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RIP140 as a novel therapeutic target in the treatment of atherosclerosis
Journal of Molecular and Cellular Cardiology 81 (2015) 136–138
Contents lists available at ScienceDirect
Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Editorial
RIP140 as a novel therapeutic target in the treatment of atherosclerosis
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]. 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]. 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]. 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]. 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] report that receptor-interacting protein RIP140, also known as nuclear receptor-interacting protein 1 (Nrip1), functions as a novel corepressor of LXR-induced ABCA1 and ABCG1 expression and regulates cholesterol homeostasis in macrophages. RIP140 was originally identified as a transcriptional cofactor that interacts with estrogen receptors. It suppresses the transcriptional activity of these receptors in humans [6] and acts as a corepressor of testicular receptor 2 in mice [7]. Subsequent studies have revealed that RIP140 is expressed mainly in metabolic tissues such as the liver, adipose tissue, and skeletal muscle. It binds and represses a number of other nuclear receptors including peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptors (ERRs) [8]. However, recent studies have suggested that RIP140 could function not only as a transcriptional co-repressor but also as a coactivator, regulating the processes of lipid metabolism and inflammation. The metabolic function of RIP140 has been primarily reported in the adipose tissue. RIP140 null mice have low fat accumulation and increased resistance to high-fat diet-induced obesity [9]. The following study shows that RIP140 is involved in oxidative metabolism and mitochondrial biogenesis in the adipose tissue
http://dx.doi.org/10.1016/j.yjmcc.2015.02.009 0022-2828/© 2015 Elsevier Ltd. All rights reserved.
[10]. Other studies have shown that RIP140 directly binds to the promoter region of uncoupling protein 1 (UCP-1) and negatively regulates its expression [11]. RIP140 also suppresses the oxidative metabolism in the skeletal muscle [12]. Hepatic RIP140 acts both as a corepressor and coactivator of LXR. For instance, RIP140 is required for LXR-dependent repression of phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the first rate-limiting step in gluconeogenesis [13]. In contrast, RIP140 acts as a co-activator of LXR, inducing a transcription factor, sterol-regulatory element binding protein (SREBP)-1c, which regulates fatty acid and triglyceride synthesis. These results suggest that the hepatic RIP140 suppresses gluconeogenesis but stimulates lipogenesis. Notably, recent studies have revealed a role of RIP140 in inflammatory responses in macrophages [14,15]. RIP140 binds the NF-κB subunit RelA and enhances inflammatory responses by upregulating the target genes such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 [14]. Furthermore, Dr. Wei's group has recently demonstrated that lipopolysaccharide (LPS) triggers the degradation of RIP140, leading to the reduction of proinflammatory cytokine production and resolution of inflammatory responses, and increasing the tolerance to endotoxin shock [15]. In the current issue, Dr. Wei and colleagues reported that RIP140 suppressed the expression of ABCA1 and ABCG1 in macrophages; thus, affecting the cholesterol homeostasis. The shRNA-mediated knockdown of RIP140 in mouse peritoneal macrophages resulted in elevated expression of ABCA1 and ABCG1, increased cholesterol efflux, and decreased modified low-density lipoprotein (LDL)-induced cholesterol accumulation. In contrast, overexpression of RIP140 reduced the expression of ABCA1 and ABCG1 and promoted modified LDL-induced cholesterol accumulation. It is known that RIP140 activity is regulated by posttranscriptional modifications such as phosphorylation, lysine acetylation, and lysine methylation. The authors have previously reported that extracellular signal-related kinase 2 (ERK2) stimulates Tyr204 phosphorylation of RIP140, leading to its lysine acetylation in RIP140 and consequently enhancing its gene-repression activity [16–19]. The current study found that modified LDL promoted lysine acetylation in RIP140 via ERK2 phosphorylation and enhanced the binding of RIP140 to the LXR response element on the promoters of ABCA1 and ABCG1. The authors have previously reported another mechanism by which modified LDL enhances the expression of RIP140. They have found that cholesterol-responsive microRNA miR-33 negatively regulates RIP140 expression by directly binding its 3′-UTR in macrophages [20]. Because miR-33 is encoded in the intron of cholesterol sensitive transcription factor SREBP-2, it is upregulated in response to cholesterol depletion caused by statin treatment. In contrast, downregulation of miR-33 as well as upregulation of RIP140 are observed in cholesterol-loaded macrophages. The role of miR-33 was not investigated in the current
Editorial
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Fig. 1. The role of RIP140 in LXR-mediated cholesterol efflux in macrophages. Modified LDL induces LXR-mediated expression of ABCA1 and ABCG1, and consequently promotes cholesterol efflux from macrophages. Three possible mechanisms of LXR regulation have been postulated. 1. LXR is activated by cholesterol metabolites (oxysterols). 2. RIP140 expression is elevated by reducing miR-33 expression, and elevated RIP140 inhibits LXR activity. 3. RIP140 activity is enhanced by ERK2-stimulated lysine acetylation.
