We have previously reported that liver X receptor (LXR) agonist, TO901317, could significantly inhibit hepatic apolipoprotein M (apoM) expression. It has been reported that TO901317 could activate the ATP-binding cassette transporter A1 (ABCA1) that mediates cholesterol efflux to the lipid-poor apoAI, which is an essential step for the high-density lipoprotein (HDL) formation. It is unknown if ABCA1 may regulate hepatic apoM expression. In the present study, HepG2 cells were cultured with the synthetic LXR agonists, TO901317 or GW3965 in the presence or absence of ABCA1 antagonist, disodium 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS). The mRNA levels of ABCA1, apoM and liver receptor homologue-1 (LRH-1) determined by the real-time RT-PCR. It demonstrated that both TO901317 and GW3965 could significantly enhance ABCA1 expression, and simultaneously, inhibit LRH1 expression. However, TO901317 alone could significantly inhibit apoM expression, while GW3965 alone did not influence apoM expression. ABCA1 antagonist, DIDS, have no effects on GW3965 induced upregulation of ABCA1 and downregulation of LRH1. However, apoM mRNA level was significantly decreased when the cells cultured with GW3965 together with DIDS. The present study demonstrated that apoM expression could be elevated by ABCA1 via the RXR/LXR pathway and LRH1 does not involve in the regulation of apoM by the activation of ABCA1, although the direct regulative pathway(s) between ABCA1 and apoM gene is still unknown yet.The detailed mechanism needs further investigation. 4Keywords: ATP-Binding cassette transporters; Apolipoprotein M; Liver Receptor Homolog-1; Liver X receptor Apolipoprotein M (apoM), one of the most recently discovered plasma apolipoproteins, is mainly associated with high density lipoproteins (HDL), with only a small proportion located in low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles [1]. Human apoM is exclusively expressed in the hepatocytes in liver and tubular epithelial cell in kidney, and small amounts were also found in fetal liver and fetal kidney [2]. Luo, et al.,[3] demonstrated that apoM could also be abundantly expressed in human colorectal tissues, although the pathophysiological importance of this expression and if it could influence plasma apoM pool are unknown. Wolfrum, et al., [4] demonstrated that apoM, by influencing preβ-HDL formation, being an important regulator of HDL metabolism in vivo, which could influence cholesterol efflux and the susceptibility of atherosclerosis. They elucidated the molecular mechanism by which apoM affects HDL particle size and to exploit a possible new pathway for therapeutic strategies aiming to reduce the development or progression of atherosclerosis [4]. ApoM mRNA levels could be regulated by many intracellular and extracellular factors, including platelet activating factor (PAF), insulin, leptin, transforming growth factor-beta (TGF-β), epidermal growth factor (EGF), hepatic growth factor (HGF), etc., although the function of apoM is un...

BackgroundApolipoprotein M (apoM) may have potential antiatherosclerotic properties. It has been reported that apoM expression could be regulated by many intracellar and extracellar factors. In the present study we further investigated regulation of apoM expression in Caco-2 cells stimulated by a liver X receptor (LXR) agonist, TO901317.Materials and methodsCaco-2 cells were cultured in the presence of either TO901317, farnesoid X receptor (FXR) antagonist guggulsterone or TO901317 together with guggulsterone at different concentrations for 24 hrs. The mRNA levels of ATP-binding cassette transporter A1 (ABCA1), apoA1, apoM, liver receptor homologue-1 (LRH-1) and short heterodimer partner 1 (SHP1) were determined by real-time RT-PCR.ResultsWhen Caco-2 cell cultured with TO901317 alone, the mRNA levels of ABCA1, apoA1, apoM, LRH-1 and SHP1 were significantly increased with dose-dependent manners (p < 0.05), whereas when the cells cultured with guggulsterone alone, the mRNA levels of apoM, SHP1 and LRH-1 (p < 0.05) were strongly inhibited. Moreover, guggulsterone could abolish the TO901317 enhanced mRNA levels of apoA1 apoM, SHP1 and LRH-1.ConclusionThe present study demonstrated that LXR agonist TO901317 induced apoM expression in Caco-2 cells might be mediated via the LXR/FXR pathway.