Browsing by Subject "Triglycerides"

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  • Task Force Members; ESC Comm Practice Guidelines CPG; ESC Natl Cardiac Societies; Mach, Francois; Baigent, Colin; Taskinen, Marja-Riitta (2019)
  • Matikainen, Niina; Taskinen, Marja-Riitta (2020)
  • Taskinen, Marja-Riitta; Packard, Chris J.; Boren, Jan (2019)
    Purpose of ReviewApolipoprotein C-III (apoC-III) is known to inhibit lipoprotein lipase (LPL) and function as an important regulator of triglyceride metabolism. In addition, apoC-III has also more recently been identified as an important risk factor for cardiovascular disease. This review summarizes the mechanisms by which apoC-III induces hypertriglyceridemia and promotes atherogenesis, as well as the findings from recent clinical trials using novel strategies for lowering apoC-III.Recent FindingsGenetic studies have identified subjects with heterozygote loss-of-function (LOF) mutations in APOC3, the gene coding for apoC-III. Clinical characterization of these individuals shows that the LOF variants associate with a low-risk lipoprotein profile, in particular reduced plasma triglycerides. Recent results also show that complete deficiency of apoC-III is not a lethal mutation and is associated with very rapid lipolysis of plasma triglyceride-rich lipoproteins (TRL). Ongoing trials based on emerging gene-silencing technologies show that intervention markedly lowers apoC-III levels and, consequently, plasma triglyceride. Unexpectedly, the evidence points to apoC-III not only inhibiting LPL activity but also suppressing removal of TRLs by LPL-independent pathways.SummaryAvailable data clearly show that apoC-III is an important cardiovascular risk factor and that lifelong deficiency of apoC-III is cardioprotective. Novel therapies have been developed, and results from recent clinical trials indicate that effective reduction of plasma triglycerides by inhibition of apoC-III might be a promising strategy in management of severe hypertriglyceridemia and, more generally, a novel approach to CHD prevention in those with elevated plasma triglyceride.
  • Almeda-Valdes, Paloma; Cuevas-Ramos, Daniel; Mehta, Roopa; Munoz-Hernandez, Liliana; Cruz-Bautista, Ivette; Perez-Mendez, Oscar; Teresa Tusie-Luna, Maria; Gomez-Perez, Francisco J.; Pajukanta, Paivi; Matikainen, Niina; Taskinen, Marja-Riitta; Aguilar-Salinas, Carlos A. (2014)
  • Luukkonen, Panu K.; Zhou, You; Haridas, Nidhina P. A.; Dwivedi, Om P.; Hyotylainen, Tuulia; Ali, Ashfaq; Juuti, Anne; Leivonen, Marja; Tukiainen, Taru; Ahonen, Linda; Scott, Emma; Palmer, Jeremy M.; Arola, Johanna; Orho-Melander, Marju; Vikman, Petter; Anstee, Quentin M.; Olkkonen, Vesa M.; Oresic, Matej; Groop, Leif; Yki-Jarvinen, Hannele (2017)
    Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Linnaranta, O; Trontti, KT; Honkanen, J; Hovatta, I; Keinanen, J; Suvisaari, J (2021)
    he excess availability of glucose and lipids can also have an impact on the dynamics of activation and regulation of peripheral immune cellsWe aimed at understanding the correlations between peripheral metabolic state and immune system during the first year in first-episode psychosis (FEP). Patients with FEP (n = 67) and matched controls (n = 38), aged 18?40 years, were met at baseline, 2 and 12 months. Fasting peripheral blood samples were collected. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 178 candidate genes reflecting activation of the immune system. Serum triglycerides, highdensity lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol and insulin and plasma glucose (fP-Gluc) were measured. We applied Ingenuity Pathway Analysis (IPA) to visualize enrichment of genes to functional classes. Strength of positive or negative regulation of the disease and functional pathways was deduced from IPA activation Z-score at the three evaluation points. We correlated gene expression with plasma glucose, triglycerids and HDL and LDL, and used hierarchical clustering of the pairwise correlations to identify groups of genes with similar correlation patterns with metabolic markers. In patients, initially, genes associated with the innate immune system response pathways were upregulated, which decreased by 12 months. Furthermore, genes associated with apoptosis and T cell death were downregulated, and genes associated with lipid metabolism were increasingly downregulated by 12 months. The immune activation was thus an acute phase during illness onset. At baseline, after controlling for multiple testing, 31/178 genes correlated positively with fasting glucose levels, and 54/178 genes negatively with triglycerides in patients only. The gene clusters showed patterns of correlations with metabolic markers over time. The results suggest a functional link between peripheral immune system and metabolic state in FEP. Metabolic factors may have had an influence on the initial activation of the innate immune system. Future work is necessary to understand the role of metabolic state in the regulation of immune response in the early phases of psychosis.
