Down-regulation of hepatic lecithin : cholesterol acyltransferase gene expression in chronic renal failure

Background. Chronic renal failure (CRF) is associated with premature arteri osclerosis, impaired high-density lipoprotein (HDL) maturation, increased p re-beta HDL (a lipid-poor HDL species), reduced HDL/total cholesterol ratio , hypertriglyceridemia, and depressed lipolytic activity. The latter has be en, in part, attributed to elevated pre-beta HDL, which is a potent inhibit or of lipoprotein lipase (LPL). Accumulation of cholesterol in the arterial wall is a critical step in atherogenesis, and HDL-mediated cholesterol rem oval from peripheral tissues mitigates atherosclerosis. Lecithin:cholestero l acyltransferase (LCAT) is essential for maturation of HDL and cholesterol removal by HDL from peripheral tissues. Earlier studies have revealed depr essed plasma LCAT enzymatic activity in patients with CRF. This study was c onducted to determine whether impaired LCAT activity can he confirmed in CR F animals and if so whether it is due to down-regulation of hepatic LCAT ex pression. Methods. Hepatic tissue LCAT mRNA and plasma LCAT enzymatic activity were m easured in male Sprague-Dawley rats six weeks after excisional 5/6 nephrect omy or sham operation. Results. Compared with the controls, the CRF group exhibited a significant reduction of hepatic tissue LCAT mRNA abundance. The reduction in hepatic L CAT mRNA was accompanied by a marked reduction of plasma LCAT activity and elevation of serum-free cholesterol in the CRF animals. LCAT activity corre lated positively with the HDL/total cholesterol ratio and inversely with fr ee cholesterol and triglyceride concentrations. Conclusions. CRF leads to a marked down-regulation of hepatic LCAT mRNA exp ression and plasma LCAT activity. This abnormality can impair HDL-mediated cholesterol uptake from the vascular tissue and contribute to cardiovascula r disease. In addition, LCAT deficiency can, in part, account for elevated serum-free cholesterol, reduced HDL/total cholesterol, and elevated pre-bet a HDL in CRF. The latter can, in turn, depress lipolytic activity and hinde r triglyceride-rich lipoprotein clearance in CRF.