Synthetic LXR ligand inhibits the development of atherosclerosis in mice

Abstract

The nuclear receptors LXR␣ and LXR␤ have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR ؊͞؊ mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE ؊͞؊ mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR ؊͞؊ and apoE ؊͞؊ mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.R ecent work has identified the nuclear receptors LXR␣ and LXR␤ as central regulators of lipid homeostasis. The physiologic ligands for these receptors are likely to be specific intermediates in the cholesterol biosynthetic pathway such as 24(S),25-epoxycholesterol (1-3). LXR␣ is expressed primarily in liver, intestine, adipose tissue, and macrophages, whereas LXR␤ is expressed in many cell types (4). In peripheral cells such as macrophages, LXRs seem to coordinate a physiologic response to cellular cholesterol loading. LXRs directly control transcription of several genes involved in the cholesterol efflux pathway, including ATP-binding cassette (ABC) A1 (5-8), ABCG1 (9), and apolipoprotein E (apoE) (10). In the intestine, ligand activation of LXR͞RXR heterodimers dramatically reduces dietary cholesterol absorption, an effect postulated to be mediated by ABCA1 (6).In the liver, LXRs seem to regulate both cholesterol and fatty acid metabolism. Mice carrying a targeted disruption of the Lxr␣ gene fail to induce transcription of the gene encoding cholesterol 7␣-hydroxylase (CYP7A1) in response to dietary cholesterol, implicating LXRs in the control of bile acid synthesis (11). Mice lacking LXR␣ were also observed to be deficient in expression of fatty acid synthase, steroyl-coA desaturase 1, acyl-coA carboxylase, and sterol regulatory element binding protein-1, suggesting an additional role in lipogenesis. This hypothesis was supported by the subsequent demonstration that the synthetic LXR ligand T1317 induces expression of lipogenic genes and raises plasma trigly...

Importance of blood cellular genomic profile in coronary heart disease

“…Our findings are in conformity with the observations: (a) statin downregulates genomic expression of PPARc and CD36 [29], and upregulates LXRa gene expression (Figure 5b)) synthetic LXRa ligands have been shown to inhibit development of atherosclerosis in mice [30]. Based on abovementioned observations, it is not unlikely that LXRa gene may be a protective mechanism against the development of coronary atherosclerosis.…”

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

“…32,48,49 In animal models of atherosclerosis, such as apolipoprotein E-deficient (apoE Ϫ/Ϫ ) and LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice, we found that LXR ligand treatment reduced the development of atherosclerosis. 34 Moreover, recent studies revealed that the LXR signaling pathway links innate immunity to macrophage cholesterol metabolism. 50 Thus, the ability of LXRs to promote reverse cholesterol transport, attenuate inflammation, and improve glucose tolerance identifies the LXR pathway as a potential target for novel therapeutic interventions in human cardiovascular disease.…”

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

“…Active LXR regulates cholesterol absorption, transport and catabolism (Venkateswaran et al ., 2000; Yu et al ., 2003). Because of its cholesterol efflux and reverse cholesterol transport stimulating properties via up‐regulation of http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=756 and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=155#791, LXR agonists are widely investigated as potential therapeutic agents for the treatment of cholesterol‐driven diseases such as atherosclerosis (Joseph et al ., 2002b; Naik et al ., 2006; Viennois et al ., 2012; Komati et al ., 2017). However, the LXR also regulates de novo hepatic lipogenesis via activation of the transcription factor sterol regulatory element‐binding protein 1c (SREBP1c) and direct interaction with hepatic lipogenic genes (Joseph et al ., 2002a; Talukdar and Hillgartner, 2006; Cha and Repa, 2007).…”