The agonists of liver X receptors (LXRs, NR1H2 and NR1H3) increased expression of myosin regulatory light chain interacting protein (MYLIP aka inducible degrader of the LDLR (IDOL)) in multiple cells in an LXR-dependent manner, including human liver carcinoma HepG2 cells, primary mouse hepatocytes and macrophages (Zelcer N et al. 2009; Hong C et al. 2010, Sorrentino V & Zelcer N 2012, Zhang L et al. 2012).
MYLIP (IDOL) functions as an E3 ubiquitin-protein ligase to promote ubiquitylation of the low density lipoprotein receptor (LDLR) (Zelcer N et al. 2009; Zhang et al. 2012; Scotti E et al. 2011; Sorrentino V et al. 2013 a,b). LDLR is expressed primarily in liver and removes cholesterol-carrying LDL from plasma by receptor-mediated endocytosis (Brown MS & Goldstein JL 1986). Once ubiquitylated, LDLR is rapidly removed from the plasma membrane and sorted by the ESCRT (endosomal sorting complexes required for transport) machinery toward the lysosome for degradation (Sorrentino V et al. 2013a,b; Scotti E et al. 2013). The cholesterol-sensing NR1H2 and NR1H3 can increase MYLIP expression, which in turn triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby regulating cholesterol uptake (Zelcer N et al. 2009, Sorrentino V & Zelcer N 2012, Zhang L et al. 2012).