Functionality of postprandial larger HDL2 particles is enhanced following CETP inhibition therapy

ObjectiveTo evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspecies to promote key steps of the reverse cholesterol transport pathway.MethodsThe capacity of HDL particles to mediate cellular free cholesterol efflux and selective hepatic uptake of cholesteryl esters was evaluated throughout postprandial phase (0–8 h) following consumption of a standardised mixed meal before and after treatment for 6 weeks with atorvastatin alone (10 mg/d) and subsequently with combination torcetrapib/atorvastatin (60/10 mg/d) in 16 patients displaying low HDL-C levels (<40 mg/dl).ResultsThe larger HDL2b and HDL2a subfraction displayed a superior capacity to mediate cellular free cholesterol efflux via both SR-BI and ABCG1-dependent pathways than smaller HDL3 subspecies. CETP inhibition specifically enhanced the capacity of HDL2b subfraction for both SR-BI and ABCG1 dependent efflux. However, only the SR-BI-dependent efflux to HDL2b subspecies can be further enhanced during postprandial lipemia following CETP inhibition. Concomitantly, postprandial lipemia was associated with a reduced capacity of total HDL particles to deliver cholesteryl esters to hepatic cells in a drug independent manner.ConclusionCETP inhibition specifically improves postprandial SR-BI and ABCG1-dependent efflux to larger HDL2b subspecies. In addition, CETP inhibition improves HDL-CE delivery to hepatic cells and maintains an efficient direct return of cholesteryl esters to the liver during postprandial lipemia.     

Lipases and HDL metabolism.

Plasma levels of high-density lipoprotein (HDL) cholesterol are strongly inversely associated with atherosclerotic cardiovascular disease, and overexpression of HDL proteins, such as apolipoprotein A-I in animals, reduces progression and even induces regression of atherosclerosis. Therefore, HDL metabolism is recognized as a potential target for therapeutic intervention of atherosclerotic vascular diseases. The antiatherogenic properties of HDL include promotion of cellular cholesterol efflux and reverse cholesterol transport, as well as antioxidant, anti-inflammatory and anticoagulant properties. The molecular regulation of HDL metabolism is not fully understood, but it is influenced by several extracellular lipases. Here, we focus on new developments and insights into the role of secreted lipases on HDL metabolism and their relationship to atherosclerosis.     

The role of CETP inhibition in dyslipidemia

Cholesteryl ester transfer protein (CETP) inhibitors are currently being investigated because of their ability to increase high-density lipoprotein cholesterol levels. In various metabolic settings, the relationship between CETP and lipoprotein metabolism is complex and may depend largely on the concentration of triglyceriderich lipoproteins. Two CETP inhibitors, JTT-705 and torcetrapib, are in an advanced phase of development. Following hopeful intermediate results, a large endpoint study using torcetrapib has just been discontinued due to increased mortality in torcetrapib-treated subjects. In this review we summarize clinical data on the use of CETP inhibitors.     

HDL metabolism in diabetes

Based on the data reviewed, it is necessary to conclude that diabetes is associated with profound changes in HDL metabolism. However, once we go beyond this simple generalization, it is apparent that the relationship between diabetes and HDL metabolism is not a simple one. A good deal of the complication evolves from the fact that IDDM and NIDDM seem to affect HDL metabolism quite differently, with the only apparent similarity the fact that plasma HDL-cholesterol concentration can be low in untreated patients with either IDDM or NIDDM. Thus, in patients with IDDM the primary event seems to be related to the insulin-deficient state, which results in a decrease in HDL turnover rate and resultant decline in plasma HDL-cholesterol concentration. In contrast, HDL turnover appears to be accelerated, not reduced in patients with NIDDM, and the low plasma HDL-cholesterol concentration is a consequence of the increased turnover rate. In addition, patients with NIDDM are not absolutely insulin deficient, and available evidence suggests that the higher the plasma insulin level, the lower the plasma HDL-cholesterol concentration in these patients. The differences noted above in the effect of IDDM and NIDDM on HDL metabolism are of great interest, and, unfortunately, not very well understood. There is, however, one additional difference, which may be of paramount clinical importance. For reasons not totally clear, plasma HDL-cholesterol concentrations in patients with IDDM treated with insulin are not lower than normal, and even tend to be higher than these values in a nondiabetic population. Possibly as a result of this phenomenon, there is no evidence that changes in plasma HDL-cholesterol concentration play a role in the development of macrovascular complications in IDDM. Although it is apparent from the considerations discussed in this review that a great deal more needs to be learned about the effect of insulin deficiency on HDL metabolism, changes in HDL metabolism do not appear to be clinically important in patients with IDDM. Unfortunately, this does not appear to be the situation in patients with NIDDM. Plasma HDL-cholesterol concentrations are lower than normal in patients with NIDDM, and this finding seems to be related to increased morbidity and mortality from CAD. Furthermore, there is no form of anti-diabetic treatment, irrespective of how effective it has been in achieving glycemic control, that has been shown to substantially increase plasma HDL-cholesterol level. Indeed, it has been difficult to demonstrate a consistent effect of any therapeutic approach on plasma HDL-cholesterol concentration.(ABSTRACT TRUNCATED AT 400 WORDS)     

