Abstract The cholesteryl ester transfer protein (CETP) is a plasma protein that transfers cholesteryl esters and triglycerides between plasma lipoproteins. Humans with a genetic CETP deficiency have high plasma high density lipopoprotein cholesterol (HDL-C) levels, whereas the CETP transgene lowers plasma HDL-C levels in mice. The role of CETP in the development of atherosclerosis is unclear due to the controversial results of many human and animal studies. The present research was designed to investigate the CETP gene as a candidate gene in the regulation of plasma HDL-C levels and the development of atherosclerosis in humans. The CETP gene was screened for mutations and polymorphisms associated with these traits in a well-characterized, homogenous population sample of 515 men and women and in a sample of 115 men with low HDL-C levels and coronary heart disease (CHD). Using polymerase chain reaction and single-strand conformation polymorphism analysis (PCR-SSCP), three polymorphic sites were found (A373P, I405V, R451Q) in the exons of the CETP gene, one in intron 9 and one in the 3'untranslated region of the CETP gene. In addition, the genotypes of a functional promoter polymorphism were determined. The V405 allele was associated with lower plasma CETP activity in the whole population sample, and the Q451 allele and the P373 allele were associated with higher plasma CETP activity in men, whereas the genotypes of the promoter polymorphism were not significantly associated with plasma CETP activity. The genotypes of the CETP gene explained about 20 % of the variation of plasma CETP activity in men. The CETP gene polymorphisms were found to be a minor regulator of plasma HDL-C levels, and these associations interacted with alcohol consumption, sex and triglyceride levels. The strongest association was detected between the promoter polymorphism and HDL-C levels in women. The variation at the CETP gene locus explained about 8 % of the variation in plasma HDL-C levels in women, but less than 1 % in men. CETP gene polymorphisms (A373P, I405V and R451Q) were associated with carotid intima-media thickness, explaining about 6 % of the variation in men and 4 % in women. However, none of the polymorphisms were associated significantly with the CHD risk. In conclusion, the CETP gene was found to be polymorphic and a minor regulator of plasma HDL-C levels and the development of atherosclerosis.

L’objectif général de ce travail était de mieux définir à travers des études cliniques le rôle de l’inflammation hépatique dans l’histoire naturelle de la NAFLD. La première étude a montré que les lésions d’inflammation lobulaire ou de fibrose, même minimes, sont associées avec un risque de progression de la maladie à moyen terme. Souvent cette progression s’accompagnait d’une aggravation des facteurs de risque métabolique. La deuxième étude a démontré que les facteurs de risque métaboliques sont fréquents chez les patients avec une maladie alcoolique du foie et augmentent significativement le risque de carcinome hépatocellulaire au stade de cirrhose. Ces résultats permettent d’identifier un groupe des patients buveurs excessifs ayant un risque élevé de carcinome hépatocellulaire. La troisième étude a porté sur une cohorte transversale de plus de 5000 patients. La stéatose était un facteur associé avec la présence des lésions d’athérosclérose indépendamment des facteurs de risque cardiovasculaire classiques. Dans une cohorte de 1800 patients suivis en moyenne 8 ans, nous avons montré que la stéatose était associée à la survenue des lésions d’athérosclérose carotidienne. Ces résultats, suggèrent que la stéatose est non seulement un marqueur de risque mais un facteur qui intervient dans la pathogenèse de l’athérosclérose carotidienne. En conclusion, nos résultats suggèrent que l'inflammation hépatique, dans un contexte de stéatose contribue à la progression des lésions hépatiques, favorise l'expression de médiateurs pro-athérogènes et l’activation des voies de carcinogenèse ce qui aurait pour effet l'apparition des complications extrahépatiques chez les patients avec NAFLD. / The aim of this work was to analyze the role of chronic systemic inflammation into the natural history of NAFLD. We first undertook a study of NAFLD patients with repeat liver biopsies and demonstrated that mild lobular or portal inflammation or fibrosis in any location substantially increases the risk of progression to steatohepatitis or advanced fibrosis. Disease progression occurred concomitant with worsening of the metabolic conditions during follow-up. In the second study, we analyzed the prevalence and the impact of steatosis and metabolic risk factors on the risk of developing hepatocellular carcinoma in patients with alcoholic cirrhosis undergoing liver transplantation. The main finding of this study was that patients with advanced ALD have a high prevalence of NAFLD, and that this comorbid association confers a significantly increased risk of hepatocellular carcinoma. These findings are important for risk stratification of HCC in patients with ALD. In the third study we demonstrated that steatosis predicted carotid atherosclerosis independently of the association with classical cardiovascular risk factors. Second, in a subset of patients with longitudinal follow-up we demonstrated that baseline NAFLD was an independent predictor for incident carotid plaques. These results suggest that NAFLD is not only a marker but also an “active player” in the pathogenesis of atherosclerosis. In conclusion, our results suggests that low-grade chronic inflammation responsible for the production of pro-atherogenic cytokines and the activation of pro-oncogenic signaling pathways might be the link between liver fibrosis progression, hepatocellular carcinoma and cardiovascular risk.

