Nephrotic hyperlipidemia: is inhibition of receptor-mediated edocytosis involved?

Abstract

Hyperlipidemia is a consistent feature of the nephrotic syndrome (NS) and is usually of the IIa or IIb Fredrickson type. In cases with severe hypoalbuminemia (15 g/l or less) very low density lipoproteins (VLDL) also increase and the ratio of cholesterol to triglyceride falls. The nephrotic hyperlipidemia is generally considered to be due to increased hepatic synthesis and secretion of lipoproteins, but there are also investigations showing altered lipoprotein clearance. Warwick et al have found a trend towards lower fractional catabolic rate of intermediate density lipoproteins (IDL) and low density lipoproteins (LDL) in nephrotic patients with relatively well maintained serum albumin despite the heavy proteinuria. In another group of nephrotic patients with lower plasma albumin levels, the amount of LDL cleared by receptor-mediated endocytosis (RME) was only 55% of the value seen in controls, while 60% more LDL were channeled into alternative catabolic pathways. In experimental NS, delayed removal of chylomicron remnants was revealed as well. Chylomicron remnants are taken up by the liver via the LDL receptor-related protein (LRP). Recently, evidences were provided that receptor for activated α2-macroglobulin (α2-macroglobulin-proteinase complex) and the LRP are one and the same entity. α2-macroglobulin seems to control the activity of proteinases not by active site-directed inhibition but by steric shielding and rapid clearance. The plasma levels of α2-macroglobulin are consistently elevated in NS, but to the best of my knowledge, there are insufficient data about the uptake of α2-macroglobulin-proteinase complexes. Asami et al reported a glomerular deposition of α2-macroglobulin in a child with steroid refractory NS, but such depositions were not detected in other nephrotic patients. Biochemical and clinical improvement was observed in this case after treatment with the synthetic proteinase inhibitor camostat mesylate, but the dynamics of α2-macroglobulin depositions was not examined. Biomedical Reviews 1994; 3: 77-79.