IMPAIRED BINDING OF LOW-DENSITY-LIPOPROTEIN TO HEPATIC MEMBRANES FROM UREMIC GUINEA-PIGS

Chronic renal failure is associated with abnormalities in lipoprotein metabolism that may contribute to premature atherosclerosis and early mortality in patients on dialysis. In previous studies, we found that plasma clearance of radiolabelled low density lipoprotein (LDL) was retarded in nephrectomized guinea pigs left with one-sixth of normal functioning renal mass. To elucidate potential mechanisms of delayed LDL clearance, we compared binding of LDL to hepatic membranes from both normal and uremic guinea pigs. One hundred micrograms of the 8000 - 100 000 x g hepatic microsomal protein was incubated with I-125-labelled normal guinea pig LDL (10-150-mu-g/mL) for 1 h at 37-degrees-C, and the membrane washed and pelleted by centrifugation in a Beckman Ti 42.2 rotor. Parallel incubations with excess unlabelled LDL were done to determine specific binding. LDL specific binding to uremic hepatic membranes was significantly impaired compared with normal ones. The major abnormality, as determined by Scatchard transformation of the binding data, was a reduction of the apparent maximal binding of LDL to uremic membranes, with an average B(max) of 4.1-mu-g/mg protein compared with 6.6-mu-g/mg protein for normal hepatic microsomes. The affinity of LDL for uremic liver membranes was only slightly diminished with a mean apparent K(d) of 35.2-mu-g/mL in comparison with 21.8-mu-g/mL for normal liver membranes. These results provide a biochemical explanation for the diminished LDL clearance in uremia and may account for the dyslipidemia of renal failure.