study and its contribution to the RIP140/LXR regulatory pathway remains unclear. The expression and activity of RIP140 may be elevated in the macrophages treated with modified LDL, and thus repress the cholesterol efflux. The authors investigated the role of macrophage RIP140 in the development of atherosclerosis by crossing apoE-null mice with mice transgenic for RIP140-targeted shRNA under the CD68 promoter. They showed that macrophage-specific RIP140 knockdown ameliorated high-cholesterol diet-induced progression of atherosclerosis, with a concurrent increase in the expression of ABCA1 and ABCG1. The reduction of RIP140 expression in the macrophages also suppressed the expression of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, as well as adhesion molecules, including ICAM-1, and VCAM-1, in the aortic root. Macrophage-specific RIP140 knockdown did not affect the plasma lipid profile. The study by Dr. Wei's group clearly demonstrates that the macrophage RIP140 plays an important role in the regulation of cholesterol efflux. The suppression of this transcription cofactor could prevent atherosclerosis. Although both LXR and RIP140 may be activated in cholesterol-loaded macrophages, these two transcription factors have distinct effects on cholesterol efflux (Fig. 1). LXR is activated by cholesterol metabolites (oxysterols) and directly induces the expression of ABCA1 and ABCG1. In contrast, RIP140 is elevated or activated in macrophages treated with modified LDL, and inhibits LXR-induced ABCA1 and ABCG1 expression. Although ligand-dependent LXR activation is considered a potential therapeutic approach in the prevention of atherosclerosis, some adverse effects, such as hypertriglyceridemia and hepatic steatosis, have been reported. The RIP140-targeted approaches may avoid the drawbacks of ligand dependent LXR activation. In contrast to ligand-dependent LXR activation, it is likely that systemic inhibition of
RIP140 activity would repress the atherogenic transcription factor SREBP-1c in hepatocytes [13,21], while promoting cholesterol efflux in the peripheral tissues. However, there is a report suggesting that RIP140 acts as a corepressor of LXR in the liver [22]. The report has shown that specific RIP140 knockdown in the liver by an adenoviral vector increases SREBP-1c expression in fasting mice. In summary, cholesterol efflux promoted by LXR-mediated induction of ABCA1 and ABCG1 has been thought to be a potential therapeutic target in the treatment of atherosclerosis. The study by Dr. Wei and colleagues identified RIP140 as a corepressor of LXR in induction of ABCA1 and ABCG1. These findings would be valuable because suppression of RIP140 could be a novel approach to enhance cholesterol efflux. To date, no known compound can specifically modulate RIP140 activity; screening for such compounds becomes one of the priorities in the field. Improved understanding of the molecular mechanisms underlying the regulation of RIP140 will also help to develop RIP140-targeted therapeutic approaches. Acknowledgments MT is supported by grants from the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for Next Generation World-Leading Researchers (NEXT Program, LS107),” initiated by the Council for Science and Technology Policy (CSTP). TK is supported by the JSPS through the “Grant-in-Aid for Young Scientists (B) (Grant Number: 26860699)”. Disclosure statement None.
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References [1] Rosenson RS, Brewer Jr HB, Davidson WS, Fayad ZA, Fuster V, Goldstein J, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 2012;125:1905–19. [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;117:3900–8. [3] Tontonoz P. Transcriptional and posttranscriptional control of cholesterol homeostasis by liver X receptors. Cold Spring Harb Symp Quant Biol 2011;76:129–37. [4] Calkin AC, Tontonoz P. Liver X receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:1513–8. [5] Lin Y, Liu P, Adhikari N, Hall JL, Wei L. RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J Mol Cell Cardiol 2014;79C:287–94. [6] Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, et al. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J 1995; 14:3741–51. [7] Lee CH, Chinpaisal C, Wei LN. Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Mol Cell Biol 1998;18:6745–55. [8] Nautiyal J, Christian M, Parker MG. Distinct functions for RIP140 in development, inflammation, and metabolism. Trends Endocrinol Metab 2013;24:451–9. [9] Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S, Bell J, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci U S A 2004;101: 8437–42. [10] Powelka AM, Seth A, Virbasius JV, Kiskinis E, Nicoloro SM, Guilherme A, et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J Clin Invest 2006;116:125–36. [11] Kiskinis E, Hallberg M, Christian M, Olofsson M, Dilworth SM, White R, et al. RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes. EMBO J 2007;26:4831–40. [12] Seth A, Steel JH, Nichol D, Pocock V, Kumaran MK, Fritah A, et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab 2007;6:236–45. [13] Herzog B, Hallberg M, Seth A, Woods A, White R, Parker MG. The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor. Mol Endocrinol 2007; 21:2687–97. [14] Zschiedrich I, Hardeland U, Krones-Herzig A, Berriel Diaz M, Vegiopoulos A, Muggenburg J, et al. Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine gene expression. Blood 2008;112:264–76.
