Current opinion in lipidology最新文献

{"title":"The pathophysiology of excess plasma-free cholesterol.","authors":"Baiba K Gillard, Corina Rosales, Antonio M Gotto, Henry J Pownall","doi":"10.1097/MOL.0000000000000899","DOIUrl":"10.1097/MOL.0000000000000899","url":null,"abstract":"<p><strong>Purpose of review: </strong>Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol is determined as a sum of free cholesterol and cholesteryl ester, two molecules with vastly different metabolic itineraries. We examine the evidence supporting the concept that the pathological effects of elevations of plasma HDL-cholesterol are due to high levels of the free cholesterol component of HDL-C.</p><p><strong>Recent findings: </strong>In a small population of humans, a high plasma HDL-cholesterol is associated with increased mortality. Similar observations in the HDL-receptor deficient mouse (Scarb1 -/- ), a preclinical model of elevated HDL-C, suggests that the pathological component of HDL in these patients is an elevated plasma HDL-FC.</p><p><strong>Summary: </strong>Collective consideration of the human and mouse data suggests that clinical trials, especially in the setting of high plasma HDL, should measure free cholesterol and cholesteryl esters and not just total cholesterol.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":" ","pages":"278-286"},"PeriodicalIF":4.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41113506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia.","authors":"M D Reijman,&nbsp;J C Defesche,&nbsp;A Wiegman","doi":"10.1097/MOL.0000000000000863","DOIUrl":"10.1097/MOL.0000000000000863","url":null,"abstract":"<p><strong>Background: </strong>Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD). Both the heterozygous form and the very severe homozygous form can be diagnosed by genetic testing and by clinical criteria. Genetic testing can discern FH in a form caused by complete absence of the LDL-receptors, the negative variant and a form leading to reduced activity of the LDL receptors, the defective variant. The aim of this study is to provide more insight in the genotype-phenotype correlation in children and adolescents diagnosed with heterozygous FH (HeFH) and with homozygous FH (HoFH), specifically in relation to the clinical and therapeutic consequences of the negative and defective variant of FH.</p><p><strong>Methods and results: </strong>Data of 5904 children with a tentative diagnosis of FH referred to our center for genetic testing were collected. A lipid-profile was present in 3494 children, who became the study cohort. In this large cohort of children, which includes 2714 HeFH and 41 HoFH patients, it is shown that receptor negative variants are associated with significant higher LDL-C levels in HeFH patients than receptor defective variants (6.0 versus 4.9 mmol/L; p  < 0.001). A negative/negative variant is associated with a significant higher LDL-C level jn HoFH patients than a negative/defective variant, which in itself has a higher LDL-C level than a defective/defective variant. Significantly more premature CVD is present in close relatives of children with HeFH with negative variants compared to close relatives of HeFH children with defective variants (75% vs 59%; p  < 0.001).</p><p><strong>Conclusions: </strong>Performing genetic testing and identifying the type of underlying genetic variant is of added value in order to distinguish between pediatric patients with higher risks of premature CVD and to identify those that will benefit most from new types of lipid-lowering therapies. Since in children the phenotype of FH is less affected by environmental factors, the study substantiates the genotype-phenotype correlation in this large pediatric population.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":" ","pages":"287-295"},"PeriodicalIF":4.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9576177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial introductions.","authors":"","doi":"10.1097/MOL.0000000000000901","DOIUrl":"https://doi.org/10.1097/MOL.0000000000000901","url":null,"abstract":"","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":"34 6","pages":"v"},"PeriodicalIF":4.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71421637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triglyceride-rich lipoprotein cholesterol and cardiovascular risk.","authors":"Selin Bilgic, Alan T Remaley, Allan D Sniderman","doi":"10.1097/MOL.0000000000000905","DOIUrl":"10.1097/MOL.0000000000000905","url":null,"abstract":"<p><strong>Purpose of review: </strong>The triglyceride-rich apoB lipoprotein particles make up a minority of the apoB particles in plasma. They vary in size, in lipid, and in protein content. Most are small enough to enter the arterial wall and therefore most are atherogenic. But how important a contribution TRL particles make to the total risk created by the apoB lipoproteins remains controversial. A recent Mendelian randomization analysis determined that the cardiovascular risk related to the cholesterol within these apoB particles--the TRL cholesterol--was greater than--and independent of--the risk related to apoB. If correct, these observations have major clinical significance.