HEPATIC CHOLESTEROL-METABOLISM IN HUMAN OBESITY

Hepatic cholesterol metabolism was studied in operative liver biopsies from 17 morbidly obese subjects and compared with that in samples fro m 15 nonobese controls. The aim was to understand the mechanisms causi ng the hypersecretion of cholesterol into bile. The content of cholest eryl esters was increased threefold in the liver of obese subjects com pared with that of the controls (P < .0001). The activity and the mess enger RNA (mRNA) level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG C oA) reductase, the rate limiting enzyme for cholesterol synthesis, wer e higher in the obese subjects compared with the nonobese subjects (75 % and 140%, respectively; P < .01). In the obese subjects, the activit y and mRNA level of cholesterol 7 alpha-hydroxylase, which regulates t he catabolism of cholesterol to bile acids, were also increased by 140 % (P < .05) and 180% (P = .06), respectively, as compared with the con trols. There was a significant correlation between the activities and the mRNA levels of cholesterol 7 alpha-hydroxylase among the obese sub jects (r = +0.65, P < .01). The activities of acyl-coenzyme A:choleste rol acyltransferase (ACAT), which governs cholesteryl ester formation, in obese and nonobese patients were 12.5 +/- 1.7 and 8.1 +/- 1.2 pmol /min/mg protein, respectively (P < .05), and the low-density Lipoprote in (LDL) receptor mRNA levels were 5.3 +/- 0.7 and 4.5 +/- 0.9 molecul es of mRNA/mu g of RNA, respectively. We conclude that the activities of three key enzymes in hepatic cholesterol metabolism were increased in morbidly obese subjects compared with nonobese controls, as were mR NA levels of HMG CoA reductase and cholesterol 7 alpha-hydroxylase. Th e mRNA level of the LDL receptor in the obese subjects was not signifi cantly changed, The hypersecretion of cholesterol occurring in obesity is neither due to a reduced conversion of cholesterol to bile acids n or to a decreased esterification of hepatic cholesterol but may be due to an increased synthesis of cholesterol.