L’athérosclérose est caractérisée par l’accumulation de lipides dans les artères de gros et moyen calibre. Cette accumulation est due à une série de mécanismes complexes aboutissant a une réaction inflammatoire chronique et l’accumulation de cellules spumeuse dans l’espace neointimale de la paroi vasculaire. Les complications liées à cette pathologie peuvent entraîner des événements vasculaires graves, tels que l’infarctus du myocarde ou les accidents vasculaires cérébraux. Nos travaux de recherches s’inscrivent dans le cadre de la Gutenberg Health Study, une étude de population dans la région de Mayence (Mainz) en Allemagne, dont le but est d’identifier de nouveaux marqueurs biologiques et cibles thérapeutiques liées aux maladies cardiovasculaires, avec un accent particulier sur l’athérosclérose. Nos précédents travaux ont démontré que l’expression de certains gènes dans les monocytes circulants était corrélée à la fois au tabagisme et à l’athérosclérose, ouvrant ainsi de nouvelles perspectives pour expliquer les mécanismes par lesquels le tabagisme accélère la formation des plaques d’athérosclérose. Parmi ces gènes, SASH1, un gène suppresseur de tumeur était le plus corrélé au tabagisme, tout en étant également corrélé au nombre de plaques. Un autre gène, SLC39A8, montrait la plus forte corrélation avec le nombre de plaque. Mon travail de thèse a consisté à explorer le rôle de SASH1, un gène suppresseur de tumeur, et SLC39A8, un symporteur HCO3-/ion métallique divalent, in vitro pour tenter de déterminer par quels mécanismes cellulaires et moléculaires ils pouvaient affecter la formation de la plaque d’athérosclérose. L’étude sur SASH1 porte en particulier sur la paroi vasculaire où SASH1 a été détectée dans toutes les cellules présentes (cellules endothéliales, cellules musculaires lisses, monocytes et macrophages). De plus, des mesures en RT-qPCR ont montré que l’expression de SASH1 était plus élevée dans les carotides de fumeurs que dans celles des non-fumeurs et ex-fumeurs, confirmant ainsi les observations déjà faites dans les monocytes circulants humains... / Atherosclerosis is characterized by lipids accumulation in medium and big size arteries, as the result of a complex series of mechanisms leading to chronic inflammation and accumulation of macrophage-derived foam cells in the intimal space of the vessels leading to atherosclerotic plaque formation. Rupture of the plaque can lead to life threatening events, such as myocardial infarction and stroke. Our scientific work is in the frame of the Gutenberg Health Study, a population based study in the region of Mainz in Germany, which goal is to identify new biological markers and therapeutic targets, with a particular focus on atherosclerosis. These previous studies have shown through transcriptomic analyses that a number of gene expression were correlated to both smoking and atherosclerosis, opening new perspective to better characterize mechanisms linking smoking to atherosclerosis. Among those genes SASH1, a tumor suppressor was the most correlated to smoking and was also correlated to plaques. Another gene of interest, SLC39A8 showed the strongest correlation to plaques. This thesis project aimed at exploring the role of the tumor suppressor SASH1 and the metallic ion transporter in vitro to determine the cellular and molecular mechanisms by which they could affect plaque formation during atherosclerosis...