</p><p><strong>Recent findings: </strong>Accordingly, we have analyzed these results in detail. In our view, the independent strength of the association between TRL cholesterol and apoB with cardiovascular risk seems inconsistent with the biological connections between apoB and cholesterol as integral and highly correlated constituents of apoB particles. These results are also inconsistent with other lines of evidence such as the results of the fibrate randomized clinical trials. Moreover, we are also concerned with other aspects of the analysis.</p><p><strong>Summary: </strong>We do not regard the issue as settled. However, this enquiry has led us to a fuller understanding of the determinants of the cholesterol content of the TRL apoB particles and the complex processing of cholesterol amongst the plasma lipoproteins.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":" ","pages":"259-266"},"PeriodicalIF":3.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10872610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41113507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ups and downs in PCSK9 inhibition in the cardiovascular arena: a review.","authors":"Daniel J McClintick,&nbsp;Robert P Giugliano","doi":"10.1097/MOL.0000000000000897","DOIUrl":"10.1097/MOL.0000000000000897","url":null,"abstract":"<p><strong>Purpose of review: </strong>This article reviews PCSK9 inhibitors (PCSK9i) with a focus on clinically relevant studies published in the last 18 months.</p><p><strong>Recent findings: </strong>Prespecified subgroup evaluations, secondary analyses, and open-label extension studies from the two landmark trials, FOURIER and ODYSSEY Outcomes, have provided new data on the safety and efficacy of the monoclonal PCSK9 antibodies evolocumab and alirocumab. Recent studies of PCSK9i early in ACS and post percutaneous coronary intervention have explored early effects on biomarkers and plaque morphology with various imaging modalities. Two large outcome trials with PCSK9i in lower risk patients without prior myocardial infarction or stroke are ongoing and could expand the eligible population for these potent therapies. Additionally, novel methods to inhibit PCSK9 using oral administration, vaccination, and gene therapy are in various stages of clinical development.</p><p><strong>Summary: </strong>PCSK9i represent a potent class of lipid-lowering therapies that are well tolerated and effective in a wide group of patients with high-risk atherosclerotic cardiovascular disease. Ongoing studies of PCSK9i in patients at lower risk and with acute myocardial infarction have the potential to broaden their indication. Alternative methods of PCSK9i are being evaluated and could provide easier and less expensive options for this important class of medication.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":" ","pages":"243-251"},"PeriodicalIF":4.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10030580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phospholipid transport by ABCA1: the extracellular translocase or alternating access model?","authors":"Jere P Segrest, W Sean Davidson, Jay W Heinecke","doi":"10.1097/MOL.0000000000000895","DOIUrl":"10.1097/MOL.0000000000000895","url":null,"abstract":"<p><strong>Purpose of review: </strong>ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) biogenesis and cholesterol export from artery wall cells. Recent evidence challenges the generally accepted model for lipid transport by ABCA1, termed the alternating access mechanism, which proposes that phospholipid moves from the inner leaflet to the outer leaflet of the plasma membrane.</p><p><strong>Recent findings: </strong>In contrast to the standard model, our computer simulations of ABCA1 indicate that ABCA1 extracts phospholipid from the plasma membrane's outer leaflet. The lipid then diffuses into the interior of ABCA1 to contact a structure termed the 'gateway'. A conformational change opens the gateway and forces the lipid through a ring-shaped domain, the 'annulus orifice', into the base of an elongated hydrophobic tunnel in the transporter's extracellular domain. Engineered mutations in the gateway and annulus strongly inhibited lipid export by ABCA1 without affecting cell-surface expression levels of the transporter, strongly supporting the proposed model.</p><p><strong>Summary: </strong>Our demonstration that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it into an elongated hydrophobic tunnel contrasts with the alternating access model, which flops phospholipid from the membrane's inner leaflet to its outer leaflet. These results suggest that ABCA1 is a phospholipid translocase that transports lipids by a mechanism distinct from that of other ABC transporters.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":"34 5","pages":"208-213"},"PeriodicalIF":3.8,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10199687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage inflammarafts in atherosclerosis.","authors":"Shenglin Li,&nbsp;Juliana M Navia-Pelaez,&nbsp;Soo-Ho Choi,&nbsp;Yury I Miller","doi":"10.1097/MOL.0000000000000888","DOIUrl":"10.1097/MOL.0000000000000888","url":null,"abstract":"<p><strong>Purpose of review: </strong>Advances in single cell techniques revealed a remarkable diversity in macrophage gene expression profiles in atherosclerosis. However, the diversity of functional processes at the macrophage plasma membrane remains less studied. This review summarizes recent advances in characterization of lipid rafts, where inflammatory receptors assemble, in macrophages that undergo reprogramming in atherosclerotic lesions and in vitro under conditions relevant to the development of atherosclerosis.