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1.
Efficacy of Dietary Manipulations for Depleting Intrahepatic Triglyceride Content: Implications for the Management of Non-alcoholic Fatty Liver Disease.
Sandby, K, Geiker, NRW, Dalamaga, M, Grønbæk, H, Magkos, F
Current obesity reports. 2021;(2):125-133
Abstract
PURPOSE OF REVIEW Understanding the effects of dietary manipulations on intrahepatic triglyceride (IHTG) balance will have important implications for the prevention and treatment of non-alcoholic fatty liver disease (NAFLD). RECENT FINDINGS Reducing calorie intake to induce weight loss is the most potent intervention to decrease IHTG. Carbohydrate restriction during the initial stages of weight loss may be particularly beneficial, but at later stages, the amount of weight loss predominates over diet composition. By contrast, during weight stability, restricting calories from fat seems to be optimal for depleting liver fat. The degree of dietary fat saturation and the glycemic index of the carbohydrate have inconsistent effects on IHTG. Recently, the matrix of some foods (e.g., dairy) has been inversely associated with NAFLD. Dietary macronutrients differ in their effects on liver fat depending on the energy balance and the matrix of the food in which they are consumed. Therefore, investigations into dietary approaches for managing NAFLD should shift their perspective from that of isolated nutrients to that of whole foods and diets and include useful mechanistic insights.
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2.
New Therapies for Lowering Triglyceride-Rich Lipoproteins: JACC Focus Seminar 3/4.
Rosenson, RS, Shaik, A, Song, W
Journal of the American College of Cardiology. 2021;(18):1817-1830
Abstract
Emerging evidence suggests that elevated concentrations of triglyceride-rich lipoprotein remnants (TRLs) derived from hepatic and intestinal sources contribute to the risk of atherosclerotic cardiovascular events. Natural selection studies support a causal role for elevated concentrations of remnant cholesterol and the pathways contributing to perturbations in metabolic pathways regulating TRLs with an increased risk of atherosclerotic cardiovascular disease events. New therapies targeting select catalytic pathways in TRL metabolism reduce atherosclerosis in experimental models, and concentrations of TRLs in patients with a vast range of triglyceride levels. Clinical trials with inhibitors of angiopoietin-like 3 protein and apolipoprotein C-III will be required to provide further guidance on the potential contribution of these emerging therapies in the paradigm of cardiovascular risk management in patients with elevated remnant cholesterol.
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3.
Fasting, non-fasting and postprandial triglycerides for screening cardiometabolic risk.
Keirns, BH, Sciarrillo, CM, Koemel, NA, Emerson, SR
Journal of nutritional science. 2021;:e75
Abstract
Fasting triacylglycerols have long been associated with cardiovascular disease (CVD) and other cardiometabolic conditions. Evidence suggests that non-fasting triglycerides (i.e. measured within 8 h of eating) better predict CVD than fasting triglycerides, which has led several organisations to recommend non-fasting lipid panels as the new clinical standard. However, unstandardised assessment protocols associated with non-fasting triglyceride measurement may lead to misclassification, with at-risk individuals being overlooked. A third type of triglyceride assessment, postprandial testing, is more controlled, yet historically has been difficult to implement due to the time and effort required to execute it. Here, we review differences in assessment, the underlying physiology and the pathophysiological relevance of elevated fasting, non-fasting and postprandial triglycerides. We also present data suggesting that there may be a distinct advantage of postprandial triglycerides, even over non-fasting triglycerides, for early detection of CVD risk and offer suggestions to make postprandial protocols more clinically feasible.
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4.
Changes in serum lipid levels during pregnancy in women with gestational diabetes. A narrative review.
Cibickova, L, Schovanek, J, Karasek, D
Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2021;(1):8-12
Abstract
We review current knowledge on lipid metabolism changes during pregnancy with special focus on changes in gestational diabetes. In physiological pregnancy, total plasma cholesterol, triglyceride and HDL-cholesterol level rises, the atherogenic index (LDL-cholesterol / HDL-cholesterol remains unchanged. Compared with healthy women, women with GDM show more pronounced signs of mixed dyslipidaemia - increased levels of triglyceride, changes in cholesterol and lipoprotein concentrations with a shift towards greater small dense LDL subtractions, which is typical for insulin resistance states. Dyslipidaemia, particularly hypertriglyceridemia, is thought to be one of the key drivers of foetal macrosomia and that is why measurements of plasma lipids may be valuable in detecting the metabolic abnormality in GDM and in predicting foetal outcome. Dyslipidaemia in GDM is seen as proatherogenic and potentially harmful for the baby and therefore it should be monitored more carefully.