[15] Ho PC, Tsui YC, Feng X, Greaves DR, Wei LN. NF-kappaB-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol 2012;13:379–86. [16] Huq MD, Wei LN. Post-translational modification of nuclear co-repressor receptorinteracting protein 140 by acetylation. Mol Cell Proteomics 2005;4:975–83. [17] Huq MD, Ha SG, Barcelona H, Wei LN. Lysine methylation of nuclear co-repressor receptor interacting protein 140. J Proteome Res 2009;8:1156–67. [18] Mostaqul Huq MD, Gupta P, Wei LN. Post-translational modifications of nuclear corepressor RIP140: a therapeutic target for metabolic diseases. Curr Med Chem 2008; 15:386–92. [19] Ho PC, Gupta P, Tsui YC, Ha SG, Huq M, Wei LN. Modulation of lysine acetylationstimulated repressive activity by Erk2-mediated phosphorylation of RIP140 in adipocyte differentiation. Cell Signal 2008;20:1911–9. [20] Ho PC, Chang KC, Chuang YS, Wei LN. Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production. FASEB J 2011; 25:1758–66. [21] Karasawa T, Takahashi A, Saito R, Sekiya M, Igarashi M, Iwasaki H, et al. Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2011;31:1788–95. [22] Berriel Diaz M, Krones-Herzig A, Metzger D, Ziegler A, Vegiopoulos A, Klingenspor M, et al. Nuclear receptor cofactor receptor interacting protein 140 controls hepatic triglyceride metabolism during wasting in mice. Hepatology 2008;48:782–91.
Tadayoshi Karasawa Masafumi Takahashi⁎ Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan ⁎Corresponding author at: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Tel.: +81 285 58 7446; fax: +81 285 44 5365. E-mail addresses: [email protected]. 13 January 2015
Contents lists available at ScienceDirect
Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Editorial
RIP140 as a novel therapeutic target in the treatment of atherosclerosis
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]. 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]. 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]. 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]. 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] report that receptor-interacting protein RIP140, also known as nuclear receptor-interacting protein 1 (Nrip1), functions as a novel corepressor of LXR-induced ABCA1 and ABCG1 expression and regulates cholesterol homeostasis in macrophages. RIP140 was originally identified as a transcriptional cofactor that interacts with estrogen receptors. It suppresses the transcriptional activity of these receptors in humans [6] and acts as a corepressor of testicular receptor 2 in mice [7]. Subsequent studies have revealed that RIP140 is expressed mainly in metabolic tissues such as the liver, adipose tissue, and skeletal muscle. It binds and represses a number of other nuclear receptors including peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptors (ERRs) [8]. However, recent studies have suggested that RIP140 could function not only as a transcriptional co-repressor but also as a coactivator, regulating the processes of lipid metabolism and inflammation. The metabolic function of RIP140 has been primarily reported in the adipose tissue. RIP140 null mice have low fat accumulation and increased resistance to high-fat diet-induced obesity [9]. The following study shows that RIP140 is involved in oxidative metabolism and mitochondrial biogenesis in the adipose tissue
http://dx.doi.org/10.1016/j.yjmcc.2015.02.009 0022-2828/© 2015 Elsevier Ltd. All rights reserved.
