Cholesterol and hepatic lipoprotein assembly and secretion

The assembly and secretion of apo B100 containing lipoproteins (i.e., VLDL) by the liver and cholesterol metabolism are interrelated on several differ ent levels and for several different physiologic reasons. Firstly, hepatic VLDL is the major precursor for LDL, which in the human is the major vehicl e responsible for transporting cholesterol to peripheral tissues. Secondly, cholesterol is supplied to many tissues by a specific uptake of LDL via LD L receptor, which is expressed in a regulated manner by most mammalian tiss ues. Thirdly, the rate of hepatic cholesterol biosynthesis and metabolism t o bile acids correlates with production of VLDL. This apparent coordinate e xpression of cholesterol biosynthetic/catabolic enzymes and hepatic VLDL as sembly/secretion are mediated at least in part through the sterol response element binding protein (SREBP) transcription factor family. Their gene tar gets include a plethora of enzymes that regulate glycolysis, energy product ion, lipogenesis and cholesterol catabolism. Studies of hepatoma cells over expressing CYP7A1, the rate-limiting enzyme controlling bile acid synthesis , show that as a result of increased mature SREBP1, there is a coordinate i nduction of lipogenesis and the assembly and secretion of VLDL. These and a dditional studies show that the bile acid synthetic pathway and the VLDL as sembly/secretion pathway are coordinately linked through SREBP-dependent tr anscription. Based on studies showing that within the liver acinus, the exp ression of CYP7A1 is mainly in the pericentral region while HMG-CoA reducta se is mainly periportal, we propose that a 'metabolic zonal segregation' pl ays an important role in coordinate regulation of cholesterol and VLDL meta bolism. This putative 'metabolic zonal segregation' may provide segregation of metabolic functions which may be mutually antagonistic. For example, th ere may be physiologic states in which the bile acid synthetic pathway may compete with the VLDL assembly/secretion pathway for a limited amount of ch olesterol. Metabolic antagonism (e.g., competition for cholesterol) may be avoided via inducing SREBP-mediated transcription. Adaptation of catabolic hepatocytes to accommodate the expression of VLDL assembly/secretion may oc cur in response to activation of SREBP-mediated transcription. Support for these is discussed. (C) 2000 Elsevier Science B.V. All rights reserved.