Current opinion in lipidology最新文献

Purpose of review: The angiopoietin-like (ANGPTL) proteins ANGPTL3 and ANGPTL4 are critical lipoprotein lipase (LPL) inhibitors. This review discusses the unique ability of the insulin-responsive protein ANGPTL8 to regulate triglyceride (TG) metabolism by forming ANGPTL3/8 and ANGPTL4/8 complexes that control tissue-specific LPL activities.

Recent findings: After feeding, ANGPTL4/8 acts locally in adipose tissue, has decreased LPL-inhibitory activity compared to ANGPTL4, and binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin, which cleaves ANGPTL4/8 and other LPL inhibitors. This enables LPL to be fully active postprandially to promote efficient fatty acid (FA) uptake and minimize ectopic fat deposition. In contrast, liver-derived ANGPTL3/8 acts in an endocrine manner, has markedly increased LPL-inhibitory activity compared to ANGPTL3, and potently inhibits LPL in oxidative tissues to direct TG toward adipose tissue for storage. Circulating ANGPTL3/8 levels are strongly correlated with serum TG, and the ANGPTL3/8 LPL-inhibitory epitope is blocked by the TG-lowering protein apolipoprotein A5 (ApoA5).

Summary: ANGPTL8 plays a crucial role in TG metabolism by forming ANGPTL3/8 and ANGPTL4/8 complexes that differentially modulate LPL activities in oxidative and adipose tissues respectively. Selective ANGPTL8 inhibition in the context of the ANGPTL3/8 complex has the potential to be a promising strategy for treating dyslipidemia.

Purpose of review: Apolipoprotein E (apoE) plays a pivotal role in lipid metabolism in the peripheral circulation and in the brain. This has been recognized for decades; however, the importance of the full spectrum of variation in the APOE gene has been less investigated. This review focusses on current progresses in this field with main focus on apoE in dyslipidemia and vascular disease.

Recent findings: Whereas ε4 is the risk increasing allele for Alzheimer disease, ε2 is associated with increased risk for age-related macular degeneration. Rare functional ε2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but recent findings suggest a simultaneous high risk of age-related macular degeneration, in line with observations for the ε2 allele.

Summary: ApoE plays an important and well established role in dyslipidemia, vascular disease, and dementia. Recent evidence from large general population studies now also suggests that apoE is involved in age-related macular degeneration. ApoE-targeted therapeutics are being developed for multiple purposes; this heralds a promising change in the approach to disease processes involving apoE. The different risk profile for dementia and age-related macular degeneration should, however, be kept in mind when developing drugs targeting mechanisms resembling these variants.

Purpose of review: Lipid droplets are increasingly recognized as distinct intracellular organelles that have functions exclusive to the storage of energetic lipids. Lipid droplets modulate macrophage inflammatory phenotype, control the availability of energy for muscle function, store excess lipid, sequester toxic lipids, modulate mitochondrial activity, and allow transfer of fatty acids between tissues.

Recent findings: There have been several major advances in our understanding of the formation, dissolution, and function of this organelle during the past two years. These include new information on movement and partition of amphipathic proteins between the cytosol and lipid droplet surface, molecular determinants of lipid droplet formation, and pathways leading to lipid droplet hydrophobic lipid formation. Rapid advances in mitochondrial biology have also begun to define differences in their function and partnering with lipid droplets to modulate lipid storage versus oxidation.

Summary: This relationship of lipid droplets biology and cellular function provides new understanding of an important cellular organelle that influences muscle function, adipose lipid storage, and diseases of lipotoxicity.

Purpose of review: Despite familial hypercholesterolemia (FH) being the most common genetic cause of cardiovascular disease (CVD), genetic testing is rarely utilized in the US. This review summarizes what is known about the clinical utility of genetic testing and its role in the diagnosis and screening of FH.

Recent findings: The presence of an FH-causative variant is associated with a substantially higher risk of CVD, even when low-density lipoprotein cholesterol (LDL-C) levels are only modestly elevated. Genetic testing can facilitate the identification of FH cases who may be missed by clinical diagnostic criteria, improve risk stratification beyond LDL-C and family history, guide treatment decisions, and improve treatment initiation and adherence. Genetic testing can be incorporated into FH screening and diagnosis algorithms, including cascade, targeted, and universal screening. Integrating genetic testing into cascade screening can enhance the effectiveness of the process. Several models of universal FH screening with coordinated genetic and lipid testing are feasible and effective.