[10]. Other studies have shown that RIP140 directly binds to the promoter region of uncoupling protein 1 (UCP-1) and negatively regulates its expression [11]. RIP140 also suppresses the oxidative metabolism in the skeletal muscle [12]. Hepatic RIP140 acts both as a corepressor and coactivator of LXR. For instance, RIP140 is required for LXR-dependent repression of phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the first rate-limiting step in gluconeogenesis [13]. In contrast, RIP140 acts as a co-activator of LXR, inducing a transcription factor, sterol-regulatory element binding protein (SREBP)-1c, which regulates fatty acid and triglyceride synthesis. These results suggest that the hepatic RIP140 suppresses gluconeogenesis but stimulates lipogenesis. Notably, recent studies have revealed a role of RIP140 in inflammatory responses in macrophages [14,15]. RIP140 binds the NF-κB subunit RelA and enhances inflammatory responses by upregulating the target genes such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 [14]. Furthermore, Dr. Wei's group has recently demonstrated that lipopolysaccharide (LPS) triggers the degradation of RIP140, leading to the reduction of proinflammatory cytokine production and resolution of inflammatory responses, and increasing the tolerance to endotoxin shock [15]. In the current issue, Dr. Wei and colleagues reported that RIP140 suppressed the expression of ABCA1 and ABCG1 in macrophages; thus, affecting the cholesterol homeostasis. The shRNA-mediated knockdown of RIP140 in mouse peritoneal macrophages resulted in elevated expression of ABCA1 and ABCG1, increased cholesterol efflux, and decreased modified low-density lipoprotein (LDL)-induced cholesterol accumulation. In contrast, overexpression of RIP140 reduced the expression of ABCA1 and ABCG1 and promoted modified LDL-induced cholesterol accumulation. It is known that RIP140 activity is regulated by posttranscriptional modifications such as phosphorylation, lysine acetylation, and lysine methylation. The authors have previously reported that extracellular signal-related kinase 2 (ERK2) stimulates Tyr204 phosphorylation of RIP140, leading to its lysine acetylation in RIP140 and consequently enhancing its gene-repression activity [16–19]. The current study found that modified LDL promoted lysine acetylation in RIP140 via ERK2 phosphorylation and enhanced the binding of RIP140 to the LXR response element on the promoters of ABCA1 and ABCG1. The authors have previously reported another mechanism by which modified LDL enhances the expression of RIP140. They have found that cholesterol-responsive microRNA miR-33 negatively regulates RIP140 expression by directly binding its 3′-UTR in macrophages [20]. Because miR-33 is encoded in the intron of cholesterol sensitive transcription factor SREBP-2, it is upregulated in response to cholesterol depletion caused by statin treatment. In contrast, downregulation of miR-33 as well as upregulation of RIP140 are observed in cholesterol-loaded macrophages. The role of miR-33 was not investigated in the current
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Fig. 1. The role of RIP140 in LXR-mediated cholesterol efflux in macrophages. Modified LDL induces LXR-mediated expression of ABCA1 and ABCG1, and consequently promotes cholesterol efflux from macrophages. Three possible mechanisms of LXR regulation have been postulated. 1. LXR is activated by cholesterol metabolites (oxysterols). 2. RIP140 expression is elevated by reducing miR-33 expression, and elevated RIP140 inhibits LXR activity. 3. RIP140 activity is enhanced by ERK2-stimulated lysine acetylation.
study and its contribution to the RIP140/LXR regulatory pathway remains unclear. The expression and activity of RIP140 may be elevated in the macrophages treated with modified LDL, and thus repress the cholesterol efflux. The authors investigated the role of macrophage RIP140 in the development of atherosclerosis by crossing apoE-null mice with mice transgenic for RIP140-targeted shRNA under the CD68 promoter. They showed that macrophage-specific RIP140 knockdown ameliorated high-cholesterol diet-induced progression of atherosclerosis, with a concurrent increase in the expression of ABCA1 and ABCG1. The reduction of RIP140 expression in the macrophages also suppressed the expression of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, as well as adhesion molecules, including ICAM-1, and VCAM-1, in the aortic root. Macrophage-specific RIP140 knockdown did not affect the plasma lipid profile. The study by Dr. Wei's group clearly demonstrates that the macrophage RIP140 plays an important role in the regulation of cholesterol efflux. The suppression of this transcription cofactor could prevent atherosclerosis. Although both LXR and RIP140 may be activated in cholesterol-loaded macrophages, these two transcription factors have distinct effects on cholesterol efflux (Fig. 1). LXR is activated by cholesterol metabolites (oxysterols) and directly induces the expression of ABCA1 and ABCG1. In contrast, RIP140 is elevated or activated in macrophages treated with modified LDL, and inhibits LXR-induced ABCA1 and ABCG1 expression. Although ligand-dependent LXR activation is considered a potential therapeutic approach in the prevention of atherosclerosis, some adverse effects, such as hypertriglyceridemia and hepatic steatosis, have been reported. The RIP140-targeted approaches may avoid the drawbacks of ligand dependent LXR activation. In contrast to ligand-dependent LXR activation, it is likely that systemic inhibition of
RIP140 activity would repress the atherogenic transcription factor SREBP-1c in hepatocytes [13,21], while promoting cholesterol efflux in the peripheral tissues. However, there is a report suggesting that RIP140 acts as a corepressor of LXR in the liver [22]. The report has shown that specific RIP140 knockdown in the liver by an adenoviral vector increases SREBP-1c expression in fasting mice. In summary, cholesterol efflux promoted by LXR-mediated induction of ABCA1 and ABCG1 has been thought to be a potential therapeutic target in the treatment of atherosclerosis. The study by Dr. Wei and colleagues identified RIP140 as a corepressor of LXR in induction of ABCA1 and ABCG1. These findings would be valuable because suppression of RIP140 could be a novel approach to enhance cholesterol efflux. To date, no known compound can specifically modulate RIP140 activity; screening for such compounds becomes one of the priorities in the field. Improved understanding of the molecular mechanisms underlying the regulation of RIP140 will also help to develop RIP140-targeted therapeutic approaches. Acknowledgments MT is supported by grants from the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for Next Generation World-Leading Researchers (NEXT Program, LS107),” initiated by the Council for Science and Technology Policy (CSTP). TK is supported by the JSPS through the “Grant-in-Aid for Young Scientists (B) (Grant Number: 26860699)”. Disclosure statement None.
