Effects of pancreas transplantation on distribution and composition of plasma lipoproteins.

In type I (insulin-dependent) diabetic patients, peripheral hyperinsulinemia due to subcutaneous insulin treatment is associated with increased high-density lipoprotein (HDL) cholesterol, and also with an altered surface composition of HDL. Pancreas grafts also release insulin into the systemic rather than into the portal venous system, giving rise to pronounced peripheral hyperinsulinemia. We hypothesized that if peripheral hyperinsulinemia is responsible for high HDL cholesterol and/or altered surface composition of HDL in diabetic subjects, similar changes in the lipid profile should be present in pancreas-kidney transplant recipients (PKT-R). Using zonal ultracentrifugation, we isolated HDL2, HDL3, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) from fasting plasma of 14 type I diabetic PKT-R, eight nondiabetic kidney transplant recipients (KT-R), and 14 healthy control subjects and determined the level and composition of the above lipoproteins. HDL2 cholesterol was increased in PKT-R as compared with KT-R and healthy controls (both P < .05), whereas HDL3 cholesterol was unchanged. However, an altered lipoprotein surface composition was evident in PKT-R: HDL2, HDL3, and LDL were enriched in unesterified cholesterol ([UC] PKT-R v KT-R, P=.13, P < .005, and P < .05, respectively; PKT-R v controls, all P < .005); HDL2 was enriched in phospholipids; and LDL was depleted of phospholipid. KT-R, in contrast, showed no changes in lipoprotein surface composition but a substantial triglyceride enrichment of HDL2 as compared with PKT-R and healthy controls (both P < .05). LDL size as determined by gradient gel electrophoresis was increased in PKT-R compared with controls (P < .005). The plasma concentration of cholesteryl ester (CE) transfer protein (CETP), involved also in phospholipid transfer, was increased in both transplant groups compared with healthy controls (both P < .05). Insulin concentrations in fasting plasma were directly related to CETP levels and to the weight-percentage of UC in HDL3, and inversely to the weight-percentage of phospholipids in LDL (all P < .05). We explain the increase in HDL2 cholesterol and LDL size in PKT-R by their high lipoprotein lipase (LPL) activity conferring an excellent capacity to clear chylomicron triglycerides. Effective handling of postprandial triglycerides, high HDL2 cholesterol, and predominance of LDL pattern A, respectively, are established indicators of a low risk of atherosclerosis. However, it is presently unclear what effects the compositional changes on the surface of HDL and LDL may have on cardiovascular risk in clinically stable PKT-R.

Treatment of primary mixed hyperlipidemia with etophylline clofibrate: effects on lipoprotein-modifying enzymes, postprandial lipoprotein metabolism, and lipoprotein distribution and composition.

In 17 patients with primary mixed hyperlipidemia we studied levels and composition of lipoproteins in fasting plasma, lipoprotein-modifying enzymes, and postprandial lipoprotein metabolism after an oral fat-tolerance test supplemented with vitamin A before, and 12 weeks after treatment with etophylline clofibrate. With treatment, fasting plasma cholesterol, triglycerides, and the levels of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) decreased significantly; high density lipoprotein (HDL) cholesterol increased significantly. Treatment caused also an increase in the protein content of IDL, a decrease in the triglyceride content of LDL, and an increase in the size of LDL as assessed by gradient gel electrophoresis. Concentrations of triglycerides, chylomicrons, and chylomicron remnants after an oral fat load supplemented with vitamin A decreased by 33%, 30% and 6%, respectively (P < 0.005; P < 0.01; and P < 0.05). The activity of lipoprotein lipase and hepatic lipase in postheparin plasma increased by 51% and 45%, respectively (P < 0.01; P < 0.05). We found a decrease in the mass concentration of cholesteryl ester transfer protein (P < 0.05). Stepwise multiple regression analysis showed that the triglyceride content of LDL is determined primarily by fasting triglycerides (r = + 0.53, P < 0.05;baseline) and cholesteryl ester transfer protein (r = + 0.49, P < 0.05; 12 weeks); in contrast, the triglyceride content of HDL3 is determined exclusively by accumulation of postprandial triglycerides (r = + 0.67; P < 0.05; baseline) and postprandial chylomicrons (r = +0.87; P < 0.005; 12 weeks). We conclude that hypolipidemic treatment with etophylline clofibrate favorably affects the cardiovascular risk factor profile in primary mixed hyperlipidemia.

Fenofibrate improves postprandial chylomicron clearance in II B hyperlipoproteinemia.

In 11 patients with IIB hyperlipoproteinemia we studied fasting lipids, lipoproteins, lipoprotein-modifying enzymes, and postprandial lipid metabolism after a standardized oral fat load supplemented with vitamin A before and 12 weeks after treatment with fenofibrate, a third-generation fibric acid derivative. Fasting plasma cholesterol, triglycerides, low-density lipoprotein cholesterol decreased significantly (P < 0.05, P < 0.01, P < 0.01), high-density lipoprotein subfraction 3 cholesterol increased significantly (P < 0.05), and high-density lipoprotein subfraction 2 cholesterol remained unchanged. Postprandial lipemia, i.e., the integrated postprandial triglyceride concentrations corrected for the fasting triglyceride level, and postprandial chylomicron concentrations, as assessed by biosynthetic labeling of chylomicrons with retinyl palmitate, decreased by 40.6% and 60.1% (P < 0.05; P < 0.05), respectively. The activity of lipoprotein lipase (LPL) increased by 33.6% (P < 0.05); the increase in LPL during fenofibrate treatment was positively correlated with the increase in high-density lipoprotein cholesterol (r = 0.84; P < 0.005). Hepatic lipase and cholesteryl ester transfer protein mass and activity remained unchanged. We conclude that lipid-lowering therapy with fenofibrate ameliorates fasting and, more profoundly, postprandial lipoprotein transport in hypertriglyceridemia by curbing postprandial triglyceride and chylomicron accumulation, at least in part, through an increase in LPL activity.