Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences

Abstract

Nephrotic syndrome results in hyperlipidemia and profound alterations in lipid and lipoprotein metabolism. Serum cholesterol, triglycerides, apolipoprotein B (apoB)-containing lipoproteins (very low-density lipoprotein [VLDL], immediate-density lipoprotein [IDL], and low-density lipoprotein [LDL]), lipoprotein(a) (Lp[a]), and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are increased in nephrotic syndrome. This is accompanied by significant changes in the composition of various lipoproteins including their cholesterol-to-triglyceride, free cholesterol-to-cholesterol ester, and phospholipid-to-protein ratios. These abnormalities are mediated by changes in the expression and activities of the key proteins involved in the biosynthesis, transport, remodeling, and catabolism of lipids and lipoproteins including apoproteins A, B, C, and E; 3-hydroxy-3-methylglutaryl-coenzyme A reductase; fatty acid synthase; LDL receptor; lecithin cholesteryl ester acyltransferase; acyl coenzyme A cholesterol acyltransferase; HDL docking receptor (scavenger receptor class B, type 1 [SR-B1]); HDL endocytic receptor; lipoprotein lipase; and hepatic lipase, among others. The disorders of lipid and lipoprotein metabolism in nephrotic syndrome contribute to the development and progression of cardiovascular and kidney disease. In addition, by limiting delivery of lipid fuel to the muscles for generation of energy and to the adipose tissues for storage of energy, changes in lipid metabolism contribute to the reduction of body mass and impaired exercise capacity. This article provides an overview of the mechanisms, consequences, and treatment of lipid disorders in nephrotic syndrome.

Keywords: atherosclerosis; chronic kidney disease; hyperlipidemia; nephrotic syndrome; proteinuria; statins.

Figure 1. Via downregulation of the lipoprotein lipase (LPL) adapter molecule GPIHP-1 and upregulation of the LPL inhibitor molecule ANGPTL4, nephrotic syndrome results in a marked decrease in abundance and activity in muscle and adipose tissue

The impact of LPL deficiency is compounded by the scarcity of cholesterol ester–rich high-density lipoprotein (HDL), which is the apoE and apoC donor to the nascent very low-density lipoprotein (VLDL) and chylomicrons (CM) enabling their ability to bind to the endothelial lining and activate LPL. The resulting LPL deficiency and dysfunction limits delivery of lipid fuel to the muscles for generation of energy and to the adipose tissue for storage of energy. In addition, nephrotic syndrome causes hepatic lipase deficiency, which impairs the ability of the liver to extract the triglyceride (TG) and phospholipid (PL) contents of immediate-density lipoprotein (IDL) and HDL. Together, these abnormalities contribute to the development of hypertriglyceridemia, elevation of serum VLDL, and accumulation of atherogenic IDL, CM remnants, and triglyceride (TG)-rich LDL in patients with nephrotic syndrome.

Figure 2. Via a marked increase in serum proprotein convertase subtilisin kexin type 9 (PCSK9) and the liver tissue inducible degrader of the LDL receptor (IDOL), which are potent degraders of low-density lipoprotein (LDL) receptor (LDLR), nephrotic syndrome results in acquired LDLR deficiency

Acquired LDLR deficiency accounts for the impaired clearance and increased serum LDL in nephrotic patients and animals. In addition, nephrotic syndrome leads to a significant increase in liver acyl-CoA cholesterol acyltransferase-2 (ACAT-2) expression and activity, which results in enhanced esterification of cholesterol and reduction of intracellular free cholesterol. The reduction in cholesterol uptake occasioned by LDLR deficiency and the reduction in intracellular free cholesterol by ACAT-2 work in concert to promote activation of sterol regulatory element-binding protein-2 (SREBP-2) and SREBP-1. Activation of SREBP-2 heightens 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase–mediated cholesterol production, and activation of SREBP-1 increases production of fatty acids, events that contribute to hypercholesterolemia and hypertriglyceridemia in nephrotic syndrome.

Figure 3. Nephrotic syndrome results in significant elevation of vascular and renal tissue acyl-CoA cholesterol acyltransferase-1 (ACAT-1) expression and heavy urinary losses and marked reduction of serum lecithin cholesteryl ester acyltransferase (LCAT) level, which work in concert to limit high-density lipoprotein (HDL)–mediated extraction of cholesterol from lipid-laden macrophages and mesangial and other cell types

This is compounded by a marked increase in serum cholesterol ester transfer protein (CETP), which leads to further depletion of HDL cholesterol and enrichment of its triglyceride (TG) cargo. In addition, by inducing downregulation of PDZ-containing kidney protein 1 (PDZK1), nephrotic syndrome results in a marked reduction in liver HDL docking receptor (scavenger receptor class B, type 1 [SR-B1]), which is the gateway for unloading of HDL’s cholesterol cargo and hepatic lipase-mediated extraction of its TG and phospholipid (PL) cargos. Together these abnormalities severely impair reverse cholesterol transport and contribute to the atherogenic diathesis in nephrotic syndrome. Chol, cholesterol.

Figure 4. By causing lecithin cholesteryl ester acyltransferase (LCAT) deficiency and hypoalbuminemia, which limit the transfer of cholesterol from peripheral tissues to high-density lipoprotein (HDL), and increase cholesterol ester transfer protein (CETP), which increases the transfer of HDL cholesterol cargo to immediate-density lipoprotein (IDL)/low-density lipoprotein (LDL), nephrotic syndrome limits cholesterol enrichment of HDL

In addition, downregulation of the hepatic HDL docking receptor SR-B1 (scavenger receptor class B, type 1), occasioned by downregulation of PDZ-containing kidney protein 1, limits HDL’s ability to unload its cholesterol cargo in the liver. Together, these abnormalities contribute to profound impairment of reverse cholesterol transport. ATP, adenosine triphosphate; CE, cholesterol ester; FC, free cholesterol.