Summary: More systematic integration of genetic testing into FH diagnosis and screening can significantly reduce the burden of this condition through early detection and treatment. Further pragmatic implementation studies are needed to determine how to more effectively and affordably integrate genetic testing into clinical lipid screening programs.

Purpose of review: Human genetics studies have sparked great interest in the pseudokinase Tribbles homolog 1, as variant at the TRIB1 gene locus were robustly linked to several cardiometabolic traits, including plasma lipids and coronary artery disease. In this review, we summarize recent findings from mouse models that investigated the function of hepatic and adipocyte Trib1 in lipid metabolism and its role in atherosclerosis.

Recent findings: Studies in atherosclerosis prone low-density lipoprotein (LDL)-receptor knockout mice suggested that systemic Trib1 -deficiency promotes atherosclerotic lesion formation through the modulation of plasma lipids and inflammation. Further, investigations in mice with hepatocyte specific deletion of Trib1 identified a novel role in the catabolism of apoB-containing lipoproteins via regulation of the LDL-receptor. Moreover, recent studies on Trib1 in adipocytes uncovered critical functions in adipose tissue biology, including the regulation of plasma lipid and adiponectin levels and the response to β3-adrenergic receptor activation.

Summary: Functional studies in mice have expanded our understanding of how Trib1 contributes to various aspects of cardiometabolic diseases. They support the notion that Trib1 exerts tissue-specific effects, which can result in opposing effects on cardiometabolic traits. Additional studies are required to fully elucidate the molecular mechanisms underlying the cellular and systemic effects of Trib1 .

Purpose of review: Cardiovascular diseases (CVD) pose a significant public health challenge, contributing to 422 million disability-adjusted life years in 2021. The role of high-density lipoproteins (HDL) and alcohol consumption, one of their major modifiable determinants, remains controversial. The objective of this review is to provide a comprehensive narrative overview of HDL functionality and its predictive value for CVD in relation to patterns of alcohol consumption.

Recent findings: HDL phenotypes beyond HDL-cholesterol (HDL-c) such as distribution of HDL subspecies, HDL particle abundance, and reverse cholesterol transport capacity are promising indicators of atherosclerotic CVD risk. Low-to-moderate alcohol consumption seems to improve HDL functionality and reduce the incidence of CVD among primarily middle-aged men and postmenopausal women. Advancements in our understanding of HDL biogenesis, structure, and function hold promise for improving HDL-related measures and their predictive value for cardiovascular health.

Summary: Low-to-moderate alcohol consumption appears to not only increase HDL-c concentration found in the HDL fraction of plasma but also enhance HDL functionality, providing insights into the underlying mechanisms linking alcohol exposure and cardiovascular health benefits. However, rigorous, well designed intervention trials of alcohol consumption on hard cardiovascular outcomes are needed to identify robust causal associations of HDL phenotypes and alcohol consumption with cardiovascular risk.

Purpose of review: This review aims to provide an in-depth perspective on the importance of diet for cardiovascular disease (CVD) prevention in heterozygous familial hypercholesterolemia (HeFH).

Recent findings: Even though data on diet and CVD prevention in HeFH are limited, the currently available evidence supports its cholesterol-lowering effect and its favorable association with CVD risk on the long-term. However, qualitative evidence from individuals with HeFH suggests that there is a common perception that diet is useless compared to medication, and this misconception serves as a barrier to healthy eating. On the other hand, evidence also suggests that individuals with HeFH are at higher risk of eating disorders compared with unaffected individuals. Family history of premature death and the chronic nature of the disease would be in cause.

Summary: Emphasizing a healthy diet needs to remain at the foundation of CVD prevention in HeFH. Evidence are limited but supportive of the cholesterol-lowering and cardioprotective potential effects of diet. Engaging in conversations about healthy dieting with individuals in HeFH is likely to help prevent misconceptions about diet. Additionally, it could help reduce the risk of eating disorders, which, altogether, is likely to improve overall CVD prevention.