Retinoic acid (RA), the biologically active form of vitamin A, acts, primarily, by binding to nuclear RA receptor (RAR) and retinoid receptor X (RXR) to regulate gene expression. But the activities of RAR and RXR ultimately depend on the recruitment of coregulators. The project has initially focused on an RA-dependent RAR corepressor named Nuclear Receptor Interacting Protein 1 (NRIP1, also known as RIP140), which was later found as a wide spectrum coregulator for many other transcription factors. Previous progress includes systemic characterization of NRIP1 with regards to its wide spectrum corepressive activity in RA-targeted genes, functional domains, and post-translational modifications (PTMs) that alter its property and subcellular localization (i.e., export into cytoplasm) to elicit additional biological activities beyond RA gene regulation. These novel non-genomic activities of NRIP1 were demonstrated in regulating insulin sensitivity, glucose uptake, lipolysis and adiponectin secretion in adipocytes. The genomic and non-genomic activities of NRIP1 together establish its critical role in the development and progression of metabolic diseases in relation to vitamin A signaling. More recent results revealed a new role for NRIP1 in controlling innate immunity by enhancing M1 and repressing M2 macrophages. This is modulated by RA and also affects RA synthesis capacity in macrophages. We hypothesize that i) NRIP1 acts as a specific coregulator in a cell-context and chromatin-locus dependent manner, i.e., it can be a coactivator or a corepressor depending upon the type of transcription factor it interacts, the cellular state and specific chromatin loci, ii) NRIP1's versatility is reglated by PTM and is relevant to RA homeostasis, and iii) NRIP1's versatility enhances macrophage genome plasticity (or epigenetics) in response to nutritional (vitamin A) or pathological challenges. We propose two aims to address these hypotheses.
Aim 1 will address the molecular mechanisms of NRIP1's differential coregulatory functions in macrophages.
Aim 2 will determine the physiological and nutritional relevance of NRIP1 in innate immunity control by exploiting a macrophage-specific NRIP1-knockdown mouse model with or without vitamin A deficiency. This mouse model shows reduced inflammation (M1), improved wound healing (M2) and elevated RA synthesizing enzyme RALDH2 mRNA level. We will also employ rescue strategies by using various NRIP1 proteins mutated in specific PTMs. The results will be key to future translational application of targeting NRIP1, such as in maintaining the homeostasis of nutritional (vitamin A) and metabolic status, and in managing metabolic diseases.

Public Health Relevance

Nuclear receptor interacting protein 1 (NRIP1, also known as RIP140) is a wide spectrum coregulatory protein for hormone targeted gene expression, and is involved in signal integration of various hormones including vitamin A (retinoic acid, or RA, specifically) and others like thyroid hormones and lipids. This project was initiated from studying NRIP1 in mediating RA signaling, and the long-term goal of this project is to understand how vitamin A, or RA, signaling interacts with other hormonal or physiological factors through a common coregulatory molecule like NRIP1 and how NRIP1 may serves as a new disease marker (such as in immunity and metabolic diseases) relevant to vitamin A nutritional status. Extended from previously funded research, the current renewal proposal focuses on the new function of NRIP1 in innate immunity in relation to RA homeostasis and how RA may affect innate immunity by engaging NRIP1 as one of the mediators.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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University of Minnesota Twin Cities
Schools of Medicine
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Lin, Yi-Wei; Liu, Pu-Ste; Adhikari, Neeta et al. (2015) RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J Mol Cell Cardiol 79:287-94
Feng, Xudong; Krogh, Kelly A; Wu, Cheng-Ying et al. (2014) Receptor-interacting protein 140 attenuates endoplasmic reticulum stress in neurons and protects against cell death. Nat Commun 5:4487
Flaisher-Grinberg, S; Tsai, H C; Feng, X et al. (2014) Emotional regulatory function of receptor interacting protein 140 revealed in the ventromedial hypothalamus. Brain Behav Immun 40:226-34
Wu, Cheng-Ying; Feng, Xudong; Wei, Li-Na (2014) Coordinated repressive chromatin-remodeling of Oct4 and Nanog genes in RA-induced differentiation of embryonic stem cells involves RIP140. Nucleic Acids Res 42:4306-17
Feng, X; Wu, C-Y; Burton, F H et al. (2014) *-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia. Cell Death Differ 21:397-406
Persaud, Shawna D; Lin, Yi-Wei; Wu, Cheng-Ying et al. (2013) Cellular retinoic acid binding protein I mediates rapid non-canonical activation of ERK1/2 by all-trans retinoic acid. Cell Signal 25:19-25
Ho, Ping-Chih; Tsui, Yao-Chen; Lin, Yi-Wei et al. (2012) Endothelin-1 promotes cytoplasmic accumulation of RIP140 through a ET(A)-PLCýý-PKCýý pathway. Mol Cell Endocrinol 351:176-83
Ho, Ping-Chih; Tsui, Yao-Chen; Feng, Xudong et al. (2012) NF-?B-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol 13:379-86
Wei, Li-Na (2012) Chromatin remodeling and epigenetic regulation of the CrabpI gene in adipocyte differentiation. Biochim Biophys Acta 1821:206-12
Ho, Ping-Chih; Wei, Li-Na (2012) Negative regulation of adiponectin secretion by receptor interacting protein 140 (RIP140). Cell Signal 24:71-6

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