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| Open AccessStructure of dimeric lipoprotein lipase reveals a pore adjacent to the active site
LPL hydrolyzes triglycerides from lipoproteins. LPL can adopt many oligomeric forms. Here, the authors solve a 3.9 Å cryoEM structure of the previously uncharacterized LPL dimer. Key features include a C-terminal dimerization interface and a hydrophobic pore next to the active site.
- Kathryn H. Gunn
- & Saskia B. Neher
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| Open AccessMild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells
Obesity and inflammation have been associated to cancer progression. Here, the authors show that high fat and cholesterol diet, in a non-obese context, promotes tumourigenesis through increasing inflammatory monocytes and myeloid-derived pro-angiogenic factors.
- Thi Tran
- , Jean-Remi Lavillegrand
- & Stephane Potteaux
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| Open AccessDeficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)
Ectopic lipid accumulation and inflammation are the essential signs of NASH. Here, the authors show that hepatic WTAP is a key integrative repressor of ectopic lipid accumulation and inflammation during NASH progression, and hepatic deletion of Wtap promotes both of them, leading to NASH
- Xinzhi Li
- , Kaixin Ding
- & Zheng Chen
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| Open AccessSIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase
NAD + metabolism is potential target to treat metabolic disorders, in part due to the effects of the NAD + dependent enzyme Sirt1. Here the authors report that hepatic nicotinamide phosphoribosyltransferase, a rate-limiting step in the NAD + salvage pathway, regulates dark-cycle thermogenesis in a Sirt1-dependent but light-cycle thermogenesis and glucose homeostasis in a Sirt1-independent manner.
- Cassandra B. Higgins
- , Allyson L. Mayer
- & Brian J. DeBosch
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| Open AccessCaffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
Caffeine may reduce cardiovascular disease risk, but the underlying mechanisms for these effects are incompletely understood. Here the authors report that caffeine inhibits the activation of the transcription factor SREBP2 to promote LDLc clearance through the PCSK9-LDLR axis.
- Paul F. Lebeau
- , Jae Hyun Byun
- & Richard C. Austin
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Article
| Open AccessMMAB promotes negative feedback control of cholesterol homeostasis
The mechanisms governing cholesterol homeostasis remain incompletely understood. Here, the authors develop an integrative genomic strategy to identify MMAB, and enzyme in the adenosylcobalamin pathway, as a regulator of hepatic LDLR activity and cholesterol biosynthesis.
- Leigh Goedeke
- , Alberto Canfrán-Duque
- & Carlos Fernández-Hernando
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| Open AccessRole of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels
Diverse macrophage subsets are found in adipose tissue where they regulate its physiology. Here, the authors used single-cell RNA sequencing to analyse the effect of post-prandial lipids on adipose tissue macrophages and identify Tim4 as a regulator of ABCA1+ macrophage function and post-prandial cholesterol transport.
- M. S. Magalhaes
- , P. Smith
- & C. Bénézech
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| Open AccessA multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids
Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.
- Min-A Jhun
- , Michael Mendelson
- & Themistocles L. Assimes
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| Open AccessTissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice
CRISPR-Cas9 is a gene editing tool that can be used to modulate gene expression. Here, the authors report the generation of a mouse model that express all components of the CRISPR-Cas9 guide directed Synergistic Activation Mediator (SAM), demonstrate that gene activation can be achieved with various delivery methods and include generation of a disease model of hypercholesterolemia
- Charleen Hunt
- , Suzanne A. Hartford
- & Guochun Gong
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| Open AccessFasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patients
Nutritional modification including fasting has been shown to reduce cardiometabolic risk linked to western diet. Here the authors show implementation of fasting resulted in alterations to the intestinal microbiota, and circulating immune cells, improving blood pressure and body weight in patients with metabolic syndrome.
- András Maifeld
- , Hendrik Bartolomaeus
- & Sofia K. Forslund
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Article
| Open AccessMembrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis
Elevated plasma LDL cholesterol levels increase the risk of atherosclerotic cardiovascular disease. Here, the authors show that inhibition of MT1-MMP reduces plasma LDL cholesterol levels and the risk of atherosclerosis, indicating the potential of MT1-MMP inhibition as a lipid-lowering therapy.
- Adekunle Alabi
- , Xiao-Dan Xia
- & Da-Wei Zhang
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| Open AccessScavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr−/− mice
Hypercholesterolemia is associated with lipid peroxidation induced reactive dicarbonyl adducts. Here the authors show that the dicarbonyl scavenger, 2-hydroxybenzylamine(2-HOBA), decreases reactive dicarbonyl modifications of LDL and HDL, improves HDL function, reduces atherosclerosis and promotes features of stable plaques in a mouse model of hypercholestrolemia.
- Huan Tao
- , Jiansheng Huang
- & MacRae F. Linton
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Article
| Open AccessCollaborative interactions of heterogenous ribonucleoproteins contribute to transcriptional regulation of sterol metabolism in mice
Heterogeneous nuclear ribonucleoproteins (hnRNPs) play critical roles in the biogenesis, localization and transport of RNA. Here authors investigate a role for hnRNPs in sterol metabolism in mice and provide insights into their role in selective promoter activation.
- Zhengyi Zhang
- , An-Chieh Feng
- & Tamer Sallam
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| Open AccessMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration
Sleep duration is associated with an adverse lipid profile. Here, the authors perform genome-wide gene-by-sleep interaction analysis and find 49 previously unreported lipid loci when considering short or long total sleep time.