</p><p><strong>Recent findings: </strong>The term inflammarafts refers to enlarged lipid rafts with increased cholesterol content, hosting components of inflammatory receptor complexes assembled in close proximity, including TLR4-TLR4, TLR2-TLR1 and TLR2-CD36 dimers. Macrophages decorated with inflammarafts maintain chronic inflammatory gene expression and are primed to an augmented response to additional inflammatory stimuli. In mouse atherosclerotic lesions, inflammarafts are expressed primarily in nonfoamy macrophages and less in lipid-laden foam cells. This agrees with the reported suppression of inflammatory programs in foam cells. In contrast, nonfoamy macrophages expressing inflammarafts are the major inflammatory population in atherosclerotic lesions. Discussed are emerging reports that help understand formation and persistence of inflammarafts and the potential of inflammarafts as a novel therapeutic target.</p><p><strong>Summary: </strong>Chronic maintenance of inflammarafts in nonfoamy macrophages serves as an effector mechanism of inflammatory macrophage reprogramming in atherosclerosis.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":"34 5","pages":"189-195"},"PeriodicalIF":4.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10209275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Established and potential cardiovascular risk factors in metabolic syndrome: Effect of bariatric surgery.","authors":"Bilal Bashir,&nbsp;Safwaan Adam,&nbsp;Jan H Ho,&nbsp;Zara Linn,&nbsp;Paul N Durrington,&nbsp;Handrean Soran","doi":"10.1097/MOL.0000000000000889","DOIUrl":"10.1097/MOL.0000000000000889","url":null,"abstract":"<p><strong>Purpose of review: </strong>The aim of this review was to provide an overview of the role of novel biomarkers in metabolic syndrome, their association with cardiovascular risk and the impact of bariatric surgery on these biomarkers.</p><p><strong>Recent findings: </strong>Metabolic syndrome encompasses an intricate network of health problems, and its constituents extend beyond the components of its operational definition. Obesity-related dyslipidaemia not only leads to quantitative changes in lipoprotein concentration but also alteration in qualitative composition of various lipoprotein subfractions, including HDL particles, rendering them proatherogenic. This is compounded by the concurrent existence of obstructive sleep apnoea (OSA) and nonalcoholic fatty liver disease (NAFLD), which pave the common pathway to inflammation and oxidative stress culminating in heightened atherosclerotic cardiovascular disease (ASCVD) risk. Bariatric surgery is an exceptional modality to reverse both conventional and less recognised aspects of metabolic syndrome. It reduces the burden of atherosclerosis by ameliorating the impact of obesity and its related complications (OSA, NAFLD) on quantitative and qualitative composition of lipoproteins, ultimately improving endothelial function and cardiovascular morbidity and mortality.</p><p><strong>Summary: </strong>Several novel biomarkers, which are not traditionally considered as components of metabolic syndrome play a crucial role in determining ASCVD risk in metabolic syndrome. Due to their independent association with ASCVD, it is imperative that these are addressed. Bariatric surgery is a widely recognized intervention to improve the conventional risk factors associated with metabolic syndrome; however, it also serves as an effective treatment to optimize novel biomarkers.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":"34 5","pages":"221-233"},"PeriodicalIF":4.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10199696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new SPRING in lipid metabolism.","authors":"Sebastian Hendrix,&nbsp;Noam Zelcer","doi":"10.1097/MOL.0000000000000894","DOIUrl":"10.1097/MOL.0000000000000894","url":null,"abstract":"<p><strong>Purpose of review: </strong>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.</p><p><strong>Recent findings: </strong>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.</p><p><strong>Summary: </strong>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.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":"34 5","pages":"201-207"},"PeriodicalIF":4.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10199685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis.","authors":"Arnab Chattopadhyay,&nbsp;Srinivasa T Reddy,&nbsp;Alan M Fogelman","doi":"10.1097/MOL.0000000000000890","DOIUrl":"10.1097/MOL.0000000000000890","url":null,"abstract":"<p><strong>Purpose of review: </strong>To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis.</p><p><strong>Recent findings: </strong>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.</p><p><strong>Summary: </strong>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.</p>","PeriodicalId":11109,"journal":{"name":"Current opinion in lipidology","volume":"34 5","pages":"196-200"},"PeriodicalIF":4.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10263103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}