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  • Title: Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure.
    Author: Vaziri ND, Liang K, Parks JS.
    Journal: Kidney Int; 2001 Jun; 59(6):2192-6. PubMed ID: 11380821.
    Abstract:
    BACKGROUND: Chronic renal failure (CRF) is associated with premature arteriosclerosis, impaired high-density lipoprotein (HDL) maturation, increased pre-beta HDL (a lipid-poor HDL species), reduced HDL/total cholesterol ratio, hypertriglyceridemia, and depressed lipolytic activity. The latter has been, in part, attributed to elevated pre-beta HDL, which is a potent inhibitor of lipoprotein lipase (LPL). Accumulation of cholesterol in the arterial wall is a critical step in atherogenesis, and HDL-mediated cholesterol removal from peripheral tissues mitigates atherosclerosis. Lecithin:cholesterol acyltransferase (LCAT) is essential for maturation of HDL and cholesterol removal by HDL from peripheral tissues. Earlier studies have revealed depressed plasma LCAT enzymatic activity in patients with CRF. This study was conducted to determine whether impaired LCAT activity can be confirmed in CRF animals and if so whether it is due to down-regulation of hepatic LCAT expression. METHODS: Hepatic tissue LCAT mRNA and plasma LCAT enzymatic activity were measured in male Sprague-Dawley rats six weeks after excisional 5/6 nephrectomy 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 LCAT mRNA was accompanied by a marked reduction of plasma LCAT activity and elevation of serum-free cholesterol in the CRF animals. LCAT activity correlated positively with the HDL/total cholesterol ratio and inversely with free cholesterol and triglyceride concentrations. CONCLUSIONS: CRF leads to a marked down-regulation of hepatic LCAT mRNA expression and plasma LCAT activity. This abnormality can impair HDL-mediated cholesterol uptake from the vascular tissue and contribute to cardiovascular disease. In addition, LCAT deficiency can, in part, account for elevated serum-free cholesterol, reduced HDL/total cholesterol, and elevated pre-beta HDL in CRF. The latter can, in turn, depress lipolytic activity and hinder triglyceride-rich lipoprotein clearance in CRF.
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