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5.
Efficacy and Safety of Evinacumab for the Treatment of Hypercholesterolemia: A Meta-Analysis.
Jin, M, Meng, F, Yang, W, Liang, L, Wang, H, Fu, Z
Journal of cardiovascular pharmacology. 2021;(3):394-402
Abstract
Angiopoietin-like protein 3 is essential in lipid metabolism regulation. However, the efficacy and safety of evinacumab (angiopoietin-like protein 3 inhibition drug) for hypercholesterolemia treatment is unknown. In this study, a meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of evinacumab. RCTs published between January 1, 2000, and November 1, 2020, were obtained from PubMed, Embase, and Cochrane Library. All RCTs evaluating the efficacy and safety of evinacumab were included without language restrictions. Our primary end points included the percent change of low-density lipoprotein cholesterol (LDL-C) from baseline and the incidence of at least one treatment emergent adverse events including nasopharyngitis, influenza-like illness, headache, dizziness, injection-site reaction, increased aspartate aminotransferase, increased alanine aminotransferase, and any other discomfort during treatments. Percentage changes of triglycerides and high-density lipoprotein cholesterol (HDL-C) from baseline indicated secondary end points. A random-effects model was used to assess pooled data if there was moderate to high heterogeneity between studies. Four studies with 5 RCTs (568 participants) were identified. Evinacumab significantly reduced LDL-C [mean difference (MD) -33.123%, 95% confidence interval (CI), -48.639% to -17.606%, P < 0.0001], triglycerides (MD -50.959%, 95% CI, -56.555% to -45.362%, P < 0.0001), and HDL-C (MD -12.773%, 95% CI, -16.359% to -9.186%, P < 0.0001) compared with placebo. The incidence of at least 1 treatment emergent adverse events was not significantly different between evinacumab and placebo groups (relative risk 1.080, 95% CI, 0.901-1.296, P = 0.405). Evinacumab decreased triglycerides, LDL-C, and HDL-C without significant adverse effects, indicating that it can be a therapeutic strategy for hypercholesterolemia.
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6.
Metabolic basis and treatment of citrin deficiency.
Hayasaka, K
Journal of inherited metabolic disease. 2021;(1):110-117
Abstract
Citrin deficiency is a hereditary disorder caused by SLC25A13 mutations and manifests as neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Citrin is a component of the malate-aspartate nicotinamide adenine dinucleotide hydrogen (NADH) shuttle, an essential shuttle for hepatic glycolysis. Hepatic glycolysis and the coupled lipogenesis are impaired in citrin deficiency. Hepatic lipogenesis plays a significant role in fat supply during growth spurt periods: the fetal period, infancy, and puberty. Growth impairment in these periods is characteristic of citrin deficiency. Hepatocytes with citrin deficiency cannot use glucose and fatty acids as energy sources due to defects in the NADH shuttle and downregulation of peroxisome proliferator-activated receptor α (PPARα), respectively. An energy deficit in hepatocytes is considered a fundamental pathogenesis of citrin deficiency. Medium-chain triglyceride (MCT) supplementation with a lactose-restricted formula and MCT supplementation under a low-carbohydrate diet are recommended for NICCD and CTLN2, respectively. MCT supplementation therapy can provide energy to hepatocytes, promote lipogenesis, correct the cytosolic NAD+ /NADH ratio via the malate-citrate shuttle and improve ammonia detoxification, and it is a reasonable therapy for citrin deficiency. It is very important to administer MCT at a dose equivalent to the liver's energy requirements in divided doses with meals. MCT supplementation therapy is certainly promising for promoting growth spurts during infancy and adolescence and for preventing CTLN2 onset. Intravenous administration of solutions containing fructose is contraindicated, and persistent hyperglycemia should be avoided due to glucose intoxication for patients receiving hyperalimentation or with complicating diabetes.
