Anacetrapib-driven triglyceride lowering explained: the fortuitous role of CETP in the intravascular catabolism of triglyceride-rich lipoproteins.
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ABSTRACT:
SUBMITTER: Brown AL
PROVIDER: S-EPMC5454498 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
Publications
Anacetrapib-driven triglyceride lowering explained: the fortuitous role of CETP in the intravascular catabolism of triglyceride-rich lipoproteins.
Brown Amanda L AL Brown J Mark JM
Journal of lipid research 20170421 6
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Project description:Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.
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Project description:Approximately 25% of US adults are estimated to have hypertriglyceridemia (triglyceride [TG] level ≥150 mg/dL [≥1.7 mmol/L]). Elevated TG levels are associated with increased cardiovascular disease (CVD) risk, and severe hypertriglyceridemia (TG levels ≥500 mg/dL [≥5.6 mmol/L]) is a well-established risk factor for acute pancreatitis. Plasma TG levels correspond to the sum of the TG content in TG-rich lipoproteins (TRLs; ie, very low-density lipoproteins plus chylomicrons) and their remnants. There remains some uncertainty regarding the direct causal role of TRLs in the progression of atherosclerosis and CVD, with cardiovascular outcome studies of TG-lowering agents, to date, having produced inconsistent results. Although low-density lipoprotein cholesterol (LDL-C) remains the primary treatment target to reduce CVD risk, a number of large-scale epidemiological studies have shown that elevated TG levels are independently associated with increased incidence of cardiovascular events, even in patients treated effectively with statins. Genetic studies have further clarified the causal association between TRLs and CVD. Variants in several key genes involved in TRL metabolism are strongly associated with CVD risk, with the strength of a variant's effect on TG levels correlating with the magnitude of the variant's effect on CVD. TRLs are thought to contribute to the progression of atherosclerosis and CVD via a number of direct and indirect mechanisms. They directly contribute to intimal cholesterol deposition and are also involved in the activation and enhancement of several proinflammatory, proapoptotic, and procoagulant pathways. Evidence suggests that non-high-density lipoprotein cholesterol, the sum of the total cholesterol carried by atherogenic lipoproteins (including LDL, TRL, and TRL remnants), provides a better indication of CVD risk than LDL-C, particularly in patients with hypertriglyceridemia. This article aims to provide an overview of the available epidemiological, clinical, and genetic evidence relating to the atherogenicity of TRLs and their role in the progression of CVD.
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Project description:GPIHBP1 is a new addition to a group of proteins required for the lipolysis of triglyceride-rich lipoproteins. GPIHBP1 contains an acidic domain and an Ly6 domain with ten cysteines. GPIHBP1 binds lipoprotein lipase (LPL) avidly and likely tethers LPL to the luminal surface of capillaries.Inactivation of Gpihbp1 in mice is associated with milky plasma and severe chylomicronemia, even on a low-fat chow diet. Recently, four missense mutations in GPIHBP1 were identified in humans with severe chylomicronemia (C65Y, C65S, C68G, and Q115P). All four mutations involve highly conserved residues within GPIHBP1's Ly6 domain.This review will provide an update on GPIHBP1's role in the processing of chylomicrons and the pathogenesis of chylomicronemia.
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Project description:BackgroundPemafibrate is a potent selective peroxisome proliferator-activated receptor α modulator. Whether this agent favorable modulates atherosclerosis in vivo remains unknown. This is the first case report to evaluate serial changes of coronary atherosclerosis under pemafirate use in type 2 diabetic patients already taking a high-intensity statin.Case descriptionA 75-year-old gentleman was hospitalized due to peripheral artery disease, which was treated by endovascular treatment. One year later, non-ST-elevation myocardial infarction (NSTEMI) occurred and severe stenosis at his proximal segment of right coronary artery received primary percutaneous coronary intervention (PCI). Due to his suboptimal control of low-density lipoprotein cholesterol (LDL-C) level with moderate intensity statin, high-intensity one (20 mg atorvastatin) and 10 mg ezetimibe were commenced, which enabled to achieve very low LDL-C level (50 mg/dL). However, he required additional PCI due to progression of left circumflex artery one year after NSTEMI. Despite his optimally controlled LDL-C level (46 mg/dL), near-infrared spectroscopy and intravascular (NIRS/IVUS) imaging after PCI visualized the presence of lipid-rich plaque [maximum 4-mm lipid-core burden index (LCBI4mm) =482] at non-culprit segment in his right coronary artery. Given his continuing residual hypertriglyceridemia (triglyceride =248 mg/dL), 0.2 mg pemafibrate was commenced, which lowered triglyceride to 106 mg/dL. One-year follow-up NIRS/IVUS imaging was conducted to evaluate coronary atheroma. A reduction of attenuated ultrasonic signals was observed, accompanied by plaque calcification. In addition, the amount of yellow signal was lowered, and its MaxLCBI4mm was 358. Since then, this case does not experience any cardiovascular events. His LDL-C and triglyceride-rich lipoprotein levels are favourably controlled.ConclusionsA delipidation of coronary atheroma, accompanied by greater plaque calcification was observed after the commencement of pemafibrate. This finding highlights potential anti-atherosclerotic benefit of pemafibrate use in patients receiving a statin.
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Project description:Cholesteryl ester transfer protein (CETP) facilitates the transfer of HDL cholesteryl ester to triglyceride-rich lipoproteins (TRL). This study aimed to determine the effects of CETP inhibition with torcetrapib on TRL composition and apoB-48 metabolism. Study subjects with low HDL cholesterol (<40 mg/dl), either untreated (n = 9) or receiving atorvastatin 20 mg daily (n = 9), received placebo for 4 weeks, followed by torcetrapib 120 mg once daily for the next 4 weeks. A subset of the subjects not treated with atorvastatin participated in a third phase (n = 6), in which they received torcetrapib 120 mg twice daily for an additional 4 weeks. At the end of each phase, all subjects received a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine, while in the constantly fed state, to determine the kinetics of TRL apoB-48 and TRL composition. Relative to placebo, torcetrapib markedly reduced TRL CE levels in all groups (≥-69%; P < 0.005). ApoB-48 pool size (PS) and production rate (PR) decreased in the nonatorvastatin once daily (PS: -49%, P = 0.007; PR: -49%, P = 0.005) and twice daily (PS: -30%, P = 0.01; PR: -27%, P = 0.13) cohorts. In the atorvastatin cohort, apoB-48 PS and PR, which were already lowered by atorvastatin, did not change with torcetrapib. Our findings indicate that CETP inhibition reduced plasma apoB-48 concentrations by reducing apoB-48 production but did not have this effect in subjects already treated with atorvastatin.
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