Abstract
Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.
Document Type
Article
Publication Date
10-25-2017
Digital Object Identifier (DOI)
https://doi.org/10.7554/eLife.28766
Funding Information
This work was supported by NIH grants HL030568 and DK063491 (to PT) and American Heart Association Scientist Development Grant 16SDG31180008 (to LZ). Funding provided by the Howard Hughes Medical Institute (to PT), and National Heart, Lung, and Blood Institute grants HL088528 and HL111932 (to RT).
Related Content
Transparent reporting form DOI: https://doi.org/10.7554/eLife.28766.014
Major datasets: LXRa LXRb Macrophage ChiP-seq, publicly available at NCBI Gene Expression Omnibus (accession no: GSE10 4027).
Repository Citation
Zhang, Li; Rajbhandari, Prashant; Priest, Christina; Sandhu, Jaspreet; Wu, Xiaohui; Temel, Ryan E.; Castrillo, Antonio; de Aguiar Vallim, Thomas Q.; Sallam, Tamer; and Tontonoz, Peter, "Inhibition of Cholesterol Biosynthesis Through RNF145-Dependent Ubiquitination of SCAP" (2017). Saha Cardiovascular Research Center Faculty Publications. 36.
https://uknowledge.uky.edu/cvrc_facpub/36
Transparent reporting form
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Cardiology Commons, Cell and Developmental Biology Commons, Circulatory and Respiratory Physiology Commons, Physiological Processes Commons
Notes/Citation Information
Published in eLife, v. 6, e28766, p. 1-20.
© 2017, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.