Journal of Lipid and Atherosclerosis最新文献

{"title":"Mitochondrial Genome Editing: Exploring the Possible Relationship of the Atherosclerosis-Associated Mutation m.15059G>A With Defective Mitophagy.","authors":"Vasily N Sukhorukov, Victoria A Khotina, Vladislav A Kalmykov, Alexander D Zhuravlev, Vasily V Sinyov, Daniil Y Popov, Andrey Y Vinokurov, Igor A Sobenin, Alexander N Orekhov","doi":"10.12997/jla.2024.13.2.166","DOIUrl":"10.12997/jla.2024.13.2.166","url":null,"abstract":"<p><strong>Objective: </strong>The aim of this study was to evaluate the effect of the m.15059G>A mitochondrial nonsense mutation on cellular functions related to atherosclerosis, such as lipidosis, pro-inflammatory response, and mitophagy. Heteroplasmic mutations have been proposed as a potential cause of mitochondrial dysfunction, potentially disrupting the innate immune response and contributing to the chronic inflammation associated with atherosclerosis.</p><p><strong>Methods: </strong>The human monocytic cell line THP-1 and cytoplasmic hybrid cell line TC-HSMAM1 were used. An original approach based on the CRISPR/Cas9 system was developed and used to eliminate mitochondrial DNA (mtDNA) copies carrying the m.15059G>A mutation in the <i>MT-CYB</i> gene. The expression levels of genes encoding enzymes related to cholesterol metabolism were analyzed using quantitative polymerase chain reaction. Pro-inflammatory cytokine secretion was assessed using enzyme-linked immunosorbent assays. Mitophagy in cells was detected using confocal microscopy.</p><p><strong>Results: </strong>In contrast to intact TC-HSMAM1 cybrids, Cas9-TC-HSMAM1 cells exhibited a decrease in fatty acid synthase (<i>FASN</i>) gene expression following incubation with atherogenic low-density lipoprotein. TC-HSMAM1 cybrids were found to have defective mitophagy and an inability to downregulate the production of pro-inflammatory cytokines (to establish immune tolerance) upon repeated lipopolysaccharide stimulation. Removal of mtDNA harboring the m.15059G>A mutation resulted in the re-establishment of immune tolerance and the activation of mitophagy in the cells under investigation.</p><p><strong>Conclusion: </strong>The m.15059G>A mutation was found to be associated with defective mitophagy, immune tolerance, and impaired metabolism of intracellular lipids due to upregulation of <i>FASN</i> in monocytes and macrophages.</p>","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 2","pages":"166-183"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Relationship of Fetuin-A with Coronary Calcification, Carotid Atherosclerosis, and Mortality Risk in Non-Dialysis Chronic Kidney Disease.","authors":"Osama Nady Mohamed, Mahmoud Ragab Mohamed Mohamed, Israa Gamal Hassan, Atef Farouk Alakkad, Ashraf Othman, Amr Setouhi, Ahmed S Issa","doi":"10.12997/jla.2024.13.2.194","DOIUrl":"10.12997/jla.2024.13.2.194","url":null,"abstract":"<p><strong>Objective: </strong>This study investigated the relationship of fetuin-A with coronary calcification, carotid atherosclerosis, and mortality risk in non-dialysis chronic kidney disease (CKD).</p><p><strong>Methods: </strong>The study included 135 adult patients with CKD at stages 3-5, who were divided into coronary artery calcification (CAC) and non-CAC groups. We excluded current smokers and individuals with diabetes mellitus, inflammatory conditions, liver diseases, acute kidney failure, chronic hemodialysis, and cancer. We conducted kidney function tests, complete blood counts, and measured serum levels of fetuin-A, tumor necrosis factor-alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), total cholesterol (TC), total triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Cardiac spiral computed tomography was used to calculate the CAC score, employing the Agatston method. Carotid ultrasonography was performed to assess carotid intima-media thickness (CIMT) and to detect the presence of plaques.