Nd. Vaziri et al., Down-regulation of hepatic lecithin : cholesterol acyltransferase gene expression in chronic renal failure, KIDNEY INT, 59(6), 2001, pp. 2192-2196
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.