Regulation of cholesterol metabolism in the liver in vivo and in vitro

Abstract

At serum cholesterol levels higher than 5 m ~ the risk for coronary heart disease mortality increases progressively with serum cholesterol concentration (Martin el al., 1986). There is good evidence now that reduction of serum cholesterol in hypercholesterolaemic men can reduce the incidence of coronary heart disease (Lipid Research Clinics Program, 1984). More insight into the regulation of cholesterol metabolism in men may offer possibilities for a sensible intervention in order to achieve such a reduction. Because of its central role in the metabolism of cholesterol, the human liver is our main study object. Here, the major part of the cholesterol synthesis, cholesterol conversion to bile acids and the delivery of cholesterol to the plasma in the form of very-low-density lipoprotein particles, take place. Also, the liver contributes an important part in the uptake of cholesterol from dietary source in the form of chylomicron remnants, from very-low-density lipoprotein remnants as intermediate density lipoproteins and lowdensity lipoproteins (LDL) and from peripheral cells via high-density lipoproteins (HDL). Studies in vitro with human hepatocytes face the major problem of the limited and infrequent availability of fresh human liver. Therefore most of our studies have been performed with the human hepatoma cell line Hep G2. We showed (Havekes c’t d.. 1983; Cohen et al., 1984, 1985) that these cells provide us with a good model for the investigation of regulation of cholesterol and lipoprotein metabolism in human he pa tocytes.