Intestinal Specific LXR Activation Stimulates Reverse Cholesterol Transport and Protects from Atherosclerosis

Abstract

Several steps of the HDL-mediated reverse cholesterol transport (RCT) are transcriptionally regulated by the nuclear receptors LXRs in the macrophages, liver, and intestine. Systemic LXR activation via synthetic ligands induces RCT but also causes increased hepatic fatty acid synthesis and steatosis, limiting the potential therapeutic use of LXR agonists. During the last few years, the participation of the intestine in the control of RCT has appeared more evident. Here we show that while hepatic-specific LXR activation does not contribute to RCT, intestinal-specific LXR activation leads to decreased intestinal cholesterol absorption, improved lipoprotein profile, and increased RCT in vivo in the absence of hepatic steatosis. These events protect against atherosclerosis in the background of the LDLR-deficient mice. Our study fully characterizes the molecular and metabolic scenario that elects the intestine as a key player in the LXR-driven protective environment against cardiovascular disease.

Liver X receptors as regulators of metabolism

“…These recent results might suggest that the beneficial reduction of lipid absorption observed after LXR activation could be transitory and would question the beneficial effect of LXR activation in the intestine in a long-term treatment of lipid disorders. However, in intestine-specific LXRα activation, mice fed a high cholesterol diet, both serum and hepatic TG levels were reduced (21). All together, these results would support the beneficial effect of LXRα activation in the intestine.…”

“…LXRβ appears to be ubiquitously expressed in the intestinal mucosal epithelium, while LXRα is mostly expressed in the fully differentiated cells lining the intestinal epithelium of the colon and in the villi of the ileum (67). Importantly, overexpression of LXRα in the intestine has been shown to protect from diet-induced atherosclerosis without any side effects such as liver steatosis and increased fatty acid synthesis (21). These results would support LXRα as a key player in the intestine RCT pathway.…”

“…Recently, Lo Sasso et al (21), using mice in which there is intestinal specific LXR activation, showed that intestinal LXRα activation moderates cholesterol absorption and induces RCT as opposed to hepatic-selective LXR activation. They demonstrated that the intestinal expression of the constitutively activated form of LXRα controlled the regulation of LXR target genes involved in cholesterol metabolism in both luminal (Abcg5/8) and plasma (Abca1) compartments, resulting in an important reduction of cholesterol absorption together with an increase in pre-βHDL particles.…”

“…Liver X receptors (LXR)α (NR1H3) and β (NR1H2) are two members of the nuclear receptor (NR) family involved in multiple metabolic pathways including energy expenditure (1-3), insulin signaling (4)(5)(6), and metabolism of glucose, lipid (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and cholesterol (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). They play key roles in atherosclerosis (28,29), inflammation (7,30), and CNS development (31,32).…”

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux

“…LXR agonists including the compound T0901317 have been shown to upregulate TICE (29), but LXR agonist treatment is accompanied by significant side effects including increased TG and LDL-C levels (87). Studies involving intestinal-specific activation of LXR have demonstrated enhanced macrophage RCT and atheroprotection (88,89), but as yet the effects of intestinal-specific LXR activation have not been traced back to TICE. Bile acids and phospholipids in the intestinal lumen have been shown to stimulate the amount of cholesterol secreted via TICE (90,91).…”