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ScienceWeek
2004 9 July C6 MEDICAL BIOLOGY: ON HDL CHOLESTEROL AND ATHEROSCLEROSIS
The following points are made by H.B. Brewer Jr (New Engl. J. Med. 2004 350:1491):
1) In the past decade, high-density lipoproteins (HDL) have emerged as a new potential therapeutic target for the treatment of cardiovascular disease. The key role of HDL as a carrier of excess cellular cholesterol in the reverse cholesterol transport pathway is believed to provide protection against atherosclerosis. In reverse cholesterol transport, peripheral tissues (e.g., vessel-wall macrophages) remove their excess cholesterol through the ATP-binding cassette transporter-1 (ABCA1) to poorly lipidated apolipoprotein A-I, forming pre-beta-HDL. Lecithin-cholesterol acyltransferase then esterifies free cholesterol to cholesteryl esters, converting pre-beta-HDL to mature spherical alpha-HDL.
2) HDL cholesterol is transported to the liver by two pathways. Through the first pathway, it is delivered directly to the liver through interaction with the scavenger receptor, class B, type I (SR-BI). Through the second pathway, cholesteryl esters in HDL are transferred by the cholesteryl ester transfer protein (CETP) to very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) and are then returned to the liver through the LDL receptor. HDL cholesterol that is taken up by the liver is then excreted in the form of bile acids and cholesterol, completing the process of reverse cholesterol transport.(1) HDL also decreases atherosclerosis by protecting LDL from oxidation.(2) Oxidized or modified LDL, unlike normal LDL, is readily taken up by the macrophage scavenger receptor SR-A or CD36, resulting in the formation of foam cells. HDL may also slow the progression of lesions by selectively decreasing the production of endothelial cell-adhesion molecules that facilitate the uptake of cells into the vessel wall.(3)
3) Several lines of evidence support the concept that increasing the HDL level may provide protection against the development of atherosclerosis. Epidemiologic studies have shown an inverse correlation between HDL cholesterol levels and the risk of cardiovascular disease.(1) Increasing the HDL cholesterol level by 1 mg may reduce the risk of cardiovascular disease by 2 to 3 percent. Overexpressing the apolipoprotein A-I gene in transgenic mice and rabbits and infusing complexes consisting of apolipoprotein A-I and phospholipids into hyperlipidemic rabbits increase HDL cholesterol levels and decrease the development of atherosclerosis.(1) In humans, infusing either of these complexes or proapolipoprotein A-I results in short-term increases in HDL cholesterol, biliary cholesterol, and fecal sterol loss, reinforcing the concept that elevating the HDL cholesterol level decreases the risk of cardiovascular disease.(1,4,5)
References:
1. Brewer HB Jr. High-density lipoprotein: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol 2004;24:387-391
2. Navab M, Anantharamaiah GM, Hama S, et al. Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 2002;105:290-292
3. Barter PJ, Baker PW, Rye KA. Effect of high-density lipoproteins on the expression of adhesion molecules in endothelial cells. Curr Opin Lipid 2002;13:285-8
4. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-2300
5. Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23:160-167
New Engl. J. Med. http://www.nejm.org
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Related Material:
MEDICAL BIOLOGY: ON CHOLESTEROL TRANSPORTERS
The following points are made by E.L. Klett and S.B. Patel (Science 2004 303:1149):
1) More than 75 years ago, Schoenheimer reported that mammals not only synthesize cholesterol de novo, but also selectively absorb dietary cholesterol from the small intestine while excluding dietary plant sterols and other noncholesterol sterols (1). Subsequent studies have built on this work, demonstrating that cholesterol homeostasis depends on a balance between de novo cholesterol synthesis, the absorption of dietary cholesterol, and excretion of excess cholesterol via the hepatobiliary system.
2) Although cholesterol synthesis and breakdown pathways are well defined, the pathway of dietary cholesterol absorption remains to be elucidated. We still need mechanistic insights to explain Schoenheimer's observations of selective sterol absorption --that is, the absorption of cholesterol but not plant sterols by intestinal epithelial cells (enterocytes). Given the link between plasma cholesterol levels and heart disease, the mechanism of dietary cholesterol absorption is of great interest (2). Some knowledge has been gained by investigating cellular processes as disparate as vesicular transport, molecular chaperones in the endoplasmic reticulum, lipid-transfer proteins, sterol-esterification enzymes, and rare genetic disorders.