  • Fruchart, Jean-Charles; Santos, Raul D.; Aguilar-Salinas, Carlos; Aikawa, Masanori; Al Rasadi, Khalid; Amarenco, Pierre; Barter, Philip J.; Ceska, Richard; Corsini, Alberto; Despres, Jean-Pierre; Duriez, Patrick; Eckel, Robert H.; Ezhov, Marat V.; Farnier, Michel; Ginsberg, Henry N.; Hermans, Michel P.; Ishibashi, Shun; Karpe, Fredrik; Kodama, Tatsuhiko; Koenig, Wolfgang; Krempf, Michel; Lim, Soo; Lorenzatti, Alberto J.; McPherson, Ruth; Millan Nunez-Cortes, Jesus; Nordestgaard, Borge G.; Ogawa, Hisao; Packard, Chris J.; Plutzky, Jorge; Ponte-Negretti, Carlos I.; Pradhan, Aruna; Ray, Kausik K.; Reiner, Zeljko; Ridker, Paul M.; Ruscica, Massimiliano; Sadikot, Shaukat; Shimano, Hitoshi; Sritara, Piyamitr; Stock, Jane K.; Su, Ta-Chen; Susekov, Andrey V.; Tartar, Andre; Taskinen, Marja-Riitta; Tenenbaum, Alexander; Tokgozoglu, Lale S.; Tomlinson, Brian; Tybjaerg-Hansen, Anne; Valensi, Paul; Vrablik, Michal; Wahli, Walter; Watts, Gerald F.; Yamashita, Shizuya; Yokote, Koutaro; Zambon, Alberto; Libby, Peter (2019)
    In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARM) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARM agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARM agonist safely reduces residual cardiovascular risk.
  • Fruchart, Jean-Charles; Santos, Raul D; Aguilar-Salinas, Carlos; Aikawa, Masanori; Al Rasadi, Khalid; Amarenco, Pierre; Barter, Philip J; Ceska, Richard; Corsini, Alberto; Després, Jean-Pierre; Duriez, Patrick; Eckel, Robert H; Ezhov, Marat V; Farnier, Michel; Ginsberg, Henry N; Hermans, Michel P; Ishibashi, Shun; Karpe, Fredrik; Kodama, Tatsuhiko; Koenig, Wolfgang; Krempf, Michel; Lim, Soo; Lorenzatti, Alberto J; McPherson, Ruth; Nuñez-Cortes, Jesus M; Nordestgaard, Børge G; Ogawa, Hisao; Packard, Chris J.; Plutzky, Jorge; Ponte-Negretti, Carlos I; Pradhan, Aruna; Ray, Kausik K; Reiner, Željko; Ridker, Paul M; Ruscica, Massimiliano; Sadikot, Shaukat; Shimano, Hitoshi; Sritara, Piyamitr; Stock, Jane K; Su, Ta-Chen; Susekov, Andrey V; Tartar, André; Taskinen, Marja-Riitta; Tenenbaum, Alexander; Tokgözoğlu, Lale S; Tomlinson, Brian; Tybjærg-Hansen, Anne; Valensi, Paul; Vrablík, Michal; Wahli, Walter; Watts, Gerald F; Yamashita, Shizuya; Yokote, Koutaro; Zambon, Alberto; Libby, Peter (BioMed Central, 2019)
    Abstract In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.
  • Ginsberg, Henry N.; Packard, Chris J.; Chapman, M. John; Boren, Jan; Aguilar-Salinas, Carlos A.; Averna, Maurizio; Ference, Brian A.; Gaudet, Daniel; Hegele, Robert A.; Kersten, Sander; Lewis, Gary F.; Lichtenstein, Alice H.; Moulin, Philippe; Nordestgaard, Borge G.; Remaley, Alan T.; Staels, Bart; Stroes, Erik S. G.; Taskinen, Marja-Riitta; Tokgozoglu, Lale S.; Tybjaerg-Hansen, Anne; Stock, Jane K.; Catapano, Alberico L. (2021)
    Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD. [GRAPHICS] .
