Abstract
Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During atherogenesis, various cell types of the aorta acquire a pro-inflammatory phenotype that initiates the cascade of signaling events facilitating the formation of these foam cells. The liver X receptors (LXRs) are nuclear receptors that upon activation induce the expression of transporters responsible for promoting cholesterol efflux. In addition to promoting cholesterol removal from the arterial wall, LXRs have potent anti-inflammatory actions via the transcriptional repression of key pro-inflammatory cytokines. These beneficial functions sparked an interest in the potential to target LXRs and the development of agonists as anti-atherogenic agents. These early studies focused on mediating the contributions of macrophages to the underlying pathogenesis. However, further evidence has since demonstrated that LXRs reduce atherosclerosis through their actions in multiple cell types apart from those monocytes/macrophages that infiltrate the lesion. LXRs and their target genes have profound effects on multiple other cells types of the hematopoietic system. Furthermore, LXRs can also mediate dysfunction within vascular cell types of the aorta including endothelial and smooth muscle cells. Taken together, these studies demonstrate the whole-body benefits of LXR activation with respect to anti-atherogenesis, and that LXRs remain a viable target for the treatment of atherosclerosis, with a reach which extends beyond plaque macrophages.
Highlights
Despite recent advances in drug development, cardiovascular disease (CVD) remains the number one cause of mortality worldwide [1]
This was attributed to the induction of the newly identified liver X receptors (LXRs) target genes involved in fatty acid synthesis: acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD-1); as well as the master regulator of lipogenesis, sterol regulatory element binding factor 1c (SREBP-1c) [5,6,7]
During the early stages of atherosclerosis, defects to the endothelium allow for adhesion and infiltration of circulating leukocytes. These types of lesions are characterized as Stage I–III [13]. These changes are broadly categorized as either: endothelial dysfunction, which includes a reduction in nitric oxide production and an increase in endothelial permeability; or endothelial activation, where endothelial cells adopt a pro-inflammatory phenotype [3]
Summary
Despite recent advances in drug development, cardiovascular disease (CVD) remains the number one cause of mortality worldwide [1]. The anti-atherogenic function was attributed to their roles in macrophages to inhibit inflammation and promote reverse cholesterol transport Around this same period, LXRs were identified as inducers of lipogenesis, where agonist treatment resulted in the development of a fatty liver [5]. This was attributed to the induction of the newly identified LXR target genes involved in fatty acid synthesis: acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD-1); as well as the master regulator of lipogenesis, sterol regulatory element binding factor 1c (SREBP-1c) [5,6,7]. We will highlight new findings on the molecular role of LXRs in other hematopoietic and vascular cell types that contribute to its anti-atherosclerotic effects
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