Chronic renal failure (CRF) is associated with increased risk of arteriosclerotic
cardiovascular disease and profound alteration of plasma
lipid profile. Uremic
dyslipidemia is marked by increased plasma concentration of
ApoB-containing
lipoproteins and impaired
high-density lipoprotein (HDL)-mediated reverse
cholesterol transport. These abnormalities are, in part, due to acquired
LCAT deficiency and upregulation of hepatic
acyl-CoA:cholesterol acyltransferase (ACAT). ACAT catalyzes intracellular esterification of
cholesterol, thereby promoting hepatic production of
ApoB-containing
lipoproteins and constraining HDL-mediated
cholesterol uptake in the peripheral tissues. In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced
dyslipidemia. 5/6 Nephrectomized rats were treated with either ACAT inhibitor IC-976 (30 mg.kg(-1).day(-1)) or placebo for 6 wk.
Sham-operated rats served as controls. Key
cholesterol-regulating
enzymes, plasma
lipids, and
creatinine clearance were measured. The untreated CRF rats exhibited increased plasma
low-density lipoprotein (
LDL) and very
LDL (
VLDL) cholesterol, unchanged plasma
HDL cholesterol, elevated total
cholesterol-to-
HDL cholesterol ratio, reduced liver microsomal free
cholesterol, and diminished
creatinine clearance. This was accompanied by reduced plasma LCAT, increased hepatic ACAT-2
mRNA, ACAT-2
protein and ACAT activity, and unchanged hepatic
HMG-CoA reductase and
cholesterol 7alpha-hydroxylase. ACAT inhibitor raised plasma
HDL cholesterol, lowered
LDL and
VLDL cholesterol, and normalized total
cholesterol-to-
HDL cholesterol ratio without changing total
cholesterol concentration (hence, a shift from
ApoB-containing
lipoproteins to HDL). This was accompanied by normalizations of hepatic ACAT activity and plasma LCAT. In conclusion, inhibition of ACAT reversed
LCAT deficiency and improved plasma HDL level in CRF rats. Future studies are needed to explore the efficacy of ACAT inhibition in humans with CRF.