биохимия атеросклероза
.pdf178 Manfredi Rizzo and Kaspar Berneis
nine other established cardiovascular risk factors, including plasma lipids and lipoproteins.
Increased intima media thickness (IMT) is considered a reliable surrogate marker of early atherosclerosis and it has been demonstrated that small dense LDL is independently related to CCA IMT in 50-year-old men [73]. IMT has been shown to correlate significantly with the presence of CHD and to predict coronary events [92–95]. In addition, significant relationships of IMT with other lipid parameters such as LDL-cholesterol [96] and apoB [97] have been demonstrated. In the study described above LDL size was significantly associated with carotid IMT in diabetes type 2 patients and LDL size was the second strongest predictor of IMT, after smoking when compared to nine other cardiovascular risk factors and the strongest of all lipid parameters.
In summary LDL size is a marker of clinical apparent (CHD) and nonapparent (IMT) atherosclerosis in type 2 diabetes. However a potential superior clinical value to predict cardiovascular events in this population needs to be shown in prospective studies, before routine laboratory measurements of LDL size can be recommended.
Effects of Hypolipidemic Treatment on LDL Size
Hypolipidemic treatment is capable of altering LDL subclass distribution. Particularly medication with triglyceride-lowering effects will shift LDL peak size from smaller denser to larger more buoyant particles. As explained in more detail earlier, reduced availability of triglyceride-rich VLDL particles lead to a reduction in the production of small dense LDL. This has been shown for fibrates and niacin: these substances lower preferentially small dense LDL, so that the LDL peak size shifts to larger particles. Statins potentially lower large, medium, and small LDL particles; therefore, the beneficial net effect of statins on LDL size is often none or only moderate. However, a strong variation has been noticed among the different statin molecules [1, 98–101].
Conclusions
Genetic and environmental factors influence the expression of small dense LDL, which is not completely independent of traditional lipids and, in fact, correlates negatively with plasma HDL concentrations and positively with plasma triglyceride levels. Small dense LDL are associated with the metabolic syndrome and with increased risk for cardiovascular disease and diabetes mellitus. LDL size seems also to be an important predictor of cardiovascular events and progression of CAD and the predominance of small dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III [7].
In addition, patients with acute myocardial infarction show an early reduction of LDL size, which persist during hospitalization and seems to precede
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all other plasma lipoprotein modifications. It has been recently shown that even angina itself (on the background of coronary artery spasm) without atherosclerosis may lower LDL size [102]. Hypolipidemic treatment is able to increase LDL particles size [1–3] and this increment correlates with regression of coronary stenosis [1–3]. However, it is still on debate whether to measure the LDL size routinely and in which categories of patients [39].
Recently, the Coordinating Committee of the National Cholesterol Education Program suggested that very high-risk patients may benefit from stronger measures of lipid-lowering therapies [84]. Since the therapeutic modulation of distinct LDL subspecies is of great benefit in reducing the risk of cardiovascular events, LDL size measurement should be extended in primary prevention as much as possible to patients at high risk of cardiovascular diseases. In addition, screening for the presence of small dense LDL in patients with coronary or noncoronary forms of atherosclerosis may also identify those with even higher vascular risk and may contribute in directing specific antiatherosclerotic treatments (secondary prevention) in order to prevent new vascular events in the same or another district.
Acknowledgments: The authors wish to thank Prof. Ronald M. Krauss (Senior Scientist, Lawrence Berkeley National Laboratory, University of California, Berkeley, USA and Director of Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, California, USA) and Prof. Alberto Notarbartolo (Head, Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy) for their strong, valuable, and unique support on the authors’ researches in this field. Kaspar Berneis was supported by a research grant from the Swiss National Foundation 3200B0-105258/1.
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Biochemistry of Atherosclerosis edited by S.K. Cheema, Springer, New York, 2006
10
Bile Acids: At the Crossroads
of Sterol, Fat, and Carbohydrate
Metabolism
LUIS B. AGELLON
Abstract
Bile acids are classically known as natural detergents that help keep cholesterol soluble in bile and aid in the absorption of lipids and lipid-soluble nutrients from the gut. Since bile acids are synthesized from cholesterol, they are also regarded as end products of cholesterol catabolism. It was recently known that bile acids can modulate cellular signaling cascades. Importantly, bile acids can regulate the expression of a variety of genes by serving as ligand and activator of a nuclear receptor transcription factor known as farnesoid X receptor (FXR). The identity of the genes that are responsive to regulation by bile acids via FXR suggests that bile acids can regulate, and possibly coordinate, the metabolism of sterols, fats, and carbohydrates.
Keywords: bile acids; cholesterol; enterohepatic circulation; fatty acids; gene regulation; glucose; liver; nuclear receptors; transgenic mice
Abbreviations: cyp7a, cholesterol 7α-hydroxylase; FXR, farnesoid X receptor; LXR, liver X receptor; LDL, low-density lipoproteins; LRH-1, liver receptor homolog pro- tein-1; NR, nuclear receptor; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; SHP, short heterodimer partner; SREBP, sterol response element binding protein; VLDL, very low-density lipoproteins
Introduction
The metabolism of cholesterol is complicated and there are many factors involved in its synthesis, assimilation from dietary sources, transport, and disposal. It is generally accepted that the removal of excess cholesterol from peripheral tissues involves the “reverse cholesterol transport pathway” which operates to off-load cholesterol from peripheral cells and delivers it to the liver for disposal.
The liver is the only organ that is capable of eliminating meaningful amounts of cholesterol from the body. This is done directly by secretion of unesterified cholesterol into bile (biliary cholesterol) and indirectly by facilitating the conversion of cholesterol into bile acids for secretion into bile
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(Fig. 10.1). However, biliary cholesterol can mix with diet-derived cholesterol and thus can reenter the body via absorption from the lumen of the intestine. Bile acids are also reabsorbed by the intestine but because cholesterol cannot be recovered from bile acids, the conversion of cholesterol into bile acids represents a terminal step in the catabolism of cholesterol. Bile acid synthesis can account for the elimination of 400–1000 mg of cholesterol per day compared to a combined total of about 100 mg via other pathways (steroid hormone synthesis and shedding of epithelial surfaces).
The synthesis of bile acids takes place only in the liver and the hepatic enzyme known as cholesterol 7α-hydroxylase (cyp7a) catalyzes the first and rate-controlling step in the classical bile acid biosynthetic pathway (Fig. 10.2). Peripheral cells can transform cholesterol into oxysterols, and upon their transport to the liver they complete their transformation into bile acids. This alternative pathway is distinguished from the classical pathway in that cholesterol is first transformed into an oxysterol other than 7α-hydroxycholesterol. The classical pathway is under complex regulatory control whereas the alternative pathway operates constitutively.
Dietary cholesterol
Liver
Bile
Small intestine
Bile
Cholesterol Plasma
acids
Portal circulation
excretion
FIGURE 10.1. Transport of cholesterol and bile acids in the enterohepatic circulation. The path traced by cholesterol (solid lines) and bile acids (broken lines) in the enterohepatic circulation is shown.