NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux

NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux The liver X receptors (LXRs), LXRα (NR1H3) and LXRβ (NR1H2), are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol (Janowski BA et al. 1996). When cellular oxysterols accumulate as a result of increasing concentrations of cholesterol, NR1H2,3 induce the transcription of genes that protect cells from cholesterol overload (Zhao C & Dahlman‑Wright K 2010; Ma Z et al. 2017). In peripheral cells such as macrophages, NR1H2 and NR1H3 increase cholesterol efflux by inducing expression of ATP-binding cassette subfamily A type 1 (ABCA1), ABCG1, and apolipoprotein APOE (Jakobsson T et al. 2009; Laffitte BA et al. 2001; Mak PA et al. 2002). In the intestine, LXR agonists decrease cholesterol absorption through induction of ABCA1, ABCG5, and ABCG8 (Repa JJ et al. 2000; Back SS et al. 2013). Cholesterol removal from non-hepatic peripheral cells, such as lipid-laden macrophages, and its delivery back to the liver for catabolism and excretion are processes collectively known as reverse cholesterol transport (RCT) (Francis GA 2010; Rosenson RS et al. 2012). This Reactome module describes the activation of several direct NR1H2,3 target genes that are closely associated with the RCT pathway, including genes encoding membrane lipid transporters, such ABCA1, ABCG1, ABCG5, ABCG8 and a cluster of apolipoprotein genes APOE, APOC1, APOC2 and APOC4 (Jakobsson T et al. 2009; Back SS et al. 2013; Mak PA et al. 2002).