</p><p><strong>Results: </strong>CAC patients had considerably higher levels of TNF-α (<i>p</i><0.001), IL-6 (<i>p</i><0.001), hs-CRP (<i>p</i>=0.006), TC, TG, parathyroid hormone (PTH) (<i>p</i><0.001) and phosphorus (<i>p</i><0.001) than non-CAC patients. They also had significantly lower levels of fetuin-A (<i>p</i><0.001). Fetuin-A was considerably lower in CKD subgroups as CKD progressed. Fetuin-A (<i>p</i>=0.046), age (<i>p</i>=0.009), TNF-α (<i>p</i>=0.027), IL-6 (<i>p</i>=0.005), TG (<i>p</i>=0.002), PTH (<i>p</i>=0.002), and phosphorus (<i>p</i>=0.004) were significant predictors of CAC. CAC and fetuin-A were strong predictors of all-cause mortality and cardiovascular (CV) mortality. Fetuin-A was a significant predictor of CIMT (<i>p</i>=0.045).</p><p><strong>Conclusion: </strong>Fetuin-A reliably predicted CAC and CIMT. Fetuin-A and CAC emerged as significant risk factors for all-cause and CV mortality in non-dialysis CKD.</p>","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 2","pages":"194-211"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dyslipidemia Treatment and Cerebrovascular Disease: Evidence Regarding the Mechanism of Stroke.","authors":"Sang Hee Ha, Bum Joon Kim","doi":"10.12997/jla.2024.13.2.139","DOIUrl":"10.12997/jla.2024.13.2.139","url":null,"abstract":"<p><p>Dyslipidemia stands as a significant risk factor for stroke, on par with the impact of hypertension, diabetes, and smoking. While the role of dyslipidemia is firmly established in the context of coronary artery disease, its influence on strokes remains somewhat enigmatic. This complexity likely arises from the diverse mechanisms underpinning strokes, which encompass a heterogeneous spectrum (hemorrhagic and ischemic; large artery atherosclerosis, small vessel occlusion, cardioembolism, and etc.). The extent to which lipid-lowering treatments affect stroke outcomes may vary depending on the specific stroke subtype. For instance, in cases of large artery atherosclerosis (LAA), the optimal target level of low-density lipoprotein cholesterol (LDL-C) is relatively clear. However, when dealing with other stroke subtypes like small vessel occlusion or cardioembolism, the appropriate LDL-C target remains uncertain. Furthermore, reperfusion therapy has emerged as the foremost treatment for acute ischemic stroke. Nevertheless, the precise relationship between LDL-C levels and outcomes in patients undergoing reperfusion therapy remains shrouded in uncertainty. Consequently, we have undertaken an in-depth exploration of the existing evidence supporting the utilization of lipid-lowering medications such as statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Our objective is to elucidate their role in secondary stroke prevention and the management of dyslipidemia across the various stroke subtypes.</p>","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 2","pages":"139-154"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Letter Regarding Article, The Role of COVID-19 Vaccination for Patients With Atherosclerotic Cardiovascular Disease in the Upcoming Endemic Era.","authors":"Kye Hun Kim","doi":"10.12997/jla.2024.13.2.213","DOIUrl":"10.12997/jla.2024.13.2.213","url":null,"abstract":"","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 2","pages":"213-214"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study.","authors":"Bobby V Li, Andrew D Laurie, Nicola J Reid, Michelle A Leath, Richard I King, Huan K Chan, Chris M Florkowski","doi":"10.12997/jla.2024.13.1.29","DOIUrl":"10.12997/jla.2024.13.1.29","url":null,"abstract":"<p><strong>Objective: </strong>Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection.</p><p><strong>Methods: </strong>We identified 213 subjects with FH gene panel reports (<i>LDLR</i>, <i>APOB</i>, <i>PCSK9</i>, and <i>APOE</i>) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded.</p><p><strong>Results: </strong>A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald.</p><p><strong>Conclusion: </strong>Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.