- Raymond Noordam
- , Maxime M. Bos
- & Susan Redline
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| Open AccessXX sex chromosome complement promotes atherosclerosis in mice
Men and women differ in their risk of developing coronary artery disease, in part due to differences in their levels of sex hormones. Here, AlSiraj et al. show that the XX sex genotype regulates lipid metabolism and promotes atherosclerosis independently of sex hormones in mice.
- Yasir AlSiraj
- , Xuqi Chen
- & Lisa A. Cassis
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| Open AccessLiver-target nanotechnology facilitates berberine to ameliorate cardio-metabolic diseases
Berberine has lipid-lowering effects and other metabolic benefits, but it presents with poor bioavailability. Here the authors conjugate berberine to liver-targeting nanoparticles, and show increased accumulation of berberine in the liver, improved metabolic profiles and reduced atherosclerotic plaques in mice.
- Hui-Hui Guo
- , Chen-Lin Feng
- & Jian-Dong Jiang
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| Open AccessMulti-ancestry study of blood lipid levels identifies four loci interacting with physical activity
GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.
- Tuomas O. Kilpeläinen
- , Amy R. Bentley
- & Ruth J. F. Loos
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| Open AccessDiscovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol
Accumulated HMG-CoA reductase (HMGCR) limits the cholesterol-lowering effect of statins via a feedback loop. Here the authors developed a compound that degrades HMGCR, thus decreasing cholesterol levels and reducing atherosclerotic plaques.
- Shi-You Jiang
- , Hui Li
- & Bao-Liang Song
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| Open AccessRNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors
Repression of gene transcription using CRISPR-Cas9 has been achieved in vitro but not for delivery into adult animal models. Here, the authors use AAV8 to deliver the transcriptional repressor dSaCas9KRAB to the cholesterol regulator Pcsk9, and show repression up to 24 weeks and reduced cholesterol levels in mice.
- Pratiksha I. Thakore
- , Jennifer B. Kwon
- & Charles A. Gersbach
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| Open AccessHyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis
Atherosclerosis is characterized by subendothelial lipid retention believed to be the result of endothelial trancytosis. Here, the authors show that endothelium can take up and process LDL, generating cholesterol crystals that are deposited on the basolateral side of the cells, causing their dysfunction that can be prevented by forskolin/rolipram treatment.
- Yvonne Baumer
- , Sara McCurdy
- & William A. Boisvert
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| Open AccessHeparan sulfate proteoglycans present PCSK9 to the LDL receptor
PCSK9 interacts with LDL receptor, causing its degradation, and consequently reduces the clearance of LDL. Here, Gustafsen et al. show that PCSK9 interacts with heparan sulfate proteoglycans and this binding favors LDLR degradation. Pharmacological inhibition of this binding can be exploited as therapeutic intervention to lower LDL levels.
- Camilla Gustafsen
- , Ditte Olsen
- & Simon Glerup
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| Open AccessRetinol saturase coordinates liver metabolism by regulating ChREBP activity
Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP.
- Steffi Heidenreich
- , Nicole Witte
- & Michael Schupp
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Article
| Open AccessSaturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2
The free fatty acid-mediated inflammatory activities are regulated through TLR4. Here the authors show that palmitic acid binds to MD2, initiating complex formation with TLR4, recruitment of MyD88, and subsequent activation of pro-inflammatory molecules, and that MD2 blockade protects against diet-induced cardiac dysfunction.
- Yi Wang
- , Yuanyuan Qian
- & Guang Liang
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Article
| Open AccessGlobal and hepatocyte-specific ablation of Bmal1 induces hyperlipidaemia and enhances atherosclerosis
Bmal1 is a key transcription factor that controls rhythmicity of diverse biological functions. Here, Pan et al. show that Bmal1 deficiency in mice increases lipoprotein secretion and reduces cholesterol excretion to bile, and decipher the molecular mechanisms underlying hyperlipidaemia and atherosclerosis promoted by the lack of Bmal1.
- Xiaoyue Pan
- , Christopher A. Bradfield
- & M. Mahmood Hussain
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| Open AccessAn imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques
Atherosclerosis progression is linked to inflammatory processes in the blood vessel wall. Here, the authors show that, with the progression of atherosclerosis, the resolution of inflammation is impaired as the result of an imbalance between specialized pro-resolving lipid mediators and leukotrienes.
- Gabrielle Fredman
- , Jason Hellmann
- & Ira Tabas
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| Open AccessExome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese
An important risk factor for coronary artery disease is the level of blood lipids. Here the authors conduct an exome-wide association study in Chinese cohorts and identify three novel loci associated with lipid levels as well as three Asian-specific variants in known loci.
- Clara S. Tang
- , He Zhang
- & Wei Gao
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Article |
The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice
Retnla is an adipokine with known roles in tissue repair and inflammation. Here Lee et al. show that Retnla also promotes cholesterol metabolism and excretion, thereby lowering blood cholesterol levels and reducing the development of atherosclerosis in mice.
- Mi-Ran Lee
- , Chae-ji Lim
- & Goo Taeg Oh
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| Open AccessAmerindian-specific regions under positive selection harbour new lipid variants in Latinos
Dyslipidemia and obesity have a high prevalence in populations with Amerindian backgrounds, such as Mexican–Americans. Here, the authors design an approach to identify Amerindian risk genes in Mexicans and identify five genomic loci, which include RORA and SIK3that may contribute to the risk of dyslipidemia and obesity in Amerindian populations.
- Arthur Ko
- , Rita M. Cantor
- & Päivi Pajukanta