Apolipoprotein A-II/A-I Ratio Is a Key Determinant in Vivo of HDL Concentration and Formation of Pre-β HDL Containing Apolipoprotein A-II

Abstract

Overexpression of human apolipoprotein A-II (apo A-II) in mice induced postprandial hypertriglyceridemia and marked reduction in plasma HDL concentration and particle size [Boisfer et al. (1999) J. Biol. Chem. 274, 11564-11572]. We presently compared lipoprotein metabolism in three transgenic lines displaying plasma concentrations of human apo A-II ranging from normal to 4 times higher, under ad libitum feeding and after an overnight fast. Fasting dramatically decreased VLDL and lowered circulating human apo A-II in transgenic mice; conversely, plasma HDL levels increased in all genotypes. The apo A-I content of HDL was inversely related to the expression of human apo A-II, probably reflecting displacement of apo A-I by an excess of apo A-II. Thus, the molar ratios of apo A-II/A-I in HDL were significantly higher in fed as compared with fasted animals of the same transgenic line, while endogenous LCAT activity concomitantly decreased. The number and size of HDL particles decreased in direct proportion to the level of human apo A-II expression. Apo A-II was abundantly present in all HDL particles, in contrast to apo A-I mainly present in large ones. Two novel findings were the presence of pre-beta migrating HDL transporting only human apo A-II in the higher-expressing mice and the increase of plasma HDL concentrations by fasting in control and transgenic mice. These findings highlight the reciprocal modifications of VLDL and HDL induced by the feeding-fasting transition and the key role of the molar ratio of apo A-II/A-I as a determinant of HDL particle metabolism and pre-beta HDL formation.

Regulation of ABCA1 expression and cholesterol efflux during adipose differentiation of 3T3-L1 cells

“…In rodents, under physiological conditions in which lipolysis is stimulated (i.e. fasting), increased levels of HDL cholesterol have been described (41). The responsible mechanisms, however, might involve interactions between lipoproteins in the circulating compartment or decreased clearance by the liver, rather than increased peripheral production.…”

In Vitro Transcriptional Induction of the Human Apolipoprotein A-II Gene by Glucose

“…We investigated the response of apoA-II gene expression to changes in diet by performing in vivo analysis on transgenic mice expressing human apoA-II at physiological levels (line ␤) (9). A refeeding with a high-carbohydrate diet induced an increase in hepatic mRNA level and plasma concentration of human apoA-II, 2.5-and 1.5-fold, respectively (Fig.…”

“…However, glycemia had not yet been determined. To evaluate the pathophysiological relevance of our results, we therefore investigated the relationship between apoA-II gene expression and glucose in two lines of transgenic mice, line ␤, which produced human apoA-II at physiological concentration (9), and line , which overproduced three times the human apoA-II (8). Blood glucose was found to be strongly correlated (R 2 ϭ 0.588, P Ͻ 0.0001) with the level of human apoA-II in transgenic mice of the ␤-and -lines (Fig.…”

“…The overproduction of human apoA-II decreases plasma HDL concentration in a dose-dependent manner (8,40) and induces postprandial hypertriglyceridemia (8,9). This phenotype resembles the dyslipidemia observed in diabetes, suggesting that stimulation of the hepatic synthesis of apoA-II may contribute to the dyslipidemia syndrome that occurs in patients with type 2 diabetes.…”

“…The overproduction of human apoA-II, at three times normal concentrations (transgenic line ), resulted in a large decrease in HDL levels, associated with very high postprandial levels of very low density lipoproteins (VLDLs). Human apoA-II was found to associate with these VLDLs, impairing their catabolism by lipoprotein lipase (8,9). Further evidence for such a role of apoA-II was provided by a recent clinical study reporting that decreasing plasma apoA-II concentration increases clearance of large-sized postprandial VLDLs (10).…”