuAITg and control mice were studied on low fat (9% cal)-low cholesterol (57 mg/1,000 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 increase in HDL-C levels. In most societies today, there is a well-known inverse correlation between coronary heart disease risk and HDL cholesterol (HDL-C)' levels ( 1-3). However, paradoxically, diets high in saturated fat and cholesterol, which increase atherosclerosis risk, raise HDL-C levels (4-9). To explore the mechanism for this phenomenon and perhaps gain greater insight into the role of HDL in heart disease, in a previous human metabolic study (9), we measured the turnover of the major HDL apolipoproteins, apo A-I and apo A-II, in 13 subjects consuming low fat (9% calories)-low cholesterol (40 mg/ 1,000 kcal) and high fat (42% calories)-high cholesterol (215 mg/ 1,000 kcal) diets. The dietary fat challenge increased HDL-C 40%, apo A-I 30% (both P < 0.001 ), with no change in apo A-II levels. The turnover studies indicated a 17% increase in apo A-I transport rate (TR) and a 10% decrease in apo A-I fractional catabolic rate (FCR). Individual changes in HDL-C levels correlated with changes in apo A-I TR (r = 0.79, P < 0.001) but not FCR (r = -0.04). This study suggested that dietary fat both increases the TR and decreases the FCR ofapo A-I with perhaps a larger effect on the TR (9). Since clinical studies do not allow further examination of how dietary fat influences apo A-I metabolism nor do they permit studies ofHDL CE metabolism, in the current study, to pursue these questions, an animal model was created. Mice were used because of the availability of human apo A-I transgenic (HuAITg) lines (10, 11). These animals express significant amounts ofhuman apo A-I in plasma, and for reasons not yet understood, they have greatly diminished mouse apo A-I levels (1 1-13). Accompanying this exchange of human for mouse apo A-I is a change from normal mouse HDL, which has a single major size distribution ofHDL particles to humanlike HDL characterized by two or more major size distributions, principally HDL2b and HDL3J (11)(12)(13). Thus, HuAITg mice might be a better model in which to study the dietary fat-HDL relationship.As in the human metabolic study, mice were fed low fat (9% calories)-low cholesterol (57 mg/ 1,000 kcal) and high fat (41% calories), high cholesterol (437 mg/ 1,000 kcal) diets. In contrast to previously used high fat-high cholesterol diets that have lowered HDL-C and apo A-I levels in some strains ofmice

Mild Hypercholesterolemia Blunts the Proinflammatory and Prothrombotic Effects of Hypertension on the Cerebral Microcirculation

“…9 Monolayers of cerebral microvascular endothelial cells exposed to Ang II also exhibit an increased permeability that is dependent on Ang II type-1 receptors. 29 Like previous studies, 30 we observed an increased plasma HDL concentration in mice placed on a high-fat, cholesterol-enriched diet. Our study also provides two lines of evidence that are consistent with a role for HDL in mediating the antiinflammatory and antithrombogenic effects of HCh.…”

Group 1B phospholipase A2 deficiency protects against diet-induced hyperlipidemia in mice

“…FPLC analysis of plasma from hypercaloric diet-fed mice showed that difference in VLDL accounted for the different plasma triglyceride levels between Pla2g1b +/+ and Pla2g1b Ϫ / Ϫ mice. Additionally, the Pla2g1b Ϫ / Ϫ mice also did not display elevated plasma HDL levels (data not shown), which are typically observed in wild-type mice after high-fat feeding ( 28 ). The mechanism underlying the differences in plasma lipid levels between Pla2g1b +/+ and Pla2g1b Ϫ / Ϫ mice was explored by comparing hepatic VLDL production rates in these animals under both basal and hypercaloric dietary conditions.…”

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

“…The plasma decay curve was used to fit an exponential curve by computer analysis. The fractional catabolic rate (FCR) was calculated as the inverse of the area under the decay curves as described (18,19).…”