Hypertriglyceridemia and delayed clearance of fat load in transgenic rabbits expressing human apolipoprotein CIII

Abstract

Apolipoprotein CIII (apoCIII) has been implicated in hypertriglyceridemia and plasma apoCIII independently predicts risk for coronary heart disease. While hypertriglyceridemia in patients has been demonstrated to correlate with elevated plasma apoCIII levels and reduced lipoprotein lipase (LPL) activity, apoCIII transgenic mice show elevated LPL activity. In this study, we generated transgenic (Tg) rabbits expressing human apoCIII gene exclusively in liver and investigated the effect of apoCIII overexpression on lipid metabolism of rabbits. In comparison with non-Tg littermates, Tg rabbits had 3- and 3.2-fold increases in fed and fasted plasma triglycerides, respectively. In contrast, no significant differences were observed in plasma total cholesterol and high density lipoprotein cholesterol levels between Tg and non-Tg rabbits. Analysis of lipoprotein fractions revealed that elevated plasma triglyceride levels in Tg rabbits were mainly attributed to an increase in very low density lipoprotein/chylomicron-sized particles. Furthermore, Tg rabbits showed markedly delayed clearance of plasma triglycerides accompanied with significantly reduced LPL activity in post-heparin plasma compared to that in non-Tg controls. In conclusion, these results indicate apoCIII transgenic rabbits develop hypertriglyceridemia with similar mechanism in hypertriglyceridemic patients via delayed clearance of plasma triglycerides, and could be used as a valuable tool for the study of human hyperlipidemia in relation with atherosclerotic disorders.

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

“…In contrast, a premature stop mutation in apolipoprotein C-III (apoC-III) is associated with low levels of plasma triglycerides (5). This finding in humans is in line with studies demonstrating that apoC-III knock-out mice are hypotriglyceridemic (6), whereas overexpression of apoC-III in mice leads to hypertriglyceridemia (7)(8)(9). ApoC-III is known to inhibit LPL activity in vitro (10 -12).…”

Lipoprotein lipase: From gene to atherosclerosis

“…In contrast, apoC-I and apoC-III have been shown to inhibit LPL activity in vitro. Overexpression of apoC-I/III in mice leads to hypertriglyceridemia [91,92]. A null-mutation in apoCIII as shown in the Lancaster Amish leads to low plasma apoCIII levels and confers a favorable lipid profile with low plasma TG levels, resulting in cardioprotection [93].…”

Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production

“…Extensive animal and human studies have established a positive correlation between plasma apo C-III and triglyceride concentrations. Genetically modified mice [1], rabbits [2], or miniature pigs [3 & ] with high-level expression of human APOC3 show severe hypertriglyceridemia. High-level expression of human apo C-III in mice deficient in the LDL receptor has been created to serve as a model for familial combined hyperlipidemia [4].…”