3) The pharmaceutical industry is actively seeking drugs that specifically inhibit cholesterol absorption without affecting the absorption of other dietary lipids. The discovery of the drug ezetimibe (Zetia) -- which specifically blocks intestinal cholesterol absorption by binding to a protein on the apical surface of enterocytes -- has garnered much interest. Elucidating the target protein of ezetimibe may reveal the identity of a putative cholesterol transporter. Altmann et al. (3) have reported the discovery of a protein that has the characteristics of a cholesterol transporter.
4) Given that ezetimibe specifically blocks cholesterol absorption, Altmann and colleagues (3) reasoned that its target must have the structural characteristics of a cholesterol transporter. They searched human and rodent expressed sequence tag (EST) databases for protein sequences that are highly expressed in the intestine and that contain characteristic features of transporters (transmembrane domains, an extracellular signal peptide, and N-linked glycosylation sites). But they also sought proteins containing a "sterol-sensing" domain as found in other proteins known to interface with cholesterol, such as Neimann-Pick C1 (NPC1), HMG CoA reductase, and the Patched receptor. They identified a single rodent protein with these features and discovered that it is homologous to human Niemann-Pick C1 Like 1 protein (NPC1L1, also known as NPC3). To test whether NPC1L1 is required for cholesterol absorption in vivo, they created a mouse deficient in the Npc1l1 gene. Absorption of dietary cholesterol was almost completely abolished in these mice, and the animals were insensitive to ezetimibe.(4,5)
References (abridged):
1. R. Schoenheimer, Z. Physiol. Chem. 180, 1 (1929)
2. E. L. Klett et al., Curr. Opin. Lipidol. 14, 341 (2003)
3. S. W. Altmann et al., Science 303, 1201 (2004)
4. K. E. Berge et al., Science 290, 1771 (2000)
5. M-H. Lee et al., Nature Genet. 27, 79 (2001)
Science http://www.sciencemag.org
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MEDICAL BIOLOGY: DIET AND BLOOD CHOLESTEROL REDUCTION
The following points are made by D.J. Jenkins et al: (J. Am. Med. Assoc. 2003 290:502):
1) Most dietary manipulations result in modest cholesterol reductions of 4% to 13%, and diet has been considered by some as a relatively ineffective therapy. In contrast, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) repeatedly have been shown to reduce mean serum low-density lipoprotein cholesterol (LDL-C) concentrations by 28% to 35% in long-term trials, with corresponding reductions in cardiovascular death of 23% to 32% in both primary and secondary prevention trials.
2) Recently, to boost effectiveness of diet for primary prevention of cardiovascular disease, the Adult Treatment Panel (ATP III) of the National Cholesterol Education Program has recommended addition of plant sterols (2 g/d) and viscous fibers (10-25 g/d) to the diet. The American Heart Association has also drawn attention to the possible benefits of soy proteins and the potential value of nuts. In turn, the US Food and Drug Administration now permits health claims for coronary heart disease (CHD) risk reduction, based on cholesterol lowering, for foods delivering adequate amounts of plant sterols, viscous fibers (oat beta-glucan and psyllium), and soy protein, and a health claim for nuts is being considered. Despite the large potential for cholesterol reduction, this dietary combination has never been compared directly with a statin.
3) To assess the effectiveness of this dietary portfolio approach, the authors studied a group of hyperlipidemic adults who were randomized to 1 of 3 treatments: the combination dietary portfolio, a diet lacking the additional active dietary ingredients but with a similar very low-saturated-fat content (control), or the same low-saturated-fat diet with addition of a statin.
4) From their results, the authors conclude. Current dietary recommendations focusing on diets low in saturated fat have been expanded to include foods high in viscous fibers (eg, oats and barley) and plant sterols. These guidelines, together with additional suggestions to include vegetable protein foods (soy) and nuts (almonds), appear to reduce LDL-C levels similarly to the initial therapeutic dose of a first-generation statin. However, before the true effectiveness of this dietary change can be assessed, studies must be undertaken in patients who assemble the diets for themselves on a routine basis. Using the experience gained, further development of this approach may provide a potentially valuable dietary option for cardiovascular disease risk reduction in primary prevention.
J. Am. Med. Assoc. http://www.jama.com
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