Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Brodeur, Mathieu R.; Rhainds, David; Charpentier, Daniel; Mihalache-Avram, Téodora; Mecteau, Mélanie; Brand, Geneviève; Chaput, Evelyne; Perez, Anne; Niesor, Eric J.; Rhéaume, Éric; Maugeais, Cyrille; Tardif, Jean‐Claude

doi:10.1194/jlr.m068940

Cited by 14 publications

(13 citation statements)

References 50 publications

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“…Serum CETP mass was increased in anacetrapib-treated mice (Fig. 1 D and E ), which was consistent with a previous report that anacetrapib treatment increases CETP mass in circulation (28). SAA1, an inflammatory factor, was increased by HFD feeding and CETP inhibition (Fig.…”

Section: Resultssupporting

confidence: 92%

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet

et al. 2018

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In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL's antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.

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Section: Resultssupporting

confidence: 92%

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet

et al. 2018

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“…Although the mechanism remains unknown, a structurally similar sphingolipid synthesis inhibitor, N-butyldeoxy-nojirimycin, did not increase cellular cholesterol efflux. Enhanced cholesterol efflux was also observed in macrophages of patients treated with the CETP inhibitors anacetrapib, dalcetrapib and torcetrapib, whereas torcetrapib also increased ABCA1 expression (Yvan-Charvet et al, 2007, 2010aBrodeur et al, 2017). This is, however, expected to be a result of the increased HDL-C levels due to CETP inhibition.…”

Section: Increasing Cellular Cholesterol Efflux Via Unknown Mechanismsmentioning

confidence: 91%

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

et al. 2019

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Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT). RCT facilitates removal of cholesterol from peripheral tissues, including atherosclerotic plaques, and its subsequent hepatic clearance into bile. Therefore, RCT is expected to limit plaque formation and progression. Cellular cholesterol efflux is initiated and propagated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Their expression and function are expected to be rate-limiting for cholesterol efflux, which makes them interesting targets to stimulate RCT and lower atherosclerotic risk. This systematic review discusses the molecular mechanisms relevant for RCT and ABCA1 and ABCG1 function, followed by a critical overview of potential pharmacological strategies with small molecules to enhance cellular cholesterol efflux and RCT. These strategies include regulation of ABCA1 and ABCG1 expression, degradation, and mRNA stability. Various small molecules have been demonstrated to increase RCT, but the underlying mechanisms are often not completely understood and are rather unspecific, potentially causing adverse effects. Better understanding of these mechanisms could enable the development of safer drugs to increase RCT and provide more insight into its relation with atherosclerotic risk.Significance Statement--Hypercholesterolemia is an important risk factor of atherosclerosis, which is a leading pathological mechanism underlying cardiovascular disease. Cholesterol is removed from atherosclerotic plaques and subsequently cleared by the liver into bile. This transport is mediated by high-density lipoprotein particles, to which cholesterol is transferred via ATP-binding cassette transporters ABCA1 and ABCG1. Small-molecule pharmacological strategies stimulating these transporters may provide promising options for cardiovascular disease treatment.

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“…However, there was no difference in all-cause mortality or death from coronary disease. It is possible that anacetrapib uniquely impacts HDL structure and function compared to other CETPi, 28 which could lead to improved clinical outcomes. Although statistically significant, the trial was clinically disappointing and well below that of a competitor drug class targeting LDL receptor degradation (proprotein convertase subtilisin-kexin type 9 inhibitors) 29 and so regulatory approval was not pursued.…”

Section: Cetp Inhibitionmentioning

confidence: 99%

Is high-density lipoprotein a modifiable treatment target or just a biomarker for cardiovascular disease?

Whyte

2019

JRSM Cardiovascular Disease

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Epidemiological data strongly support the inverse association between high-density lipoprotein cholesterol concentration and cardiovascular risk. Over the last three decades, pharmaceutical strategies have been partially successful in raising high-density lipoprotein cholesterol concentration, but clinical outcomes have been disappointing. A recent therapeutic class is the cholesteryl ester transfer protein inhibitor. These drugs can increase circulating high-density lipoprotein cholesterol levels by inhibiting the exchange of cholesteryl ester from high-density lipoprotein for triacylglycerol in larger lipoproteins, such as very low-density lipoprotein and low-density lipoprotein. Recent trials of these agents have not shown clinical benefit. This article will review the evidence for cardiovascular risk associated with high-density lipoprotein cholesterol and discuss the implications of the trial data for cholesteryl ester transfer protein inhibitors.

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Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Cited by 14 publications

References 50 publications

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

Is high-density lipoprotein a modifiable treatment target or just a biomarker for cardiovascular disease?

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