Current opinion in lipidology最新文献

Purpose of review: The SREBP transcription factors are master regulators of lipid homeostasis owing to their role in controlling cholesterol and fatty acid metabolism. The core machinery required to promote their trafficking and proteolytic activation has been established close to 20 years ago. In this review, we summarize the current understanding of a newly identified regulator of SREBP signaling, SPRING (formerly C12ORF49), its proposed mechanism of action, and its role in lipid metabolism.

Recent findings: Using whole-genome functional genetic screens we, and others, have recently identified SPRING as a novel regulator of SREBP signaling. SPRING is a Golgi-resident single-pass transmembrane protein that is required for proteolytic activation of SREBPs in this compartment. Mechanistic studies identified regulation of S1P, the protease that cleaves SREBPs, and control of retrograde trafficking of the SREBP chaperone SCAP from the Golgi to the ER as processes requiring SPRING. Emerging studies suggest an important role for SPRING in regulating circulating and hepatic lipid levels in mice and potentially in humans.

Summary: Current studies support the notion that SPRING is a novel component of the core SREBP-activating machinery. Additional studies are warranted to elucidate its role in cellular and systemic lipid metabolism.

Purpose of review: To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis.

Recent findings: A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy.

Summary: LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.

Purpose of review: Lipoprotein(a) [Lp(a)] is causally associated with cardiovascular diseases, and elevated levels are highly prevalent. However, there is a lack of available therapies to address Lp(a)-mediated risk. Though aspirin has progressively fallen out of favor for primary prevention, individuals with high Lp(a) may represent a high-risk group that derives a net benefit.

Recent findings: Aspirin has been demonstrated to have a clear benefit in secondary prevention of cardiovascular disease, but recent primary prevention trials have at best demonstrated a small benefit. However, individuals with elevated Lp(a) may be of high risk enough to benefit, particularly given interactions between Lp(a) and the fibrinolytic system / platelets, and the lack of available targeted medical therapies. In secondary analyses of the Women's Health Study (WHS) and the Aspirin in Reducing Events in the Elderly (ASPREE) trial, aspirin use was associated with a significant reduction in cardiovascular events in carriers of genetic polymorphisms associated with elevated Lp(a) levels. Further studies are needed, however, as these studies focused on narrower subsets of the overall population and genetic markers.

Summary: Individuals with elevated Lp(a) may benefit from aspirin therapy in primary prevention, but further study with plasma Lp(a) levels, broader populations, and randomization of aspirin are needed.

Purpose of review: LDL in its oxidized form, or 'oxLDL', is now generally acknowledged to be highly proatherogenic and to play a significant role in atherosclerotic plaque formation. Therefore, there has been increasing interest in understanding the significance of oxLDL and its receptors in different phases of atherosclerosis, leading to the accumulation of additional data at the cellular, structural, and physiological levels. This review focuses on the most recent discoveries about these receptors and how they influence lipid absorption, metabolism, and inflammation in various cell types.

Recent findings: Two crystal structures of lectin-like oxLDL receptor-1 (LOX-1), one with a small molecule inhibitor and the other with a monoclonal antibody have been published. We recently demonstrated that the 'surface site' of LOX1, adjacent to the positively charged 'basic spine region' that facilitates oxLDL binding, is a targetable site for drug development. Further, recent human studies showed that soluble LOX-1 holds potential as a biomarker for cardiovascular disease diagnosis, prognosis, and assessing the efficacy of therapy.

Summary: Receptor-mediated oxLDL uptake results in cellular dysfunction of various cell types involved in atherogenesis and plaque development. The current advancements clearly demonstrate that targeting oxLDL-LOX-1 axis may lead to development of future therapeutics for the treatment of atherosclerotic cardiovascular and cerebrovascular diseases.

Purpose of review: Pediatric dyslipidemias increase the risk of atherosclerosis and clinical cardiovascular disease and are the leading cause of morbidity and mortality. Lifestyle modifications and pharmacotherapies have measurably improved abnormal lipids and reduced cardiovascular events. The review will focus on current standards of care and investigative medications with the potential to improve cardiovascular health in children and adults.

Recent findings: Lifestyle interventions and statins remain cornerstones in the treatment of pediatric hyperlipidemias. Bile acid sequestrants and ezetimibe continue to be used in the pediatric population as well. In recent years, successful clinical trials have approved use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in children with familial hypercholesterolemia. Use of angiopoietin-like protein 3 (ANGPTL3) inhibitors is also promising as it causes marked improvement in low-density lipoprotein cholesterol with safe side effect profiles. Additional medications undergoing pediatric clinical trials include inclisiran, bempedoic acid, and lomitapide.

