Clinical review on triglycerides Laufs, Ulrich; Parhofer, Klaus G; Ginsberg, Henry N ...
European heart journal,
01/2020, Volume:
41, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
Hypertriglyceridaemia is a common clinical problem. Epidemiologic and genetic studies have established that triglyceride-rich lipoproteins (TRL) and their remnants as important contributors ...to ASCVD while severe hypertriglyceridaemia raises risk of pancreatitis. While low-density lipoprotein is the primary treatment target for lipid lowering therapy, secondary targets that reflect the contribution of TRL such as apoB and non-HDL-C are recommended in the current guidelines. Reduction of severely elevated triglycerides is important to avert or reduce the risk of pancreatitis. Here we discuss interventions for hypertriglyceridaemia, including diet and lifestyle, established treatments such as fibrates and omega-3 fatty acid preparations and emerging therapies, including various biological agents.
Insulin resistance (IR) affects not only the regulation of carbohydrate metabolism but all aspects of lipid and lipoprotein metabolism. IR is associated with increased secretion of VLDL and increased ...plasma triglycerides, as well as with hepatic steatosis, despite the increased VLDL secretion. Here we link IR with increased VLDL secretion and hepatic steatosis at both the physiologic and molecular levels. Increased VLDL secretion, together with the downstream effects on high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) size, is proatherogenic. Hepatic steatosis is a risk factor for steatohepatitis and cirrhosis. Understanding the complex inter-relationships between IR and these abnormalities of liver lipid homeostasis will provide insights relevant to new therapies for these increasing clinical problems.
Chylomicrons and very-low-density lipoproteins (VLDLs) are large, complex cargos that may require specific chaperones for efficient transport from the ER to Golgi. In this issue of Cell Metabolism, ...Wang et al. (2020) identify SURF4, in coordination with SAR1B, as an essential player in COPII transport of VLDLs from ER to Golgi, suggesting that SURF4 may be a target for approaches aimed at reducing secretion of triglyceride-rich, atherogenic lipoproteins from the liver.
Chylomicrons and very-low-density lipoproteins (VLDLs) are large, complex cargos that may require specific chaperones for efficient transport from the ER to Golgi. In this issue of Cell Metabolism, Wang et al. identify SURF4, in coordination with SAR1B, as an essential player in COPII transport of VLDLs from ER to Golgi, suggesting that SURF4 may be a target for approaches aimed at reducing secretion of triglyceride-rich, atherogenic lipoproteins from the liver.
High levels of lipoprotein(a) Lp(a), an apoB100-containing lipoprotein, are an independent and causal risk factor for atherosclerotic cardiovascular diseases through mechanisms associated with ...increased atherogenesis, inflammation, and thrombosis. Lp(a) is predominantly a monogenic cardiovascular risk determinant, with ≈70% to ≥90% of interindividual heterogeneity in levels being genetically determined. The 2 major protein components of Lp(a) particles are apoB100 and apolipoprotein(a). Lp(a) remains a risk factor for cardiovascular disease development even in the setting of effective reduction of plasma low-density lipoprotein cholesterol and apoB100. Despite its demonstrated contribution to atherosclerotic cardiovascular disease burden, we presently lack standardization and harmonization of assays, universal guidelines for diagnosing and providing risk assessment, and targeted treatments to lower Lp(a). There is a clinical need to understand the genetic and biological basis for variation in Lp(a) levels and its relationship to disease in different ancestry groups. This scientific statement capitalizes on the expertise of a diverse basic science and clinical workgroup to highlight the history, biology, pathophysiology, and emerging clinical evidence in the Lp(a) field. Herein, we address key knowledge gaps and future directions required to mitigate the atherosclerotic cardiovascular disease risk attributable to elevated Lp(a) levels.
Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice ...have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of
Pgc-1β (
Ppargc-1b), which promotes VLDL secretion, but decreased expression of
Srebp-1c (
Srebf1),
Srebp-2 (
Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.
Diabetes is now a pandemic disease. Moreover, a large number of people with prediabetes are at risk for developing frank diabetes worldwide. Both type 1 and type 2 diabetes increase the risk of ...atherosclerotic cardiovascular disease (CVD). Even with statin treatment to lower LDL cholesterol, patients with diabetes have a high residual CVD risk. Factors mediating the residual risk are incompletely characterized. An attractive hypothesis is that remnant lipoprotein particles (RLPs), derived by lipolysis from VLDL and chylomicrons, contribute to this residual risk. RLPs constitute a heterogeneous population of lipoprotein particles, varying markedly in size and composition. Although a universally accepted definition is lacking, for the purpose of this review we define RLPs as postlipolytic partially triglyceride-depleted particles derived from chylomicrons and VLDL that are relatively enriched in cholesteryl esters and apolipoprotein (apo)E. RLPs derived from chylomicrons contain apoB48, while those derived from VLDL contain apoB100. Clarity as to the role of RLPs in CVD risk is hampered by lack of a widely accepted definition and a paucity of adequate methods for their accurate and precise quantification. New specific methods for RLP quantification would greatly improve our understanding of their biology and role in promoting atherosclerosis in diabetes and other disorders.
The positive relationship between increased levels of circulating triglycerides and cardiovascular events has been observed for decades. Driven by genetic cohort studies, inhibitors of APOC3 ...(apolipoprotein C3) and ANGPTL (angiopoietin-like protein) 3 that reduce circulating triglycerides are poised to enter clinical practice. We will review the biology of how inhibition of these 2 proteins affects circulating lipoproteins as well as the current state of clinical development of monoclonal antibodies, antisense oligonucleotides, and silencing RNAs targeting APOC3 and ANGPTL3.
Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) Lp(a) is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease ...(CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.
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To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).
We assessed whether the association between LDL and ASCVD ...fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.
Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
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