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Cellular cholesterol metabolism is subject to tight regulation to maintain adequate levels of this central lipid molecule. Herein, the sterol-responsive Liver X Receptors (LXRs) play an important role owing to their ability to reduce cellular cholesterol load. In this context, identifying the full set of LXR-regulated genes will contribute to our understanding of their role in cholesterol metabolism. Using global transcriptional analysis we report here the identification of  RNF145  as an LXR-regulated target gene. We demonstrate that RNF145 is regulated by LXRs in both human and mouse primary cells and cell lines, and  in vivo  in mice. Regulation of  RNF145  by LXR depends on a functional LXR-element in its proximal promotor. Consistent with LXR-dependent regulation of  Rnf145  we show that regulation is lost in macrophages and fibroblasts from  Lxrαβ   (-/-)   mice, and also  in vivo  in livers of  Lxrα   (-/-)   mice treated with the LXR synthetic ligand T0901317. RNF145 is closely related to RNF139/TRC8, an E3 ligase implicated in control of SREBP processing. However, silencing of  RNF145  in HepG2 or HeLa cells does not impair SREBP1/2 processing and sterol-responsive gene expression in these cells. Similar to TRC8, we demonstrate that RNF145 is localized to the ER and that it possesses intrinsic E3 ubiquitin ligase activity. In summary, we report the identification of RNF145 as an ER-resident E3 ubiquitin ligase that is transcriptionally controlled by LXR.

Identification of the ER-resident E3 ubiquitin ligase RNF145 as a novel LXR-regulated gene