L’athérosclérose est une pathologie chronique inflammatoire qui résulte du dérèglement d’une réaction inflammatoire non résolue ayant pour but initial d’éliminer l’accumulation excessive de lipides au niveau de l’intima. Cette élimination est exercée par les monocytes/macrophages, dont l’infiltration et l’accumulation au niveau des lésions contribue à l’inflammation chronique locale.SR-BI est un récepteur scavenger multi-fonction capable de reconnaître un large spectre de ligands allant des lipoprotéines natives et modifiées jusqu’aux endotoxines. Outre de jouer un rôle crucial dans l’homéostasie du cholestérol dans le foie, est considéré comme un PRR capable d’être impliqué dans l’immunité inné. Un nombre croissant de données suggère un rôle athéro-protecteur de SR-BI dans les cellules dérivées de la moelle osseuse et notamment dans les macrophages. La contribution de SR-BI dans les macrophages au cours de l’athérosclérose et l’identification des mécanismes sous-jacents ne sont pas élucidées. Nous avons démontré que la délétion de SR-BI dans les macrophages entraîne une accélération du développement de l’athérosclérose et une augmentation de la cellularité au sein des lésions en absence d’effet sur la cholestérolémie. Ces effets athéro-protecteurs peuvent être attribués à une diminution de l’apoptose et à une augmentation de la prolifération cellulaire au sein des plaques.Nos données suggèrent également que la diminution de la susceptibilité à l’apoptose des macrophages déficients en SR-BI pourrait impliquer la voie d’activation P38. En parallèle de cette étude, le rôle de SR-BI dans la réponse inflammatoire a été exploré dans des conditions d’endotoxémie. / Atherosclerosis is a chronic inflammatory pathology which results from an uncontrolled inflammatory reaction secondary to an abnormal accumulation of lipids in the intima. The lipid clearance is performed by monocytes/macrophages. Their infiltration and accumulation in lesions contribute/ enhance the chronic local inflammation. SR-BI is a multifunction scavenger receptor capable of recognizing and binding a large spectrum of ligands from native and modified lipoproteins to endotoxins. Besides its crucial role in cholesterol homeostasis in the liver, SR-BI is also described as a PRR. An increasing number of data suggests that SR-BI exerts an atheroprotective role in bone marrow-derived cells and in particular macrophages.The specific contribution of SR-BI in macrophages in atherosclerosis development and the identification of the underlying mechanisms have yet to be elucidated.We have demonstrated that SR-BI deletion in macrophages increases atherosclerosis development and lesion cellularity without affecting cholesterolemia. These atheroprotective effects could be explained by decreased apoptosis and increased cell proliferation in plaques.Our data also suggest that the decrease in apoptosis sensitivity in SR-BI deficient macrophages could involve the P38 MAPK and STAT1 signaling pathways.In parallel to this study, the role of SR-BI in the inflammatory response has also been explored in endotoxemia and sepsis.

Philosophiae Doctor - PhD / In this century most major medical advances have resulted in part from research on animals and non-human primates such as the African green monkey and therefore often serve as a critical link between basic research and human clinical application. Due to its close evolutionary relationship to humans, the African green monkey is known to be an excellent and most sought after models for studies of human cardiovascular disease (CVD). While the human genome project and some others related to model organisms are very well advanced or even complete, little sequence information has been acquired for the African green monkey. Given the importance of this species in biomedical research generally and CVD specifically, and the fundamental significance of sequence data, it is critical that this paucity of genome information concerning this specific animal model be addressed in order to better define the molecular basis and to further understand the mechanism of cholesterol metabolism in this species which will also contribute immensely to primatology. There is a growing interest in the role of genetic polymorphisms in predicting susceptibility to disease and responsiveness to drug interventions. Since plasma lipid abnormalities are risk factors for coronary atherosclerosis, determination of these plasma lipid concentrations, especially for genes involved in lipid transport and metabolism may be influenced by genetic variations. In this study, the African green monkey was used as a model to evaluate the effect of niacin on plasma lipids and reverse cholesterol transport by examine gene expression and the influence of several polymorphisms found in genes that are involved in cholesterol metabolism in humans. A survey of genetic variation spanning ten prioritised “candidate” genes was conducted, all of which are known to produce proteins that play key roles in the reverse cholesterol pathway (RCT), and in the homeostatic regulation of blood lipid profiles related to cardiovascular health and disease. everse transcription polymerase chain reaction (RT-PCR) was used to evaluate mRNA expression of those “candidate” genes. Twenty two coincident singlenucleotide polymorphisms (cSNPs), reported to play a vital role in RCT, were genotyped within these genes. This study’s findings implicate a subset of six of the twenty two genetic variants, spanning five “candidate” genes. To assess possible involvement of these prioritised “candidate” genes and their polymorphisms, biochemical analyses of known risk factors of coronary artery disease such as HDL-C and LDL-C were conducted. Eight healthy African green monkeys were entered in this study of which four were treated with niacin at an escalating dosage. Their mean lipid-lowering response following drug therapy was analysed, compared to those with the same genotype in a control group. Niacin treatment was associated with a considerable reduction in LDL-Cholesterol, up-regulation of HDL synthesis, and increase of apo A-1 levels. Gene expression had minimal effect on niacin treatment, except CYP7A1 which was down-regulated at the same time when considerable change in HDL-C, LDL-C and apoA-1 levels was observed. The presence of CYP7A1:Asn233Ser polymorphism may have played a critical role in metabolising niacin and influencing the up-regulation of HDL-C synthesis in the African green monkey. Although cholesterol lowering alone may explain the anti-atherosclerotic effect of niacin on HDL-C, in this study, gene expression data also shed some light in supporting the hypothesis that genetic variants may influence the expression of genes involved in RCT, which may also have played a role in the anti-atherosclerotic effect of the drug.