</p>","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 1","pages":"29-40"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter by In-Kyung Jeong Regarding Article, Trends in Prevalence of Hypertriglyceridemia and Related Factors in Korean Adults: A Serial Cross-Sectional Study.","authors":"In-Kyung Jeong","doi":"10.12997/jla.2024.13.1.80","DOIUrl":"10.12997/jla.2024.13.1.80","url":null,"abstract":"","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 1","pages":"80-81"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors.","authors":"Brian Tomlinson, Qian-Yan Wu, Yi-Ming Zhong, Yan-Hong Li","doi":"10.12997/jla.2024.13.1.2","DOIUrl":"10.12997/jla.2024.13.1.2","url":null,"abstract":"<p><p>Apolipoprotein C3 (apoC3) and angiopoietin-like protein 3 (ANGPTL3) inhibit lipolysis by lipoprotein lipase and may influence the secretion and uptake of various lipoproteins. Genetic studies show that depletion of these proteins is associated with improved lipid profiles and reduced cardiovascular events so it was anticipated that drugs which mimic the effects of loss-of-function mutations would be useful lipid treatments. ANGPTL3 inhibitors were initially developed as a treatment for severe hypertriglyceridaemia including familial chylomicronaemia syndrome (FCS), which is usually not adequately controlled with currently available drugs. However, it was found ANGPTL3 inhibitors were also effective in reducing low-density lipoprotein cholesterol (LDL-C) and they were studied in patients with homozygous familial hypercholesterolaemia (FH). Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies. ApoC3 can be inhibited by the ASO volanesorsen, which reduced triglycerides by >70% in patients with FCS and it was approved for FCS in Europe but not in the United States because of concerns about thrombocytopaenia. Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies.</p>","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 1","pages":"2-20"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Appreciation to Our Reviewers in the Past Year 2023.","authors":"Hyun Kang","doi":"10.12997/jla.2024.13.1.1","DOIUrl":"https://doi.org/10.12997/jla.2024.13.1.1","url":null,"abstract":"","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 1","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Journal of Lipid and Atherosclerosis</i> Update 2024.","authors":"Hyun Kang","doi":"10.12997/jla.2024.13.1.86","DOIUrl":"10.12997/jla.2024.13.1.86","url":null,"abstract":"","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 1","pages":"86-87"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Putative Pathogenic Variants of <i>ABCG5</i> and <i>ABCG8</i> of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia.","authors":"Nobuko Kojima, Hayato Tada, Akihiro Nomura, Soichiro Usui, Kenji Sakata, Kenshi Hayashi, Atsushi Nohara, Akihiro Inazu, Masa-Aki Kawashiri, Masayuki Takamura","doi":"10.12997/jla.2024.13.1.53","DOIUrl":"10.12997/jla.2024.13.1.53","url":null,"abstract":"<p><strong>Objective: </strong>Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 (<i>ABCG5</i>) or ATP-binding cassette sub-family G member 8 (<i>ABCG8</i>). There are only few data on the pathogenicity of <i>ABCG5</i> and <i>ABCG8</i>. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia.</p><p><strong>Methods: </strong>This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on <i>ABCG5</i> or <i>ABCG8</i> (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. <i>ABCG5</i> or <i>ABCG8</i> variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL.</p><p><strong>Results: </strong>Twenty-three <i>ABCG5</i> or <i>ABCG8</i> variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5-17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5-4.1] µg/mL) in 14 individuals.</p><p><strong>Conclusion: </strong>The scheme proposed for assessing the pathogenicity of genetic variations (<i>ABCG5</i> and <i>ABCG8</i>) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in <i>ABCG5</i> or <i>ABCG</i> were classified.</p>","PeriodicalId":16284,"journal":{"name":"Journal of Lipid and Atherosclerosis","volume":"13 1","pages":"53-60"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}