Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

Kühnast, Susan; Tuin, Sam J.L. van der; Hoorn, José W.A. van der; Klinken, Jan B. van; Simić, B; Pieterman, Elsbet J.; Havekes, Louis M.; Landmesser, Ulf; Lüscher, Thomas F.; Dijk, Ko Willems van; Rensen, Patrick C.N.; Jukema, J. Wouter; Princen, H.M.G.

doi:10.1093/eurheartj/ehu319

Cited by 68 publications

(60 citation statements)

References 42 publications

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“…Similarly as in familial dyslipoproteinemia patients, in E3L and E3L.CETP mice as a model for mixed dyslipoproteinemia, a major part of plasma cholesterol is contained in the VLDL (remnant) particles, leading to the formation of ␤ -VLDL particles, which further increases after cholesterol feeding. The E3L.CETP mouse model, unlike Apoe Ϫ / Ϫ and Ldlr Ϫ / Ϫ mice, responds in a human-like way to the lipid-lowering effects of statins ( 18 ), fi brates ( 19 ), niacin ( 20,21 ), torcetrapib ( 15 ), anacetrapib ( 22 ), and antiPCSK9mabs ( 23 ), with respect to both direction and magnitude of the change. In conclusion, E3L.CETP mice have a more human-like lipoprotein metabolism when compared with C57Bl/6, Apoe…”

Section: Methodsmentioning

confidence: 99%

“…ANCOVA showed that the effect on lesion size was mainly explained by a reduction in (V)LDL-C ( 22 ). However, the mechanism by which anacetrapib reduces plasma (V)LDL-C and TG is not fully understood.…”

Section: Methodsmentioning

confidence: 99%

“…Liver pieces were obtained from a previous experiment performed by Kühnast et al ( 22 ), investigating the effects of anacetrapib on atherosclerosis in female E3L.CETP mice ( 22 ). In this study, mice were treated with a semisynthetic cholesterol-rich diet, containing 15% (w/w) cacao butter, 1% corn oil, and 0.1% cholesterol (Western-type diet; AB-Diets, Woerden, The Netherlands) with or without anacetrapib (30 mg/kg body weight per day) for 21 weeks.…”

Section: Rna Isolation Microarray and Qpcr Validationmentioning

confidence: 99%

“…To determine the effects of anacetrapib treatment on hepatic gene expression in E3L.CETP mice ( 22 ), microarray analyses were performed. A total of 95 genes (false discovery rate P < 0.05; supplementary Table 1) were differentially expressed between control and anacetrapib-treated female mice of which 46 genes were upregulated and 49 genes were downregulated.…”

Section: Pathway Analyses Predict Downregulation Of Pathways Controllmentioning

confidence: 99%

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Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

