Pharmacological activation of liver X receptor during cigarette smoke exposure adversely affects alveolar macrophages and pulmonary surfactant homeostasis

Abstract

Smoking alters pulmonary reverse lipid transport and leads to intracellular lipid accumulation in alveolar macrophages. We investigated whether stimulating reverse lipid transport with an agonist of the liver X receptor (LXR) would help alveolar macrophages limit lipid accumulation and dampen lung inflammation in response to cigarette smoke. Mice were exposed to cigarette smoke and treated intraperitoneally with the LXR agonist T0901317. Expression of lipid capture and lipid export genes was assessed in lung tissue and alveolar macrophages. Pulmonary inflammation was assessed in the bronchoalveolar lavage (BAL). Finally, cholesterol efflux capacity and pulmonary surfactant levels were determined. In room air-exposed mice, T0901317 increased the expression of lipid export genes in macrophages and the whole lung and increased cholesterol efflux capacity without inducing inflammation or affecting the pulmonary surfactant. However, cigarette smoke-exposed mice treated with T0901317 showed a marked increase in BAL neutrophils, IL-1α, C-C motif chemokine ligand 2, and granulocyte-colony-stimulating factor levels. T0901317 treatment in cigarette smoke-exposed mice failed to increase the ability of alveolar macrophages to export cholesterol and markedly exacerbated IL-1α release. Finally, T0901317 led to pulmonary surfactant depletion only in cigarette smoke-exposed mice. This study shows that hyperactivation of LXR and the associated lipid capture/export mechanisms only have minor pulmonary effects on the normal lung. However, in the context of cigarette smoke exposure, where the pulmonary surfactant is constantly oxidized, hyperactivation of LXR has dramatic adverse effects, once again showing the central role of lipid homeostasis in the pulmonary response to cigarette smoke exposure.

The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis

“…Cholesterol efflux. Cholesterol efflux assay was performed as previously described (77). Briefly, J774A.1 macrophages (ATCC, TIB-67) were grown to 70%-75% confluence in 48-well plates.…”

The effect of statins and the synthetic LXR agonist T0901317 on expression of ABCA1 transporter protein in human lung epithelial cell lines in vitro

“…It is important to note that T0901317 has affinity for both LXRα and LXRβ and newer, selective LXRβ agonists could be assessed in our in vitro model in lung epithelial cell lines. Finally, a recent in vivo study [19] pharmacological activation of LXR with T0901317 in mice exposed to cigarette smoke resulted in adverse effects related to perturbed pulmonary surfactant homeostasis. Given that surfactants are regulated by ABC transporters, selective pharmacological targeting of ABCA1 may have merit.…”

“…More recently, cigarette smoke, a major risk factor in COPD, has been shown in in vivo and in vitro studies [15][16][17] to significantly decrease ABCA1 expression resulting in impaired cholesterol efflux, exaggerated inflammatory phenotype and hallmark features of COPD. Moreover, studies are now emerging that explore the therapeutic potential of agonists directed towards Liver X Receptors (LXR) [18] to upregulate ABCA1 in an attempt to counter cigarette smoke-induced impact in the context of COPD [19].…”

Revisiting the role of pulmonary surfactant in chronic inflammatory lung diseases and environmental exposure

“…In mice exposed to cigarette smoke for 6 months, one study found that total phospholipid, cholesterol and PC levels in the BALF were decreased [91]. Conversely, after mice were acutely exposed to mainstream cigarette smoke for 4 days, no significant change in BALF PC was observed [92,93]. In another study, while rats exposed to cigarette smoke over 60 weeks showed no change in surfactant composition or total phospholipid concentration, they found that surfactant isolated from these animals exhibited impaired respreadability and reduced surface Schematic of the alveolus and pulmonary surfactant homeostasis in the context of cigarette smoke exposure and chronic obstructive pulmonary disease (COPD).…”