SR-BI and HDL cholesteryl ester metabolism

Scavenger receptor class B, type I (SR-BI) is the receptor for high density lipoprotein (HDL) that mediates cellular uptake of HDL cholesteryl ester (CE) and is a major route for cholesterol delivery to steroidogenic pathways. SR-BI is localized in specialized microvillar channel plasma membrane compartments that retain HDL and are sites for HDL CE selective uptake. In fact, adrenal gland microvillar channel formation is regulated by adrenocorticotropin hormone and requires SR-BI expression. SR-BI-mediated uptake of HDL CE is a two-step process requiring high affinity HDL binding followed by transfer of CE to the membrane. SR-BI delivers HDL CE to sites in the membrane where it is readily metabolized to free cholesterol by cell type-specific neutral CE hydrolases. The most likely candidate for the hydrolysis of HDL CE delivered via SR-BI in the adrenal gland is hormone sensitive lipase. New data in adrenocortical cells as well as the study of a mutant SR-BI receptor lend insight into the mechanism of cholesterol transfer from plasma HDL to the steroidogenic pathway in endocrine cells.     

Raising HDL with CETP inhibitor torcetrapib improves glucose homeostasis in dyslipidemic and insulin resistant hamsters

We investigated whether raising HDL-cholesterol levels with cholesteryl ester transfer protein (CETP) inhibition improves glucose homeostasis in dyslipidemic and insulin resistant hamsters. Compared with vehicle, torcetrapib 30 mg/kg/day (TOR) administered for 10 days significantly increased by ∼40% both HDL-cholesterol levels and ³H-tracer appearance in HDL after ³H-cholesterol labeled macrophages i.p. injection.     

Apolipoprotein A-II,HDL metabolism and atherosclerosis

Apolipoprotein (Apo) A-I and apo A-II are the major apolipoproteins of HDL. It is clearly demonstrated that there are inverse relationships between HDL-cholesterol and apo A-I plasma levels and the risk of coronary heart disease (CHD) in the general population. On the other hand, it is still not clearly demonstrated whether apo A-II plasma levels are associated with CHD risk. A recent prospective epidemiological (PRIME) study suggests that Lp A-I (HDL containing apo A-I but not apo A-II) and Lp A-I:A-II (HDL containing apo A-I and apo A-II) were both reduced in survivors of myocardial infarction, suggesting that both particles are risk markers of CHD. Apo A-II and Lp A-I:A-II plasma levels should be rather related to apo A-II production rate than to apo A-II catabolism. Mice transgenic for both human apo A-I and apo A-II are less protected against atherosclerosis development than mice transgenic for human apo A-I only, but the results of the effects of trangenesis of human apo A-II (in the absence of a co-transgenesis of human apo A-I) are controversial. It is highly suggested that HDL reduce CHD risk by promoting the transfer of peripherical free cholesterol to the liver through the so-called 'reverse cholesterol transfer'. Apo A-II modulates different steps of HDL metabolism and therefore probably alters reverse cholesterol transport. Nevertheless, some effects of apo A-II on intermediate HDL metabolism might improve reverse cholesterol transport and might reduce atherosclerosis development while some other effects might be deleterious. In different in vitro models of cell cultures, Lp A-I:A-II induce either a lower or a similar cellular cholesterol efflux (the first step of reverse cholesterol transport) than Lp A-I. Results depend on numerous factors such as cultured cell types and experimental conditions. Furthermore, the effects of apo A-II on HDL metabolism, beyond cellular cholesterol efflux, are also complex and controversial: apo A-II may inhibit lecithin-cholesterol acyltransferase (LCAT) (potential deleterious effect) and cholesteryl-ester-transfer protein (CETP) (potential beneficial effect) activities, but may increase the hepatic lipase (HL) activity (potential beneficial effect). Apo A-II may also inhibit the hepatic cholesteryl uptake from HDL (potential deleterious effect) probably through the SR-BI depending pathway. Therefore, in terms of atherogenesis, apo A-II alters the intermediate HDL metabolism in opposing ways by increasing (LCAT, SR-BI) or decreasing (HL, CETP) the atherogenicity of lipid metabolism. Effects of apo A-II on atherogenesis are controversial in humans and in transgenic animals and probably depend on the complex effects of apo A-II on these different intermediate metabolic steps which are in weak equilibrium with each other and which can be modified by both endogenous and environmental factors. It can be suggested that apo A-II is not a strong determinant of lipid metabolism, but is rather a modulator of reverse cholesterol transport.     

