Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype

Diabetes-related factors and atherosclerosis regression

People with diabetes have an increased risk of developing cardiovascular diseases (CVD), such as heart attacks, and are more resistant to treatment. The reason could be metabolic features of diabetes. Two of those were studied : 1. High triglycerides and low good cholesterol (=HDL), and 2. The increase in a specific immune cell population (neutrophils) induced by elevated blood sugar levels. The aim of this thesis was to identify if these diabetes-related factors impair the reduction and repair of lesions (the sites were cholesterol accumulates) in the arteries, a process named atherosclerosis regression. The results show that high triglyceride levels and low HDL does not impair atherosclerosis regression, while the elevated neutrophil levels do. The latter is due to so-called neutrophil extracellular trap formation inducing inflammation in the arteries. This thesis includes studies in mice and humans and describes possible mechanisms behind our findings

Atherosclerosis Regression and Cholesterol Efflux in Hypertriglyceridemic Mice

RATIONALE: Hypertriglyceridemia (HyperTG) and low high-density lipoprotein cholesterol (HDL-C), both of which are regulated by lipoprotein lipase (LpL) activity, associate with increased cardiovascular disease (CVD). Genetic regulators of LpL actions track with CVD risk in humans. Whether this is due to changes in HDL-C or function, or circulating triglyceride (TG) levels is unresolved. OBJECTIVE: We created HyperTG and HDL-C reduction in atherosclerotic mice to allow the assessment of how HyperTG and reduced HDL-C affect regression of atherosclerosis and the phenotype of plaque macrophages. METHODS AND RESULTS: Atherosclerosis regression was studied in control LpL floxed (Lpl(fl/fl)) mice and tamoxifen-inducible whole-body LpL KO (iLpl(−/−)) mice with HyperTG (~500mg/dL) and reduced HDL-C (~50% reduction). Atherosclerosis regression was studied using two models in which advanced plaques resulting from hypercholesterolemia are exposed to normal LDL-C levels using aortic transplantation or treatments with oligonucleotides. In a subset of mice, we expressed human cholesterol ester transfer protein (hCETP) to humanize the relationship between apoB-lipoproteins and HDL. HDL particle number (HDL-P), cholesterol efflux capacity (CEC) and HDL proteome were measured in HyperTG mice and humans. Surprisingly, HyperTG and reduced HDL-C levels due to loss of LpL did not affect atherosclerosis lesion size or macrophage content (CD68+ cells) in either model. Expression of hCETP and further reduction of HDL-C did not alter lesions. Sera from iLpl(−/−) mice had a decrease in total CEC, but not ABCA1-mediated CEC. HyperTG humans, including those with LpL deficiency, had greater ABCA1-mediated CEC and total CEC per HDL-P. CONCLUSION: Atherosclerosis regression in mice is driven by LDL-C reduction and is not affected by HyperTG and plasma HDL-C levels

High-density lipoprotein cholesterol efflux capacity is not associated with atherosclerosis and prevalence of cardiovascular outcome: the CODAM study

BACKGROUND: Cholesterol Efflux Capacity (CEC) is considered to be a key atheroprotective property of high-density lipoproteins (HDL). However, the role of HDL-CEC in atherosclerosis and cardiovascular (CV) risk is still controversial, and data in individuals with diabetes are limited. OBJECTIVE: In this study, we have investigated the relationship of CEC and other HDL characteristics with clinical and subclinical atherosclerosis in subjects with elevated cardiovascular diseases (CVD) risk and Type 2 Diabetes Mellitus (T2DM). METHODS: Using multiple linear regression analyses, we determined the relationship of HDL-CEC with carotid intima-media thickness (cIMT, Z-Score), an endothelial dysfunction (EnD) Score (Z-Score), prevalent CVD (n = 150 cases) and history of CV events (CVE, n = 85 cases) in an observational cohort (CODAM, n = 574, 59.6 ± 0.3 yr, 61.3% men, 24.4% T2DM). Stratified analyses were performed to determine if the associations differed between individuals with normal glucose metabolism (NGM) and those with disturbed glucose metabolism. RESULTS: HDL-CEC was not associated with either marker of atherosclerosis (cIMT, EnD Score) nor with CVD or CVE. In contrast, other HDL characteristics that is, HDL-Cholesterol (HDL-C, Z-Score), apolipoprotein A-I (apoA-I, Z-Score), HDL size (Z-Score) and HDL particle number (HDL-P, Z-Score) were inversely and significantly associated with the EnD Score (s -0.226 to -0.097, P < .05) and CVE (ORs 0.61 to 0.68, P < .05). In stratified analyses, HDL size and HDL-P were significantly associated with the EnD Score in individuals with NGM (P$_{interaction}$ .039 and .005, respectively), but not in those with (pre)diabetes. HDL-C and apoA-I were inversely associated with prevalent CVD in individuals with (pre)diabetes (P$_{interaction}$ = .074 and .034, respectively), but not in those with NGM. CONCLUSION: HDL-CEC is not associated with clinical or subclinical atherosclerosis, neither in the whole population nor in individuals with (pre)diabetes, while other HDL characteristics show atheroprotective associations. The atheroprotective associations of HDL-size and HDL-P are lost in (pre)diabetes, while higher concentrations of HDL-C and apoA-I are associated with a lower prevalence of CVD in (pre)diabetes