Tuin

Kühnast

Berbée

et al. 2015

Journal of Lipid Research

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High plasma levels of (V)LDL cholesterol [(V)LDL-C] and TGs, as well as low levels of HDL cholesterol (HDL-C), are important risk factors for cardiovascular diseases. The standard treatment for the reduction of cardiovascular disease risk is statin therapy aiming to reduce plasma (V) LDL-C. However, a substantial residual risk remains despite statin treatment. This has prompted the search for secondary treatment targets ( 1, 2 ). Prospective epidemiological studies indicate HDL-C as a potential target ( 3 ). The ratio of plasma (V)LDL-C to HDL-C is to a great extent affected by cholesteryl ester transfer protein (CETP). CETP facilitates the transfer of cholesteryl esters from HDL to (V)LDL in exchange for TG ( 4 ). In several mouse Abstract Recently, we showed in APOE*3-Leiden cholesteryl ester transfer protein (E3L.CETP) mice that anacetrapib attenuated atherosclerosis development by reducing (V) LDL cholesterol [(V)LDL-C] rather than by raising HDL cholesterol. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. E3L.CETP mice were fed a Western-type diet alone or supplemented with anacetrapib (30 mg/kg body weight per day). Microarray analyses of livers revealed downregulation of the cholesterol biosynthesis pathway ( P < 0.001) and predicted downregulation of pathways controlled by sterol regulatory element-binding proteins 1 and 2 ( z -scores ؊ 2.56 and ؊ 2.90, respectively; both P < 0.001). These data suggest increased supply of cholesterol to the liver. We found that hepatic proprotein convertase subtilisin/kexin type 9 ( Pcsk9 ) expression was decreased ( ؊ 28%, P < 0.01), accompanied by decreased plasma PCSK9 levels ( ؊ 47%, P < 0.001) and increased hepatic LDL receptor (LDLr) content (+64%, P < 0.01). Consistent with this, anacetrapib increased the clearance and hepatic uptake (+25%, P < 0.001) of [ 14 C]cholesteryl oleatelabeled VLDL-mimicking particles. In E3L mice that do not express CETP, anacetrapib still decreased (V)LDL-C and plasma PCSK9 levels, indicating that these effects were independent of CETP inhibition. We conclude that anacetrapib reduces (V)LDL-C by two mechanisms: 1 ) inhibition of CETP activity, resulting in remodeled VLDL particles that are more susceptible to hepatic uptake; and 2 ) a CETPindependent reduction of plasma PCSK9 levels that has the potential to increase LDLr-mediated hepatic remnant

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Rna Isolation Microarray and Qpcr Validationmentioning

confidence: 99%

Section: Pathway Analyses Predict Downregulation Of Pathways Controllmentioning

confidence: 99%

See 2 more Smart Citations

Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

Tuin

Kühnast

Berbée

et al. 2015

Journal of Lipid Research

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show abstract

“…Similarly, serum SAA levels were increased by the treatment of anacetrapib and atorvastatin in APOE*3Leiden.CETP mice (33). It is important to know whether the inflammation is correlated with any of HDL function and what is the mechanism inhibiting antioxidant activity of HDL when CETP inhibitors are used.…”

Section: Hdl Function and Anti-inflammatory Effects In Cetp Deficiencmentioning

confidence: 99%

CETP Deficiency and Concerns in CETP Inhibitor Development

Inazu

2017

The HDL Handbook

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High Density Lipoproteins: Is There a Comeback as a Therapeutic Target?

Eckardstein

2021

Handbook of Experimental Pharmacology

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Low plasma levels of High Density Lipoprotein (HDL) cholesterol (HDL-C) are associated with increased risks of atherosclerotic cardiovascular disease (ASCVD). In cell culture and animal models, HDL particles exert multiple potentially anti-atherogenic effects. However, drugs increasing HDL-C have failed to prevent cardiovascular endpoints. Mendelian Randomization studies neither found any genetic causality for the associations of HDL-C levels with differences in cardiovascular risk. Therefore, the causal role and, hence, utility as a therapeutic target of HDL has been questioned. However, the biomarker “HDL-C” as well as the interpretation of previous data has several important limitations: First, the inverse relationship of HDL-C with risk of ASCVD is neither linear nor continuous. Hence, neither the-higher-the-better strategies of previous drug developments nor previous linear cause-effect relationships assuming Mendelian randomization approaches appear appropriate. Second, most of the drugs previously tested do not target HDL metabolism specifically so that the futile trials question the clinical utility of the investigated drugs rather than the causal role of HDL in ASCVD. Third, the cholesterol of HDL measured as HDL-C neither exerts nor reports any HDL function. Comprehensive knowledge of structure-function-disease relationships of HDL particles and associated molecules will be a pre-requisite, to test them for their physiological and pathogenic relevance and exploit them for the diagnostic and therapeutic management of individuals at HDL-associated risk of ASCVD but also other diseases, for example diabetes, chronic kidney disease, infections, autoimmune and neurodegenerative diseases.

show abstract

Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

Cited by 68 publications

References 42 publications

Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

CETP Deficiency and Concerns in CETP Inhibitor Development

High Density Lipoproteins: Is There a Comeback as a Therapeutic Target?

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