  • Cui, Jing; Sun, Jianping; Wang, Wei; Yasmeen, Nafeesa; Ke, Ma; Xin, Hualei; Qiao, Qing; Ma, Aiguo; Baloch, Zulqarnain (2018)
    Background: To investigative the association of triglycerides (TG) and total cholesterol (TC) concentrations with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) in Chinese adults. Methods: The population-based cross-sectional diabetes survey was conducted in 2006 and 2009 in Qingdao, separately. 4400 participants (1 793 men and 2607 women) were include in current analysis. IFG/IGT was defined according to fasting plasma glucose (FPG) and/or 2 h post-load plasma glucose (2 h PG). Logistic regression models and areas under receiver operating characteristic curves (AUROC) were performed to estimate the associations between TG, TC levels and IFG/IGT. Results: Spearman analysis showed that serum TG and TC was independently and positively associated with FPG and 2 h PG. As compared with normoglycaemia, the odds ratio[(95% confidence intervals), OR(95% CI)] for IFG/IGT corresponding to hypertriglyceridemia (HTG) were 1.61 (1.17, 2.22) in men and 1.57(1.15, 2.14) in women for TG and accompany with Hypercholesterolemia (HTC) 1.56 (1.15, 2.13) and 1.20 (0.93, 1.54) for TC, when adjusting for confounding factor. The AUROCs of TG, TC for IFG/IGT were relatively smaller (0.50 <AUROC <0.7) in both gender. The optimal cut-offs for TG and TC was 1.61, 4.91 in men and 1.24, 5.32 in women, respectively. Conclusions: Evaluated TG in both gender and TC in men were independently associated with the present of the IFG/IGT, yet, could not be an authentic predictors of IFG/IGT in both men and women in current Chinese population.
  • Cui, Jing; Sun, Jianping; Wang, Wei; Yasmeen, Nafeesa; Ke, Ma; Xin, Hualei; Qiao, Qing; Ma, Aiguo; Baloch, Zulqarnain (BioMed Central, 2018)
    Abstract Background To investigative the association of triglycerides (TG) and total cholesterol (TC) concentrations with impaired fasting glucose/ impaired glucose tolerance (IFG/IGT) in Chinese adults. Methods The population-based cross-sectional diabetes survey was conducted in 2006 and 2009 in Qingdao, separately. 4400 participants (1 793 men and 2607 women) were include in current analysis. IFG/IGT was defined according to fasting plasma glucose (FPG) and/or 2 h post-load plasma glucose (2 h PG). Logistic regression models and areas under receiver operating characteristic curves (AUROC) were performed to estimate the associations between TG, TC levels and IFG/IGT. Results Spearman analysis showed that serum TG and TC was independently and positively associated with FPG and 2 h PG. As compared with normoglycaemia, the odds ratio[(95% confidence intervals), OR(95%CI)] for IFG/IGT corresponding to hypertriglyceridemia (HTG) were 1.61 (1. 17, 2. 22) in men and 1.57(1.15, 2.14) in women for TG and accompany with Hypercholesterolemia (HTC) 1.56 (1.15, 2.13) and 1. 20 (0.93, 1.54) for TC, when adjusting for confounding factor. The AUROCs of TG, TC for IFG/IGT were relatively smaller (0.50 < AUROC< 0. 7) in both gender. The optimal cut-offs for TG and TC was 1.61, 4.91 in men and 1. 24, 5. 32 in women, respectively. Conclusions Evaluated TG in both gender and TC in men were independently associated with the present of the IFG/IGT, yet, could not be an authentic predictors of IFG/IGT in both men and women in current Chinese population.
  • Taskinen, Marja-Riitta; Boren, Jan (2016)
    ApoC-III was discovered almost 50 years ago, but for many years, it did not attract much attention. However, as epidemiological and Mendelian randomization studies have associated apoC-III with low levels of triglycerides and decreased incidence of cardiovascular disease (CVD), it has emerged as a novel and potentially powerful therapeutic approach to managing dyslipidemia and CVD risk. The atherogenicity of apoC-III has been attributed to both direct lipoprotein lipase-mediated mechanisms and indirect mechanisms, such as promoting secretion of triglyceride-rich lipoproteins (TRLs), provoking proinflammatory responses in vascular cells and impairing LPL-independent hepatic clearance of TRL remnants. Encouraging results from clinical trials using antisense oligonucleotide, which selectively inhibits apoC-III, indicate that modulating apoC-III may be a potent therapeutic approach to managing dyslipidemia and cardiovascular disease risk.