Title: RIP140 as a novel therapeutic target in the treatment of atherosclerosis
Abstract: Reverse cholesterol transport (RCT), mediated by high-density lipoprotein (HDL), is an integral pathway that removes the excessive cellular cholesterol from peripheral tissues and delivers it to the liver for excretion in the bile and ultimately the feces [ [1] Rosenson R.S. Brewer Jr., H.B. Davidson W.S. Fayad Z.A. Fuster V. Goldstein J. et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012; 125: 1905-1919 Crossref PubMed Scopus (702) Google Scholar ]. In the first step of RCT, called cholesterol efflux, cholesterol is transported to its acceptors, lipid-depleted apolipoprotein AI (apoAI), or HDL. ATP-binding membrane cassette transporters A-1 (ABCA1) and G-1 (ABCG1) play critical roles in cholesterol efflux and protection against the foam cell formation of macrophages and the development of atherosclerosis [ [2] Yvan-Charvet L. Ranalletta M. Wang N. Han S. Terasaka N. Li R. et al. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J Clin Invest. 2007; 117: 3900-3908 Crossref PubMed Scopus (453) Google Scholar ]. The two transporters interact with different acceptors: ABCA1 and ABCG1 mediate cholesterol efflux through interaction with apoAI and HDL, respectively. The nuclear receptor liver X receptor (LXR) acts as a cholesterol sensor and induces expression of genes involved in cholesterol efflux, removing excessive intracellular cholesterol from macrophages. When activated by oxidized cholesterol metabolites (oxysterols), LXR directly binds the promoter regions of ABCA1 and ABCG1 and strongly induces the expression of these transporters [ [3] Tontonoz P. Transcriptional and posttranscriptional control of cholesterol homeostasis by liver X receptors. Cold Spring Harb Symp Quant Biol. 2011; 76: 129-137 Crossref PubMed Scopus (26) Google Scholar ]. LXR-mediated regulation of ABCA1 and ABCG1 has attracted considerable attention as the receptor and transporters may become therapeutic targets in the treatment of atherosclerosis. The athero-protective properties of several synthetic LXR ligands have been investigated for over a decade [ [4] Calkin A.C. Tontonoz P. Liver X receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010; 30: 1513-1518 Crossref PubMed Scopus (230) Google Scholar ]. Several experimental studies have demonstrated the athero-protective effects of LXR ligands. However, the activation of hepatic LXR induces lipogenesis and may cause hypertriglyceridemia and hepatic steatosis. Accordingly, new molecular strategies, to enhance peripheral LXR activity without affecting hepatic LXR, are needed. In the current issue of the Journal of Molecular and Cellular Cardiology, Dr. Wei and colleagues [ [5] Lin Y. Liu P. Adhikari N. Hall J.L. Wei L. RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J Mol Cell Cardiol. 2014; 79C: 287-294 Google Scholar ] report that receptor-interacting protein RIP140, also known as nuclear receptor-interacting protein 1 (Nrip1), functions as a novel co-repressor of LXR-induced ABCA1 and ABCG1 expression and regulates cholesterol homeostasis in macrophages.
Publication Year: 2015
Publication Date: 2015-04-01
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 3
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