Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men

Abstract

The inverse relationship between plasma HDL cholesterol concentrations and the risk of cardiovascular disease is well accepted (1, 2). There is a large body of evidence indicating that variations in plasma HDL cholesterol concentrations are inversely related to plasma triglyceride (TG) levels (3, 4). Hence, one of the most frequent metabolic abnormalities accompanying reduced plasma HDL cholesterol levels is hypertriglyceridemia. Apo A-I, the major protein of HDL, is a crucial structural and functional component in the metabolism of these particles. Studies have shown that the fractional catabolic rate (FCR) of apo A-I is a significant and powerful predictor of plasma HDL cholesterol levels (5, 6). Studies that have examined the production and clearance rates of apo A-I as a marker of HDL metabolism in humans have led to the hypothesis that hypertriglyceridemia may be one of several factors ultimately affecting plasma HDL cholesterol levels (7-9). However, these studies have not tested this hypothesis directly because they relied on correlations between HDL apo A-I FCR and plasma TG concentrations.The mechanisms underlying the enhanced catabolism of apo A-I in hypertriglyceridemic states are not well understood. Hypertriglyceridemia is associated with an increased cholesteryl ester transfer protein-mediated (CETP-mediated) transfer of TG from the expanded pool of TG-rich lipoproteins to HDL and of cholesteryl ester from HDL to TG-rich lipoproteins (10). The resulting TG enrichment of the HDL particle makes it a better substrate for lipolysis by hepatic lipase, an enzyme that plays a key role in HDL metabolism (11,12). Results from an ex vivo kidney perfusion study have indicated that TG enrichment of HDL alone, in the absence of subsequent lipolytic modification of the particle by hepatic lipase and lipoprotein lipase, may have very little impact, if any, on the uptake of apo A-I by the kidney (13). On the other hand, lipolytic modification of TG-rich HDL by lipoprotein lipase and hepatic lipase was associated with a significant increase in the uptake of apo A-I by the perfused rabbit kidney and loss of apo A-I from the HDL fraction (13). In vitro incubation of TG-enriched human HDL with hepatic lipase has also been shown to promote the loss of apo A-I from the particle (14). We have recently shown, using a rabbit model, that the FCR of apo A-I from small, lipolytically modified HDL was increased significantly compared with the FCR of apo A-I from large, TG-enriched HDL (15). This increase in HDL FCR was not observed in the absence of lipolytic modification of TG-rich HDL particles (16). In vitro and in vivo data sug- Triglyceride (TG) enrichment of HDL resulting from cholesteryl ester transfer protein-mediated exchange with TG-rich lipoproteins may enhance the lipolytic transformation and subsequent metabolic clearance of HDL particles in hypertriglyceridemic states. The present study investigates the effect of TG enrichment of HDL on the clearance of HDL-associated apo A-I in humans. HDL was isolated from plas...

Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit

“…Atorvastatin appears to inhibit CETP activity in humans, which should decrease HDL triglycerides, 31 and fails to alter hepatic and lipoprotein lipase levels in the rabbit model, 22 which should leave the HDL triglyceride content unchanged. Nonetheless, triglyceride enrichment of HDL has previously been shown to enhance HDL apoA-I catabolism in vivo, 32 and combined with other drug-induced effects, could have contributed to the enhanced HDL apoA-I clearance in the present study. Although it has not been investigated, atorvastatin-induced upregulation of candidate HDL receptors involved in holoparticle HDL uptake by tissues such as liver and kidney remains a theoretical possibility.…”

Lipid Transfer Inhibitor Protein Defines the Participation of High Density Lipoprotein Subfractions in Lipid Transfer Reactions Mediated by Cholesterol Ester Transfer Protein (CETP)

“…Thus, variations in LTIP activity sustain the rate of HDL 2 remodeling regardless of TG status. By retarding the enrichment of HDL 2 with TG, LTIP would stabilize these particles and prevent their premature clearance from plasma (60,61). Overall, our data show that LTIP regulates CETP-mediated remodeling of HDL in a subclass-specific manner.…”

Diabetic dyslipidaemia: from basic research to clinical practice*

“…Triglycerides in HDL, like in LDL, are a good substrate for hepatic lipase and the hydrolysis produces smaller particles and free apo A-I that is shed from the particle and cleared by the kidneys. Triglyceride enrichment of HDL has been ob- served to enhance in vivo clearance of HDL apo A-I in healthy men [145]. It has been shown that lipolysis of Tg enriched HDL particles by HL was required for the enhanced clearance rate of HDL [146].…”