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7.
A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions.
Tan, MSA, Honarparvar, F, Falconer, JR, Parekh, HS, Pandey, P, Siskind, DJ
Psychopharmacology. 2021;(3):615-637
Abstract
RATIONALE Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile. OBJECTIVE This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs. METHODS Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded. RESULTS A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025). CONCLUSIONS Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.
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8.
Triglyceride-Rich Lipoproteins and Their Remnants as Silent Promoters of Atherosclerotic Cardiovascular Disease and Other Metabolic Disorders: A Review.
Sascău, R, Clement, A, Radu, R, Prisacariu, C, Stătescu, C
Nutrients. 2021;(6)
Abstract
While targeting elevated serum levels of low-density lipoprotein cholesterol has been the mainstay of atherosclerosis prevention and treatment for decades, the evidence regarding the atherogenic role of hypertriglyceridemia is still controversial. Various epidemiological population-based studies on statin-treated subjects nominated triglycerides, triglyceride-rich lipoproteins (namely, chylomicrons and very-low-density lipoprotein particles), and their remnants as major determinants of the substantial residual cardiovascular risk. With the triglyceride-glucose index and triglyceride to high-density lipoprotein ratio emerging as surrogate indicators of peripheral artery disease and atherosclerotic cerebrovascular disease, one can conclude that further research addressing the intricate relationship between triglycerides and atherosclerosis is warranted. Therefore, this review aims to provide insight into the current clinical and epidemiological state of knowledge on the relationship between triglycerides and atherosclerotic cardiovascular disease. It also intends to highlight the connection between triglycerides and other metabolic disorders, including diabetes mellitus, and the potential benefits of triglyceride-lowering agents on cardiovascular outcomes and all-cause mortality.
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9.
Genetics of Triglyceride-Rich Lipoproteins Guide Identification of Pharmacotherapy for Cardiovascular Risk Reduction.
Shaik, A, Rosenson, RS
Cardiovascular drugs and therapy. 2021;(3):677-690
Abstract
OBJECTIVE Despite aggressive reduction of low-density lipoprotein cholesterol (LDL-C), there is a residual risk of cardiovascular disease (CVD). Hypertriglyceridemia is known to be associated with increased CVD risk, independently of LDL-C. Triglycerides are one component of the heterogenous class of triglyceride-rich lipoproteins (TGRLs). METHODS/RESULTS Growing evidence from biology, epidemiology, and genetics supports the contribution of TGRLs to the development of CVD via a number of mechanisms, including through proinflammatory, proapoptotic, and procoagulant pathways. CONCLUSION New genetics-guided pharmacotherapies to reduce levels of triglycerides and TGRLs and thus reduce risk of CVD have been developed and will be discussed here.
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10.
The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans.
Borén, J, Packard, CJ, Taskinen, MR
Frontiers in endocrinology. 2020;:474
Abstract
Cardiovascular disease (CVD) is the leading cause of death globally. It is well-established based on evidence accrued during the last three decades that high plasma concentrations of cholesterol-rich atherogenic lipoproteins are causatively linked to CVD, and that lowering these reduces atherosclerotic cardiovascular events in humans (1-9). Historically, most attention has been on low-density lipoproteins (LDL) since these are the most abundant atherogenic lipoproteins in the circulation, and thus the main carrier of cholesterol into the artery wall. However, with the rise of obesity and insulin resistance in many populations, there is increasing interest in the role of triglyceride-rich lipoproteins (TRLs) and their metabolic remnants, with accumulating evidence showing they too are causatively linked to CVD. Plasma triglyceride, measured either in the fasting or non-fasting state, is a useful index of the abundance of TRLs and recent research into the biology and genetics of triglyceride heritability has provided new insight into the causal relationship of TRLs with CVD. Of the genetic factors known to influence plasma triglyceride levels variation in APOC3- the gene for apolipoprotein (apo) C-III - has emerged as being particularly important as a regulator of triglyceride transport and a novel therapeutic target to reduce dyslipidaemia and CVD risk (10).