冠心病患者血浆胆固醇酯转运蛋白水平与

目的　探讨冠心病患者胆固醇酯转运蛋白（CETP）水平与血浆高密度脂蛋白（HDL）亚类组成的关系。方法　收集冠心病患者血浆116例和健康对照组血浆87例,采用双向电泳-免疫印迹检测法分析其HDL亚类浓度,用酶联免疫法测定CETP浓度。按CETP浓度均值加或减去一个标准差作为分割点,将冠心病患者分为3组：低CETP组（CETP≤0.69　mg/L）、中CETP组（0.69＜CETP<1.59　mg/L）、高CETP组（CETP≥1.59　mg/L）。结果     

High density lipoprotein (HDL) metabolism in noninsulin-dependent diabetes mellitus: measurement of HDL turnover using tritiated HDL

High density lipoprotein (HDL) kinetics were studied by injecting [3H]apoprotein A-I (apoA-I)/HDL into 12 subjects with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM). The results indicate that the mean fractional catabolic rate (FCR) of apoA-I/HDL was significantly faster [0.63 +/- 0.07 (+/- SEM) vs. 0.39 +/- 0.02 1/day; P less than 0.001] and the apoA-I/HDL synthetic rate greater (29.4 +/- 2.9 vs. 22.9 +/- 1.3 mg/kg X day; P less than 0.02) in patients with NIDDM than in normal subjects. Furthermore, there were statistically significant inverse relationships between apoA-I/HDL FCR and plasma levels of both HDL cholesterol (r = -0.71; P less than 0.001) and apoA-I (r = -0.63; P less than 0.001). In addition, the increase in apoA-I/HDL FCR was directly related to fasting plasma glucose (r = 0.78; P less than 0.001) and insulin (r = 0.76; P less than 0.001) concentrations. These data support the view that the decrease in plasma HDL cholesterol and apoA-I levels commonly found in patients with noninsulin-dependent diabetes is due to an increase in the catabolic rate of apoA-I/HDL secondary to the defects in carbohydrate metabolism present in these patients.     

HDL metabolism and the role of HDL in the treatment of high-risk patients with cardiovascular disease

Developing new therapeutic approaches to treating residual cardiovascular risk of recurrent clinical events in statin-treated patients has been a major challenge for the cardiovascular field. Data from epidemiological evidence, animal models, and initial clinical trials indicate that increasing high-density lipoprotein (HDL) may be an effective new target for treating residual cardiovascular risk. Over the past several years, major advances have occurred in our understanding of HDL metabolism and of the important roles of the ABCA1 and ABCG1 transporters as well as the SR-BI receptor in cholesterol transport. Current approaches to HDL therapy include acute HDL infusion therapy in acute coronary syndrome patients and chronic oral HDL therapy in stable patients with cardiovascular disease. Definitive clinical trials will now be required to establish the safety and efficacy of increasing HDL in the treatment of patients with cardiovascular disease.     

CETP、CETP抑制剂与动脉粥样硬化

血脂异常促进动脉粥样硬化(atherosclerosis,AS)已为既往的临床研究所证实。除低密度脂蛋白胆固醇(low-densitylipoprotein cholesterol,LDL-C)外,低水平的高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)亦是AS的危险因素之一。有研究表明,升高HDL-C,可以延缓AS进展,机制尚不十分明确,可能与其促进胆固醇逆装运、抗氧化和抗炎作用有关[1]。目前用于升高HDL-C的常用药物为烟酸类制剂和他汀类药物。但即使烟酸和他汀联合使用,亦仅能将HDL-C升高约30%。因此,寻找和开发能明显升高HDL-C的药物,可能为进一步预防和…