Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions

Abstract

The atherogenicity theory for triglyceride-rich lipoproteins (TRLs; VLDL 1 intermediate density lipoprotein) generally cites the action of apolipoprotein C-III (apoC-III), a component of some TRLs, to retard their metabolism in plasma. We studied the kinetics of multiple TRL and LDL subfractions according to the content of apoC-III and apoE in 11 hypertriglyceridemic and normolipidemic persons. The liver secretes mainly two types of apoB lipoproteins: TRL with apoC-III and LDL without apoC-III. Approximately 45% of TRLs with apoC-III are secreted together with apoE. Contrary to expectation, TRLs with apoC-III but not apoE have fast catabolism, losing some or all of their apoC-III and becoming LDL. In contrast, apoE directs TRL flux toward rapid clearance, limiting LDL formation. Direct clearance of TRL with apoC-III is suppressed among particles also containing apoE. TRLs without apoC-III or apoE are a minor, slow-metabolizing precursor of LDL with little direct removal. Increased VLDL apoC-III levels are correlated with increased VLDL production rather than with slow particle turnover. Finally, hypertriglyceridemic subjects have significantly greater production of apoC-IIIcontaining VLDL and global prolongation in residence time of all particle types. ApoE may be the key determinant of the metabolic fate of atherogenic apoC-III-containing TRLs in plasma, channeling them toward removal from the circulation and reducing the formation of LDLs, both those with apoC-III and the main type without apoC-III.-Zheng, C., C. Khoo, K. Ikewaki, and F. M. Sacks. Epidemiological studies demonstrate that apolipoprotein C-III (apoC-III) and the apoB lipoproteins that have apoC-III as a component independently predict coronary heart disease (1-3). ApoC-III is present on ?40-80% of triglyceride-rich lipoproteins (TRLs) and ?5-10% of LDLs in plasma (4-6). The mechanisms by which apoC-III causes hypertriglyceridemia and atherosclerosis are incompletely understood.Experiments in vitro show that apoC-III can inhibit lipoprotein lipase (7,8) and hepatic lipase (9) and retard the clearance of VLDL by interfering with the binding of apoB-100 (10) or apoE to hepatic receptors (11, 12). Direct evidence supporting a role of high apoC-III level in abnormal TRL metabolism has come from transgenic animal studies. Overexpression of apoC-III in mice causes hypertriglyceridemia (13-17), whereas apoC-III deficiency protects against it (18,19). In these studies, impaired particle clearance via LDL receptors (14-16), reduced binding affinity to cell surface proteoglycans (15, 17), inhibition of lipolysis (17,19), and overproduction of VLDL triglyceride (14, 16) have all been implicated as mechanisms for the hypertriglyceridemic effect of apoC-III. In humans, there is also evidence for apoC-III affecting TRL metabolism. Patients with combined deficiency of apoC-III and apoA-I experience rapid VLDL clearance (20). In a kinetic study, the plasma concentrations and secretion rates of VLDL apoC-III were correlated with those of VLDL triglycerid...

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

“…The increase in TG production may be due to excess FFA returning to the liver, particularly in the setting of visceral obesity and insulin resistance, and increased de novo TG production due to hyperinsulinemia [46][47][48]. In hypertriglyceridemia, more VLDL particles, as measured by apoB, and larger and more TG-and apoC-III-enriched lipoproteins are found [49][50][51]. Hepatic insulin resistance may contribute to a high production rate of VLDL because insulin reduces apoB synthesis and VLDL secretion in the liver [52,53].…”

Overview of the LDL receptor: relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease

“…There is in vivo evidence that VLDL that are poor in apoE content have an increased probability of being converted to LDL while VLDL enriched with apoE have an increased probability of being removed from plasma by the LDLR. 78 ApoE with a point mutation in the LDLR binding domain tends to accumulate in plasma and promote atherosclerosis. HDL is a lipoprotein that does not contain apoB but has a cholesterol-rich apoE-containing subfraction that is rapidly cleared from plasma and thought to have an anti-atherogenic role.…”

Increased Plasma Apolipoprotein C-III Concentration Independently Predicts Cardiovascular Mortality: The Hoorn Study

“…ApoC-III retards the clearance of triglyceriderich apoB-containing lipoproteins by inhibiting lipoprotein lipase (LPL), and as such plays a pivotal role in the catabolism of triglycerides (5 ). The presence of apoC-III on triglyceride-rich lipoproteins has also been shown to influence their fate by suppression of direct removal of these lipoproteins from the circulation and enhancement of their conversion to smaller and denser particles (6 ). In addition, apoC-III containing VLDL and LDL have been shown to increase monocyte adhesion to the endothelium by inducing expression of vascular cell adhesion molecule-1 in endothelial cells (7 ) and activating ␤1 integrin in monocytes (8 ).…”