Inhibiting LXRαPhosphorylation in Hematopoietic Cells Reduces Inflammation and Attenuates Atherosclerosis and Obesity

Abstract

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRa, a nuclear receptor, plays a central role in the transcription of inflammatory and lipid metabolic genes. LXRa is modulated by phosphorylation at serine 196 (LXRa pS196), however, the functional consequences of LXRa pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRa phosphorylation, bone marrow from LXRaWT and S196A mice was transplanted into Ldlr -/mice, which were fed a high fat, high cholesterol diet prior to evaluation

LXRα Phosphorylation in Cardiometabolic Disease: Insight From Mouse Models

“…Thus, expression of LXR S196A in the bone marrow significantly decreased mouse weight, total fat, pWAT, and adipocyte size in pWAT compared to WT. This phenotype was not reported in myeloidspecific S196A expressing mice in the Ldlr-KO background, suggesting that other bone marrow-derived cells in combination with macrophages are promoting this phenotype (30).…”

“…The LXRα S196A mice do not present any apparent morphological phenotype, have similar developmental growth compared to matched wild type (WT) mice, and exhibit equivalent metabolic parameters (31). These mice have been used to determine the effect of LXRα phosphorylation in vivo on various diseases, such as NAFLD (31), atherosclerosis (28), diabetes (29), and obesity (30). Their phenotypes and mechanisms are discussed below and summarized graphically in Figure 2 and the models, sex of animals, diets used and phenotypes detailed in Table 1.…”

“…In addition to macrophages, other immune cells accumulate in the arterial wall and contribute to atherosclerosis (46)(47)(48). In a complementary approach to the macrophage specific knock-in described above, Voisin et al (30) interrogated the requirement of LXRα phosphorylation on the entire cadre of immune cells expressing LXRα S196A compared to WT using a bone marrow transplantation model into the atherosclerotic-prone Ldlr-KO fed a western diet to promote plaque formation. This strategy can provide evidence for communication between immune cells types in atherosclerosis that respond to LXRα phosphorylation.…”

“…Given the pivotal role of LXR in cholesterol metabolism and inflammation and the influence of LXR pS196 on gene expression, strategies that reduce LXR pS196 could help diminish obesity. To determine the effect of LXR pS196 on diet-induced obesity, we took advantage of the bone marrow transplant model of LXRα S196A in Ldlr-KO background (30).…”

“…We have demonstrated that altering LXRα phosphorylation modifies its target gene repertoire in vitro in LXRα-overexpressing macrophage-like cell lines (22,27), and more recently in vivo in the context of cardiometabolic disease models of atherosclerosis progression (28), atherosclerosis regression and diabetes (29), obesity (30) and non-alcoholic fatty liver disease (NAFLD) (31). In this review, we discuss these recent findings and the potential of targeting LXR phosphorylation for chronic inflammatory diseases.…”