L’athérosclérose est une maladie inflammatoire chronique de la paroi artérielle, caractérisée par une infiltration des leucocytes consécutive à l’accumulation de lipoprotéines au sein de l’intima. Les molécules d'adhésion jouent un rôle important dans la progression de l’athérosclérose par leur implication dans l’infiltration des leucocytes au niveau du site de lésion. CD146 est une molécule d’adhésion présente sur les cellules endothéliales et sur certaines populations leucocytaires. Il a été récemment montré une augmentation de sa forme soluble lors de l’athérosclérose et de ses complications. De plus, son expression augmente au sein des plaques d’athérosclérose. En revanche, son implication dans la formation de la plaque d’athérosclérose n’a jamais été étudiée.Nous avons évalué le rôle in vivo de CD146 grâce au modèle murin APOEKO/CD146KO. Nous montrons que CD146 joue un rôle protecteur dans l’athérosclérose en inhibant la sécrétion de la chimiokine RANTES. La régulation de RANTES médiée par CD146 est dépendante de la voie VEGFR2-p38/MAPK. Dans une seconde étude, nous montrons que l’implication de CD146 dans l’athérosclérose est dépendante du régime alimentaire. Enfin dans une étude pilote, nous proposons une nouvelle stratégie thérapeutique de l’athérosclérose via l’injection de microvésicules CD146+. Nous montrons que l’apport du CD146 membranaire conduit à une réduction de RANTES, des neutrophiles circulants et de la plaque d’athérosclérose.En conclusion, l’ensemble de ces travaux apporte de nouvelles données dans la compréhension de la pathologie de l’athérosclérose en identifiant CD146 comme une nouvelle cible thérapeutique dans le traitement de l’athérosclérose. / Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the leukocyte infiltration consecutive to the accumulation of lipoproteins within the intima. Adhesion molecules play an important role in the progression of atherosclerosis since they are involved in the leukocyte infiltration at the lesion site. CD146 is an adhesion molecule detected on all endothelial cells of the vascular tree and also expressed on some subpopulations of leukocytes. Recently, few studies have shown that soluble form of CD146 is increased in atherosclerosis and its clinical complications. In addition, CD146 expression increases in atherosclerotic plaque. However, its involvement in atherosclerotic plaque formation has never been investigated. We evaluate the in vivo role of CD146 thanks to APOE KO/CD146 KO mice model. We demonstrate that CD146 plays a protective role in atherosclerosis by inhibiting the secretion of the RANTES chemokine responsible for neutrophils and monocytes recruitment within atherosclerotic plaque. RANTES regulation mediated by CD146 is dependent on VEGFR2-p38/MAPK pathway. In a second study, we show that the involvement of CD146 in atherosclerosis is dependent on the diet. Finally, in a pilot study, we propose a new therapeutic strategy for atherosclerosis through the injection of CD146 + microvesicles. We demonstrate that bringing CD146 membrane isoform through microvesicles leads to a reduction of RANTES, circulating neutrophils and atherosclerotic plaque.Overall, this work provides advances in atherosclerosis for a better understanding of its mechanisms by identifying CD146 as a new therapeutic target in the treatment of atherosclerosis.

