Obesity favors apolipoprotein E- and C-III-containing high density lipoprotein subfractions associated with risk of heart disease

Abstract

with an elevated risk of coronary heart disease (CHD) ( 1-5 ). However, evidence from randomized clinical trials that studied drugs that increased HDL-C has not been consistent with the hypothesis that HDL protects against CHD. In large-scale trials of novel cholesteryl ester transfer protein inhibitors, CHD incidence was not reduced despite substantial increases in HDL-C levels ( 6-8 ); trials of estrogen replacement therapy in postmenopausal women did not confi rm a protective effect on CHD despite increases in HDL-C ( 9-11 ); and two recent trials of niacin also failed to show reduction in CHD risk, although the increases in HDL-C were modest ( 12, 13 ). Furthermore, some genetic variation that is associated with high HDL-C concentration is not associated with reduced CHD ( 14 ). This raises questions regarding the effi cacy of HDL-C elevation, in general, as a strategy for CHD prevention.Accumulating evidence indicates that protein composition of HDL may be relevant to the risk of CHD ( 15-17 ). ApoE and apoC-III are found on the surface of both triglyceride-rich lipoproteins (TRLs) and . The concentration of apoE in HDL is an independent predictor of recurrent coronary events ( 15 ). More recently, a proteomic analysis showed greater apoE enrichment in small-size HDL (HDL3) in subjects with established coronary artery disease than in normal controls ( 16 ). Similarly, HDL containing apoC-III independently predicts increased risk of an initial coronary event in separate cohorts of men and women ( 17 ), and a high ratio of apoC-III to apoA-I in HDL predicts recurrent coronary events ( 15 ).Abstract Human HDLs have highly heterogeneous composition. Plasma concentrations of HDL with apoC-III and of apoE in HDL predict higher incidence of coronary heart disease (CHD). The concentrations of HDL-apoA-I containing apoE, apoC-III, or both and their distribution across HDL sizes are unknown. We studied 20 normal weight and 20 obese subjects matched by age, gender, and race. Plasma HDL was separated by sequential immunoaffi nity chromatography (anti-apoA-I, anti-apoC-III, anti-apoE), followed by nondenaturing-gel electrophoresis. Mean HDL-cholesterol concentrations in normal weight and obese subjects were 65 and 50 mg/dl ( P = 0.009), and total apoA-I concentrations were 119 and 118 mg/dl, respectively. HDL without apoE or apoC-III was the most prevalent HDL type representing 89% of apoA-I concentration in normal weight and 77% in obese ( P = 0.01) individuals; HDL with apoE-only was 5% versus 8% ( P = 0.1); HDL with apoC-III-only was 4% versus 10% ( P = 0.009); and HDL with apoE and apoC-III was 1.5% versus 4.6% ( P = 0.004). Concentrations of apoE and apoC-III in HDL were 1.5-2× higher in obese subjects ( P р 0.004). HDL with apoE or apoC-III occurred in all sizes among groups. Obese subjects had higher prevalence of HDL containing apoE or apoC-III, subfractions associated with CHD, whereas normal weight subjects had higher prevalence of HDL without apoE or apoC-III, subfractions with protective association against ...

Associations of Perfluoroalkyl substances with blood lipids and Apolipoproteins in lipoprotein subspecies: the POUNDS-lost study

“…Two independent prospective studies showed that HDL cholesterol that contains or lacks apoC-III demonstrated opposite associations with the risk of coronary heart disease (CHD): HDL cholesterol that lacks apoC-III was inversely associated with CHD, whereas HDL cholesterol that contains apoC-III (small subfraction) was associated with a higher risk of CHD [16]. Further, the associations of apoE concentrations in HDL with cardiovascular risk significantly differ in the presence of apoC-III in that HDL with both apoE and apoC-III tended to be associated with a higher cardiometabolic risk [17,33,34]. Therefore, the heterogeneous lipoprotein subspecies deserve to be characterized in order to improve the disease risk prediction rather than relying on total lipid fractions [14].…”

Using primary murine intestinal enteroids to study dietary TAG absorption, lipoprotein synthesis, and the role of apoC-III in the intestine

“…Recent epidemiological studies show that apoC-III is an independent predictor of CVD risk and progression in humans (9,40,41), and that its presence on lipoproteins promotes their atherogenicity (8,(43)(44)(45). This is likely because apoC-III, expressed in both liver and the intestine, raises plasma TAG through the inhibition of hepatic clearance of TAG-rich chylomicrons and VLDLs, stimulates VLDL secretion, and modulates intestinal TAG trafficking (12,(46)(47)(48).…”

Apolipoprotein C-III: From Pathophysiology to Pharmacology

“…Recently, it was shown that obese subjects have a higher prevalence of apoC-III-containing HDL particles compared with lean subjects, which have a higher prevalence of HDL particles without apoE or apoC-III [64]; apoC-III-containing HDL have been associated with CHD [65], suggesting that obese subjects have dysfunctional HDL particles with a lower protective ability, while normal-weight subjects have a higher prevalence of protective HDL particles.…”