Tibolone lowers high density lipoprotein cholesterol by increasing hepatic lipase activity but does not impair cholesterol efflux

Eckardstein, Arnold von; Crook, David; Elbers, Jolanda; Ragoobir, Jennifer; Ezeh, Benjamin; Helmond, F.A.; Miller, N. E.; Dieplinger, Hans; Bennink, Herjan Coelingh; Assmann, Gerd

doi:10.1046/j.1365-2265.2003.01666.x

Cited by 35 publications

(24 citation statements)

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“…Studies after the influence of the common C>T polymorphism in the hepatic lipase gene promoter do not always support this assumption. Several studies have shown that genetically lowered HL activity associated with increased HDL cholesterol is associated with increased rather than decreased CAD risk [6•,8], whereas drug-induced (eg, danazol [23] or tibolone [24]) increased HL activity leading to strongly decreased HDL cholesterol does not necessarily enhance CAD risk.…”

Section: Role Of Hepatic Lipase In High-density Lipoprotein Metabolismmentioning

confidence: 99%

Hepatic lipase: Friend or foe and under what circumstances?

Jansen¹

2004

Curr Atheroscler Rep

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Hepatic lipase (HL) plays a role in the metabolism of chylomicron and very low-density lipoprotein remnants, low-density lipoproteins (LDL), and high-density lipoproteins (HDL), which are all implicated in atherosclerosis. Considering the effects of HL on these lipoproteins, it appears that HL has pro- as well as antiatherogenic potential. In line with clinical observations, most effects of HL on lipoprotein metabolism during hypertriglyceridemia may be interpreted as promoting atherosclerosis (formation of small, dense LDL, lowering of HDL levels), whereas most effects during hypercholesterolemia seem to be potentially antiatherogenic (stimulation of reverse cholesterol transport, clearing of intermediate-density lipoprotein). The potential modulation of pro- or antiatherogenics effect of HL by other factors, such as LDL receptor, cholesterol ester transfer protein, lipoprotein lipase, and ATP-binding cassette A-1 activity, is discussed.

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Section: Role Of Hepatic Lipase In High-density Lipoprotein Metabolismmentioning

confidence: 99%

Hepatic lipase: Friend or foe and under what circumstances?

Jansen¹

2004

Curr Atheroscler Rep

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“…For more information about the following terms, which are not mentioned in the text of the present article, see von Eckardstein et al, 27 Borggreve et al, 28 Ma et al, 29 and Cilingiroglu and Ballantyne. 30 ABC A-1: adenosine triphosphate binding cassette, the initiator of cholesterol efflux from the cell membrane.…”

Section: Animal Models: Is Cetp Proatherogenic?mentioning

confidence: 99%

“…The primary action of CETP is to mediate the transfer of cholesteryl esters from HDL to VLDL and LDL in exchange for triglyceride (Figure 2). [27][28][29][30] CETP also promotes the transformation of HDL 2 to HDL 3 , an action that could promote reverse cholesterol transport. CETP inhibition, on the other hand, results in an increase in HDL by markedly delaying catabolism of apoA-I and A-II.…”

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confidence: 99%

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

2005

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Abstract-Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol.Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by Ͼ50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ lipids Ⅲ metabolism Ⅲ statins A lthough lipid-lowering therapies now have the capability of reducing LDL cholesterol to levels recommended by the National Cholesterol Education Program (NCEP) guidelines in as many as 90% of treated patients, 1 the rate of cardiovascular events is reduced by only 20% to 35% in large, randomized trials. These data suggest that the LDL target set by NCEP guidelines may be too high. 1-5 Indeed, among patients with acute myocardial infarction, Ϸ15% have LDL levels Ͻ100 mg/dL on presentation.A complementary hypothesis is that there is a finite limit to the benefit of LDL lowering and that other non-LDL lipid risk factors must be managed for optimal outcomes. Indeed, epidemiological studies suggest that low HDL cholesterol may be a risk factor comparable in importance to high LDL and that the 2 risk factors are independent (Figure 1). 6,7 Although the mechanism by which HDL reduces the development of atherosclerosis has not been defined with certainty, acceleration of reverse cholesterol transport, antioxidant activity, and antiinflammatory action are likely to play central roles. 8 -10 In contrast to the ability of potent statins to reduce the level of LDL by Ͼ50%, however, no currently approved therapy increases HDL by a comparable magnitude. The most potent, currently available HDL-raising therapy is nicotinic acid. This therapy also has a multitude of other antiatherosclerotic effects on the levels of LDL and triglycerides, lipid oxidation, and endothelial function. 11 Combination therapy with a statin has been reported to increase HDL levels by Ϸ30% 12 and to decrease cardiac events...

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“…the drug with its androgenic properties can reduce high-density lipoprotein cholesterol (HDL-C) as an unfavorable change [25]. However, there are findings that the change of HDL-C is usually transient [33]; on the other hand there are more and more data that we should not focus on HDL-C as it is not main target of the lipid-lowering therapy, also due to the lasting debate on HDL functionality in different patients' groups [42,60,61]. It should be emphasized that data on circulating Lp(a) levels were obtained from studies using different assays for Lp(a).…”

Section: Discussionmentioning

confidence: 95%