Regulation of Cholesterol Metabolism

Cholesterol within the intestinal lumen consists of a mixture of free and esterified cholesterol of both exogenous (dietary) and endogenous origin, the latter being derived chiefly from sterols reaching the intestinal lumen in bile and other intestinal secretions and from desquamation of mucosal cells. After movement across the cell membrane into the mucosal cell, cholesterol mixes with the intracellular pool which, in part, is also derived from cholesterol synthesized de novo from acetate by the epithelial cell. A major portion of this pool is esterified with long chain fatty acids, incorporated into chylomicrons, and then released into the intestinal lymph. 

---

Brown MS, Goldstein JL. The SREBP pathway regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997 89 331-340. 

Enconragingly, there is increasing, robust scientific evidence that atherosclerosis can be arrested and even decreased by pharmacologic approaches. However, the evaln-ation of drug therapy for this condition is complicated by the fact that the regulation of cholesterol metabolism alone does not necessarily have a beneficial effect on atherosclerosis. 

Includes a timely new discussion on the regulation of cholesterol metabolism at the genetic level, with consideration of sterol regulatory element-binding proteins (SREBPs). 

An important dmg in the regulation of cholesterol metabolism is lovastatin [75330-75-5] which is an HMG—CoA reductase inhibitor (see Cardiovascularagents). p-Hydroxy-p-methyl glutarate—coenzyme A (HMG—CoA) reductase is the rate-limiting enzyme of cholesterol synthesis. Lovastatin is actually a prodmg, which is eventually hydrolyzed in the liver to its active, p-hydroxylated form (5). 

Etingin OR, Hajjar DP. Evidence for cytokine regulation of cholesterol metabolism in herpesvirus-infected arterial cells by the lipoxygenase pathway. J Lipid Res 1990 31 299-305. 

Y Hidaka, H Hotta, Y Nagata, Y Iwasawa, M Horie, T Kamei. Effect of a novel squalene epoxidase inhibitor, NB-598, on the regulation of cholesterol metabolism in Hep G2 cells. J Biol Chem 266 13171-13177, 1991. 

The tight regulation of cholesterol metabolism helps explain the pathology of coronary artery disease, a major killer in developed countries. Clearly, diet affects coronary artery disease Individuals with high intake of saturated fat and cholesterol are most at risk. Furthermore, a high serum concentration of LDL cholesterol is associated with an increased risk of coronary artery disease. 

Miettinen, T.A. and Gylling, H., Regulation of cholesterol metabolism by dietary plant sterols, Curr. Opin. Lipidol, 10, 9, 1999. 

Michael S. Brown, Joseph L. Goldstein Regulation of cholesterol metabolism... 

The answer is d. (Murray, pp 258-297. Scriver, pp 2705-2716. Sack, pp 121-138. Wilson, pp 362-367.) Regulation of cholesterol metabolism is by definition exerted at the committed and rate-controlling step. This is the reaction catalyzed by 3-hydroxy-3-methylglutaryl CoA reductase. Reductase activity is reduced by fasting and by cholesterol feeding and thus provides effective feedback control of cholesterol metabolism. The statin class of drugs act at this site. 

Cellular cholesterol levels are regulated, not only by feedback inhibition of cholesterol synthesis, but also by feed-forward regulation of cholesterol metabolism. Excess cholesterol is metabolized to oxysterols. In addition to blocking SCAP-facilitated proteolysis of SREBP and thereby downregulating endogenous cholesterol synthesis and LDL receptor levels, oxysterols also activate bile acid synthesis (Chapter 15) and cholesterol esterification, which further reduces the cellular content of unesterified cholesterol. 

Michael S. Brown and Joseph Leonard Goldstein shared the 1985 Nobel Prize in physiology or medicine for their work on the regulation of cholesterol metabolism and the treatment of disease caused by elevated cholesterol levels in the blood. Brown was bom in New York in 1941 Goldstein, in South Carolina in 1940. They are both professors of medicine at the University of Texas Southwestern Medical Center. 

The LDL Pathway in Human Fibroblasts A Receptor-Mediated Mechanism for the Regulation of Cholesterol Metabolism Joseh L. Goldstein and Michael S. Brown... 

Brown, M.S., and Goldstein, J.L. (1997) The SREBP Pathway Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor, Cell 89, 331-340. 

Dietschy JM, Wilson JD. Regulation of cholesterol metabolism. N Engl J Med 1970 282 1179-1183. 

EFAs are present in all the body s cells, and especially concentrated in the brain and central nervous system. Properties attributed to EFAs include regulation of cholesterol metabolism and inflammatory processes. Table 8.1 lists some of the main dietary sources of EFAs. The quality of these dietary sources depends not only on the levels of the essential fatty acids, but also on their ratios. Many vegetable oils contain moderate levels of saturated fatty acids such as palmitic acid—they too provide therapeutic benefits. 

Quan G, Xie C, Dietschy JM, Turley SD. Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse. Dev Brain Res. 2003 146 87-98. 

Wood, P., R. Shioda, and L. Kinsell Dietary regulation of cholesterol metabolism. Lancet 1966/11, 604. 

Fatty acids in phospholipids are important for maintaining the function and integrity of cellular and subcellular membranes. These acids also play a role in the regulation of cholesterol metabolism—especially its transport, breakdown, and ultimate excretion. In addition, fatty acids have been shown to be the precursors for a group of hormonelike compounds called prostaglandins, which are important in the regulation of widely diverse physiological processes. 

HI Page, JN Beirettoni, A Butkus, FM Sones Jr. Prediction of coronary heart disease based on clinical suspicion, age, total cholesterol, and triglyceride. Circulation 42 625-645, 1970. JM Dietschy, JD Wilson. Regulation of cholesterol metabolism. N Engl J Med 282 1179-1183, 1970. 

---