Feeding-induced regulation of cholesterol metabolism: a unified proposal

It is generally agreed that the liver is a key organ in the maintenance of cholesterol homeostasis. Although species variations do exist (1), there is no question that the liver makes a very significant contribution to whole body cholesterol synthesis (2). Indeed, recent studies in the rat suggest that the liver may be responsible for the synthesis of greater than 80% of newly synthesized cholesterol in the body (3). It is also well established that the liver is a major site of uptake of cholesterol from lipoprotein particles (1). The acquisition of cholesterol from lipoprotein particles is a process which occurs via both receptor-independent and receptor-dependent pathways (1). The latter pathway is considered to be more important not only from a quantitative standpoint (1) but also because of the fact that the activity of certain receptors is regulated by the hepatic demand for cholesterol (4). These observations, combined with the fact that the liver is the major site (if not the only site) of synthesis of bile acid, the chief catabolic product of cholesterol (5), suggest that the key hepatic enzymes involved in cholesterol metabolism must be very carefully regulated in order to maintain cholesterol homeostasis. Hepatic cholesterol 7α-hydroxylase (CH-7A, EC 1.14.13.7) and β-hydroxy-β-methyl-glutaryl coenzyme A reductase (HMGCoA reductase, EC 1.1.1.34) are the two key enzymes of cholesterol metabolism in the liver (2, 6). HMGCoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol (2), while CH-7A is considered to be the rate-limiting enzyme in the biosynthesis of bile acids from cholesterol (6). Since cholesterol is the precursor for bile acid biosynthesis, changes in the rate of synthesis of bile acids, in general, affect the rate of biosynthesis of cholesterol (6). Thus, the two enzymes are regulated in a coordinated manner (6).