Summary: Recent advances in pharmacotherapy, especially for treatment of familial hypercholesterolemia, greatly impact treatment of dyslipidemias in children. Despite the overall progress in the development of these medications, therapies targeted towards treating hypertriglyceridemia have lagged behind. Continuing research for the treatment of pediatric dyslipidemias remains an important endeavor to reduce the risk of atherosclerosis and future cardiovascular events in children.

Purpose of review: The aim of this study was to highlight the current best practice for atherosclerotic cardiovascular disease (CVD) risk evaluation, including selective use of adjunctive tools for risk stratification [e.g. coronary artery calcium (CAC) scoring] and risk enhancement [e.g. lipoprotein(a) [Lp(a)], polygenic risk scoring (PRS)].

Recent findings: New studies have evaluated the efficacy of various risk assessment tools. These studies demonstrate the role of Lp(a) as a risk-enhancing factor ready for more widespread use. CAC is the gold standard method of assessing subclinical atherosclerosis, enabling true risk stratification of patients, and informing net benefit assessment for initiating or titrating lipid-lowering therapy (LLT).

Summary: Lp(a) concentration and CAC scoring, apart from the traditional risk factors, add the most value to the current CVD risk assessment approaches of all available tools, especially in terms of guiding LLT. In addition to new integrative tools such as the MESA CHD Risk Score and Coronary Age calculator, the future of risk assessment may include PRS and more advanced imaging techniques for atherosclerosis burden. Soon, polygenic risk scoring may be used to identify the age at which to begin CAC scoring, with CAC scores guiding preventive strategies.

Purpose of review: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent progressive condition that lacks a specific pharmacological treatment. ATP-citrate lyase (ACLY) is one of the emergent targets for the treatment of NAFLD. This review aims to summarize the role of ACLY in NAFLD, provide evidence of the beneficial effects of the ACLY inhibitor bempedoic acid (BemA) in NAFLD and discuss the mechanisms involved.

Recent findings: BemA is effective in reducing hepatic steatosis in several animal models that recapitulate different stages of the disease. Thus, in a dietary model of simple hepatic steatosis in female rats, BemA abrogates the accumulation of liver fat. Apart from ACLY inhibition, BemA has several functions in the liver that contribute to the antisteatotic effect: inhibition of ketohexokinase, induction of patatin-like phospholipase domain-containing protein 3 and increases in both fatty acid β-oxidation activity and hepatic H 2 S production. In models of the advanced phases of NAFLD, BemA reduces not only steatosis, but also ballooning, lobular inflammation and hepatic fibrosis, by mechanisms involving both hepatocytes and hepatic stellate cells.

Summary: BemA, an ACLY inhibitor currently approved for the treatment of hypercholesterolemia, may be a useful drug to treat NAFLD through its antisteatotic, anti-inflammatory and antifibrotic effects.

Purpose of review: Lipoprotein (a) [Lp(a)] is a likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve disease, confirmed by Mendelian randomization. With reliable assays, it has been established that Lp(a) is linearly associated with ASCVD. Current low-density lipoprotein cholesterol (LDL-C) lowering therapies do not or minimally lower Lp(a). This review focuses on the clinical importance and therapeutic consequences of Lp(a) measurement.

Recent findings: Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA, which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%.

Summary: Lp(a) should be measured in every patient at least once to identify patients with very high Lp(a) levels. These patients could benefit from Lp(a) lowering therapies when approved. In the meantime, therapy in high Lp(a) patients should focus on further reducing LDL-C and other ASCVD risk factors.

Purpose of review: To highlight critical aspects of inclisiran, from preclinical studies to current recommendations in clinical practice and future perspectives.

Recent findings: Inclisiran use has been recently approved by regulatory agencies. The evidence of its efficacy and safety makes it a promising therapeutical tool for treating dyslipidemias.

Summary: The link between LDL-cholesterol and atherosclerotic cardiovascular disease (ASCVD) is well established. Inclisiran, a small interfering RNA, has proven its safety and efficacy in reducing LDL-cholesterol, and FDA and EMA have recently approved its use. This review illustrates the development, structure, and mechanism of action of inclisiran and provides information regarding its efficacy, safety, and current recommendation in clinical practice. Moreover, it provides key information on the most recent/ongoing trials that will help us to implement the use of inclisiran in clinical practice.