INCREASED MESSENGER-RNA LEVELS FOR LOW-DENSITY-LIPOPROTEIN RECEPTOR AND 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE IN RAT-LIVER AFTER LONG-TERM ETHANOL INGESTION

Because long-term alcohol intake leads to severe alterations of choles terol metabolism resulting in both elevated serum cholesterol levels a nd increased hepatic concentrations of cholesterol esters, we investig ated the effect of long-term ethanol consumption on the hepatic messen ger RNA (mRNA) content of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-C oA) reductase and low-density lipoprotein receptor, two major regulato ry factors in cholesterol metabolism, and of apoprotein E. Twenty-four male Sprague-Dawley rats were pair-fed nutritionally adequate liquid diets containing 36% of total calories as either ethanol or isocaloric carbohydrates for 3 wk. In addition, the lipid content of the diets w as varied, resulting in 35%, 17.5%, and 8.8% of total calories corresp onding to a daily intake of cholesterol of between 1.2 and 6.3 mg/kg b ody wt. Although increasing dietary cholesterol intake resulted in a s ignificant decrease of hepatic mRNA for low-density lipoprotein recept or and HMG-CoA reductase (p < 0.05), long-term ethanol consumption led to a significant increase of the mRNA for both proteins (p < 0.01), a nd this increase was predominantly obvious in animals fed a low-choles terol diet. In contrast, mRNA content of apoprotein E was found to be significantly lower in livers from rats fed ethanol for a prolonged pe riod of time as compared with controls (p < 0.01), and this effect was found to be still present, although less pronounced, after low choles terol intake, These findings were paralleled by a significant increase in hepatic cholesterol esters (161 +/- 30 vs. 70 +/- 25 mg/100 gm; p < 0.01) but not free cholesterol and by elevated serum cholesterol lev els (129 +/- 8 vs. 85 +/- 10 mg/100 ml; p < 0.01). The data show that long-term ethanol consumption results in enhanced hepatic mRNA levels of low-density lipoprotein receptor and HMG-CoA reductase, two determi nants of cholesterol metabolism, which may contribute to hepatic chole sterol accumulation and hypercholesterolemia frequently seen in the al coholic.