Causes of dysregulation of lipid metabolism in chronic renal failure

Abstract

End-stage renal disease (ESRD) is associated with accelerated atherosclerosis and premature death from cardiovascular disease. These events are driven by oxidative stress inflammation and lipid disorders. ESRD-induced lipid abnormalities primarily stem from dysregulation of high-density lipoprotein (HDL), triglyceride-rich lipoprotein metabolism, and oxidative modification of lipoproteins. In this context, production and plasma concentration of Apo-I and Apo-II are reduced, HDL maturation is impaired, HDL composition is altered, HDL antioxidant and anti-inflammatory functions are depressed, clearance of triglyceride-rich lipoproteins and their atherogenic remnants is impaired, their composition is altered, and their plasma concentration is elevated in ESRD. The associated defect in HDL maturation is largely caused by acquired lecithin-cholesterol acyltransferase deficiency while its triglyceride enrichment is due to hepatic lipase deficiency. Hypertriglyceridemia, abnormal composition, and impaired clearance of triglyceride-rich lipoproteins and their remnants are mediated by down-regulation of lipoprotein lipase, hepatic lipase, very low-density lipoprotein (VLDL) receptor, and LDL receptor-related protein, relative reduction in ApoC-II/ApoC-III ratio, up-regulation of acyl-CoA cholesterol acyltransferase, and elevated plasma level of cholesterol ester-poor prebeta HDL. Impaired clearance and accumulation of oxidation-prone VLDL and chylomicron remnants and abnormal LDL composition in the face of oxidative stress and inflammation favors their uptake by macrophages and resident cells in the artery wall. The effect of heightened influx of lipids is compounded by impaired HDL-mediated reverse cholesterol transport leading to foam cell formation which is the central event in atherosclerosis plaque formation and subsequent plaque rupture, thrombosis, and tissue damage.

Figure 1

Diagram of the reverse cholesterol transport pathway depicting oxidized lipoprotein influx via scavenger receptors (SRA-1, LOX-1 and CD 36) and free cholesterol efflux via ABCA-1 transporter in macrophages and resident cells in the artery wall, transfer of free cholesterol from the cell surface to the lipid-poor HDL-3, esterification of free cholesterol and translocation cholesterol ester to the core of HDL, detachment of mature HDL-2 and unloading of its lipid cargo via docking receptor, SRB-1 followed by the release of lipid-depleted HDL for recycling or degradation by the HDL holo-receptor, B chain of ATP synthase.

Figure 2

Diagram illustrating secretion of nascent VLDL by the liver followed by acquisition of ApoE and ApoC from HDL, endocytic removal of VLDL by myocytes/adipocytes via VLDL receptor and their partial delipidation by lipoprotein lipase (LPL) culminating in formation and release of IDL; conversion of the majority of IDL to LDL (via CETP- and hepatic lipase- mediated cholesterol enrichment and triglyceride depletion), uptake of small fraction of IDL via LDL receptor-related protein (LRP) and removal of the bulk of LDL by LDL receptor.

Figure 3

Diagram depicting secretion of nascent chylomicron by the intestine followed by acquisition of ApoE and ApoC from HDL; partial delipidation of chylomicrons by lipoprotein lipase (LPL) culminating in formation and release of chylomicron remnants and their ultimate removal by LDL receptor-related protein (LRP).