Diabetic postprandial triglyceride-rich lipoproteins increase esterified cholesterol accumulation in THP-1 macrophages

Abstract

The risk of cardiovascular disease is increased in subjects with insulin-dependent diabetes mellitus (IDDM), although the mechanism remains unclear. To assess whether diabetic postprandial triglyceride (TG)-rich lipoprotein (TGRLP) subfractions (Sf > 400, 100-400, and 20-100) isolated from non-obese, normolipidemic IDDM subjects (n = 14) are potentially more atherogenic than lipoproteins from normal controls (n = 13), we measured cholesteryl ester (CE) synthesis and esterified cholesterol (EC) mass accumulation in THP-1 macrophages incubated with postprandial TGRLP. Diabetic Sf > 400 and Sf 100-400 but not Sf 20-100 significantly increased the mean (+/- SE) rate (pmol/mg cell protein/24 h) of CE synthesis in THP-1 macrophages compared with normal controls (Sf > 400, 673 +/- 26 v 301 +/- 64, P < .025; Sf 100-400, 560 +/- 27 v 298 +/- 39, P < .0005; Sf 20-100, 743 +/- 51 v 831 +/- 45). As well, all three diabetic TGRLP increased the mass of EC (microgram EC/mg cell protein/48 h) as compared with normal controls (Sf > 400, 4.9 +/- 0.61 v 2.9 +/- 0.50, P < .025; Sf 100-400, 5.7 +/- 0.91 v 3.4 +/- 0.34, P < .05; Sf 20-100, 5.4 +/- 0.7 v 3.2 +/- 0.52, P < .05). This effect is sustained for at least 7 hours postprandially and is greater than that of fasting Sf 100-400 (P < .03) and Sf 20-100 (P < .05) and similar to malondealdehyde low-density lipoprotein (MDA-LDL). To assess the mechanisms involved, the chemical composition and cellular degradation of diabetic and control lipoproteins were compared. Postprandial diabetic Sf 100-400 had abnormal composition (phospholipid to protein ratio, 1.86 +/- 0.14 v 1.5 +/- 0.13, P < .05) and in preliminary experiments demonstrated increased cell association (mean +/- SD at 6 hours, 126 +/- 34.3 v 57 +/- 4.2) and degradation (584 +/- 141 v 254 +/- 13) compared with that of normal controls, and may account for the observed increase in EC accumulation. In summary, postprandial diabetic Sf > 400 and Sf 100-400 TGRLP increase CE synthesis and Sf > 400, Sf 100-400, and Sf 20-100 lipoproteins increase EC accumulation in human macrophages compared with normal control lipoproteins. Diabetic Sf 100-400 lipoproteins have abnormal composition and seem to have increased cellular association and degradation compared with normal lipoproteins. Our findings suggest a role for postprandial TGRLP in the increased risk of cardiovascular disease among subjects with IDDM.