ABCA1 is believed to affect macrophage inflammatory responses, but the mechanism by which ABCA1 may impact cytokine secretion in macrophages has yet to be fully defined. We observed that the induction of ABCA1 expression in three different cell lines, namely BHK, RAW 264.7 macrophages, and primary bone marrow derived macrophages (BMDMs), results in a significant increase in phosphorylated CREB, a known protein kinase A (PKA) substrate. In RAW macrophages, induction of ABCA1 expression by the LXR-agonist T0901317 is correlated with a decrease in LPS-stimulated secretion of proinflammatory cytokines IL-6 and TNF-α. Additionally, the secretion of anti-inflammatory cytokine IL-10 was increased upon ABCA1 induction. A similar trend was observed in BMDMS: ABCA1-expressing BMDMs released less TNF-α and more IL-10 compared to ABCA1-knockout BMDMs. We speculated that the inflammation modulating effects of ABCA1 in macrophages could be a result of PKA activation. Indeed, we found that the LXR-induced ABCA1 phenotype can be mimicked by cAMP in macrophages. 8-bromo-cAMP, a PKA activator, dose-dependently suppressed inflammatory cytokine secretion while promoting IL-10 release in the absence of ABCA1 expression. Finally, we found that the T0901317-induced ABCA1 expression is correlated with higher expression levels of MKP-1, a downstream target of PKA known to suppress inflammatory responses. Together, our results suggest that ABCA1 expression may activate PKA and CREB and that such activation may contribute to the inflammatory modulating effects of ABCA1.

Macrophage foam cells are the major culprits in atherosclerotic lesions, having a prominent role in both lesion initiation and progression. With atherosclerosis being the main factor underlying cardiovascular complications, there is a long-standing interest on finding ways to reverse lipid buildup in plaques. Studies have shown that promoting reverse cholesterol transport (RCT) from macrophage foam cells is anti-atherogenic because it alleviates the cholesterol burden of the plaques. The goal of this thesis was to gain insight into the mechanisms that govern cholesterol efflux from macrophage foam cells. The first part of this study looked at the ability of different oxysterols to promote cholesterol efflux in unloaded as compared to lipid-loaded macrophages, and our major finding here is that epoxycholesterol decreases efflux in lipid-loaded macrophages. It appears that epoxycholesterol does so by impairing the release cholesterol from its cellular storage site, the lipid droplet (LD), where it accumulates in the form of cholesteryl esters (CE). These results highlighted the importance of cholesterol release from LDs for efflux; indeed, this process is increasingly being recognized as the rate-limiting step for RCT in vivo. Subsequent experiments aimed at elucidating the mechanisms that govern LD CE hydrolysis in macrophage foam cells lead to the discovery of a novel pathway involved in cholesterol efflux. Macrophage CE hydrolysis is classically defined as being entirely dependent on neutral CE hydrolases. In the second part of this study, we demonstrate that in addition to the canonical CE hydrolases, which mediate neutral lipid hydrolysis, lysosomal acid lipase (LAL) also participates in the hydrolysis of cytoplasmic CE. Autophagy is specifically triggered in macrophages by atherogenic lipoproteins and delivers LD CE to LAL in lysosomes, thus generating free cholesterol for efflux. This autophagy-mediated cholesterol efflux is a process that is primarily dependant on the ABCA1 transporter and, importantly, is important for whole-body RCT. Overall, the studies presented in this thesis support that macrophage LD CE hydrolysis is rate-limiting for cholesterol efflux and shed light on the mechanisms of cholesterol mobilization for efflux in macrophage foam cells.