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References [1] Rosenson RS, Brewer Jr HB, Davidson WS, Fayad ZA, Fuster V, Goldstein J, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 2012;125:1905–19. [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;117:3900–8. [3] Tontonoz P. Transcriptional and posttranscriptional control of cholesterol homeostasis by liver X receptors. Cold Spring Harb Symp Quant Biol 2011;76:129–37. [4] Calkin AC, Tontonoz P. Liver X receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:1513–8. [5] Lin Y, Liu P, Adhikari N, Hall JL, Wei L. RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J Mol Cell Cardiol 2014;79C:287–94. [6] Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, et al. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J 1995; 14:3741–51. [7] Lee CH, Chinpaisal C, Wei LN. Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Mol Cell Biol 1998;18:6745–55. [8] Nautiyal J, Christian M, Parker MG. Distinct functions for RIP140 in development, inflammation, and metabolism. Trends Endocrinol Metab 2013;24:451–9. [9] Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S, Bell J, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci U S A 2004;101: 8437–42. [10] Powelka AM, Seth A, Virbasius JV, Kiskinis E, Nicoloro SM, Guilherme A, et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J Clin Invest 2006;116:125–36. [11] Kiskinis E, Hallberg M, Christian M, Olofsson M, Dilworth SM, White R, et al. RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes. EMBO J 2007;26:4831–40. [12] Seth A, Steel JH, Nichol D, Pocock V, Kumaran MK, Fritah A, et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab 2007;6:236–45. [13] Herzog B, Hallberg M, Seth A, Woods A, White R, Parker MG. The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor. Mol Endocrinol 2007; 21:2687–97. [14] Zschiedrich I, Hardeland U, Krones-Herzig A, Berriel Diaz M, Vegiopoulos A, Muggenburg J, et al. Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine gene expression. Blood 2008;112:264–76.
[15] Ho PC, Tsui YC, Feng X, Greaves DR, Wei LN. NF-kappaB-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol 2012;13:379–86. [16] Huq MD, Wei LN. Post-translational modification of nuclear co-repressor receptorinteracting protein 140 by acetylation. Mol Cell Proteomics 2005;4:975–83. [17] Huq MD, Ha SG, Barcelona H, Wei LN. Lysine methylation of nuclear co-repressor receptor interacting protein 140. J Proteome Res 2009;8:1156–67. [18] Mostaqul Huq MD, Gupta P, Wei LN. Post-translational modifications of nuclear corepressor RIP140: a therapeutic target for metabolic diseases. Curr Med Chem 2008; 15:386–92. [19] Ho PC, Gupta P, Tsui YC, Ha SG, Huq M, Wei LN. Modulation of lysine acetylationstimulated repressive activity by Erk2-mediated phosphorylation of RIP140 in adipocyte differentiation. Cell Signal 2008;20:1911–9. [20] Ho PC, Chang KC, Chuang YS, Wei LN. Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production. FASEB J 2011; 25:1758–66. [21] Karasawa T, Takahashi A, Saito R, Sekiya M, Igarashi M, Iwasaki H, et al. Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2011;31:1788–95. [22] Berriel Diaz M, Krones-Herzig A, Metzger D, Ziegler A, Vegiopoulos A, Klingenspor M, et al. Nuclear receptor cofactor receptor interacting protein 140 controls hepatic triglyceride metabolism during wasting in mice. Hepatology 2008;48:782–91.
Tadayoshi Karasawa Masafumi Takahashi⁎ Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan ⁎Corresponding author at: Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Tel.: +81 285 58 7446; fax: +81 285 44 5365. E-mail addresses: [email protected]. 13 January 2015