Angiotensin II (Ang II) is an important modulator for development of atherosclerosis from early stage foam cell formation to advanced stage plaque rupture. Recently, the importance of locally generated Ang II, especially in macrophages, has become more evident. Generation of Ang II by several enzymes other than ACE and renin has been shown mainly in vitro. Cathepsin G is one these enzymes which is expressed in neutrophils and macrophages. Macrophages are one of the primary and crucial cells in atherosclerotic lesions which become lipid-laden foam cells through lipoprotein uptake. We hypothesized that activation of nuclear factors in foam cells increases Ang II by modulation of the renin angiotensin system (RAS) genes and cathepsin G. We also hypothesized that cathepsin G, through its Ang II generating activity and its other catalytic functions, promotes atherosclerosis. The present study assessed the Ang I and II levels and expression of the RAS genes in THP-1 cells, a human acute monocytic leukemia cell line, and in peritoneal and bone marrow-derived macrophages after exposure to acetylated LDL (ac-LDL). I also evaluated how RAS blockade would affect foam cell formation in THP-1 cells. In parallel, I assessed the role of cathepsin G in Ang II generation and in the progression of atherosclerosis in cathepsin G heterozygous knockout mice on an Apoe-/- background (Ctsg+/-Apoe-/- mice). Ac-LDL treatment increased Ang I and Ang II levels in cell lysates and media from THP-1 cells but not in peritoneal or bone marrow-derived macrophages from wild type C57BL/6 mice. In ac-LDL-treated THP-1 cells, ACE and cathepsin G mRNA levels and activities were elevated. Angiotensinogen mRNA is increased but not the angiotensinogen protein concentration. Renin mRNA level and activity were not altered by ac-LDL treatment. Blocking RAS by an AT1 receptor blocker, ACE inhibitors or a renin inhibitor decreased cholesteryl ester content of THP-1 cells after exposure to ac-LDL. To confirm that the Ang II effect on foam cell formation was not unique to ac-LDL, we treated the THP-1 macrophages with a renin inhibitor or an AT1 receptor inhibitor after exposure to oxidized LDL (ox-LDL). RAS blockade in ox-LDL-treated cells also abolished cholesteryl ester formation. To see how Ang II plays a role in foam cell formation we assessed the effect of RAS inhibitors on SR-A, the principal receptor for mediating ac-LDL entry into the cells and on acyl-CoA:cholesterol acyl transferase (ACAT-1), the enzyme responsible for intracellular cholesterol esterification. RAS blockade in both ac-LDL- and ox-LDL-treated cells decreased SR-A and ACAT-1 protein levels. Cathepsin G partial deficiency on an Apoe-/- background did not change Ang II levels in peritoneal or bone marrow-derived macrophage cell lysates or media. This deficiency also did not affect immunoreactive angiotensin peptide levels in atherosclerotic lesions. After 8 weeks on a high fat diet Ctsg+/-Apoe-/- mice were similar to Ctsg+/+Apoe-/- mice in terms of lesion size and serum cholesterol levels but the Ctsg+/+Apoe-/- mice had more advanced lesions with more collagen and smooth muscle cells and fewer macrophages. Moreover, Ctsg+/+Apoe-/- mice had more apoptotic cells than their Ctsg+/-Apoe-/- littermates. Overall, our findings indicate that Ang II is increased in foam cells and this endogenous Ang II is involved in cholesteryl ester formation, possibly by regulating the levels of ACAT-1 and SR-A. We did not find any role for cathepsin G in generation of Ang II in mice but cathepsin G does, nevertheless, promote the progression of atherosclerotic lesions to a more advanced stage.

Introduction: Increased activation of inflammatory pathways is associated with elevated metabolic stress, which leads to a constellation of metabolic pathologies like fatty liver, insulin resistance and atherosclerosis. Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a novel transcription co-factor that binds to and inhibits two main pro-inflammatory transcription factors, IRF2 and NFAT1. IRF2BP2 genetic variants are also linked to increased human serum cholesterol level in GWAS studies. Therefore, we hypothesized that IRF2BP2 may inhibit macrophage polarization to pro-inflammatory phenotype and considering the remarkable overlap between inflammatory and metabolic sensors, alter their metabolic function. We sought to determine if specific ablation IRF2BP2 in the mouse myeloid lineage (IRF2BP2MKO) leads to development of metabolic symptoms and alters the risk of atherosclerosis. Results: Our results indicate that IRF2BP2 ablation impairs macrophage polarization to the anti-inflammatory phenotype. IRF2BP2MKO bone marrow derived macrophages (BMDM) show increased oxidized LDL-cholesterol uptake and decreased cholesterol efflux. Also, mice with specific ablation of IRF2BP2 in macrophages are more susceptible to obesity, insulin resistance and hepatic steatosis compared to control mice, when fed high fat diet (HFD). However, LDLR-/- mice transplanted with IRF2BP2MKO bone marrow demonstrate similar extent of atherosclerotic lesions compared to LDLR-/- mice transplanted with control bone marrow, reflecting increased IRF2BP2MKO macrophage apoptosis. Conclusion: In conclusion, this is the first study to identify the metabolic and inflammatory functions of IRF2BP2 protein in macrophages, with important implications in metabolic syndrome and atherosclerosis.