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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK060521-12S1
Application #
8913322
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2002-03-15
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
$85,120
Indirect Cost
$29,120
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Park, Sung Wook; Persaud, Shawna D; Ogokeh, Stanislas et al. (2018) CRABP1 protects the heart from isoproterenol-induced acute and chronic remodeling. J Endocrinol 236:151-165
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2017) Phosphorylation of poly(rC) binding protein 1 (PCBP1) contributes to stabilization of mu opioid receptor (MOR) mRNA via interaction with AU-rich element RNA-binding protein 1 (AUF1) and poly A binding protein (PABP). Gene 598:113-130
Lin, Yu-Lung; Tsai, Hong-Chieh; Liu, Pei-Yao et al. (2017) Receptor-interacting protein 140 as a co-repressor of Heat Shock Factor 1 regulates neuronal stress response. Cell Death Dis 8:3203
Lee, Bomi; Iwaniec, Urszula T; Turner, Russell T et al. (2017) RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis. JCI Insight 2:e90517
Song, Kyu Young; Choi, Hack Sun; Law, Ping-Yee et al. (2017) Post-Transcriptional Regulation of the Human Mu-Opioid Receptor (MOR) by Morphine-Induced RNA Binding Proteins hnRNP K and PCBP1. J Cell Physiol 232:576-584
Lin, Yu-Lung; Persaud, Shawna D; Nhieu, Jennifer et al. (2017) Cellular Retinoic Acid-Binding Protein 1 Modulates Stem Cell Proliferation to Affect Learning and Memory in Male Mice. Endocrinology 158:3004-3014
Wagley, Yadav; Law, Ping-Yee; Wei, Li-Na et al. (2017) Epigenetic Activation of ?-Opioid Receptor Gene via Increased Expression and Function of Mitogen- and Stress-Activated Protein Kinase 1. Mol Pharmacol 91:357-372
Heisel, Timothy; Montassier, Emmanuel; Johnson, Abigail et al. (2017) High-Fat Diet Changes Fungal Microbiomes and Interkingdom Relationships in the Murine Gut. mSphere 2:
Lee, Bomi; Wu, Cheng-Ying; Lin, Yi-Wei et al. (2016) Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling. Nucleic Acids Res 44:7568-79
Wu, Cheng-Ying; Persaud, Shawna D; Wei, Li-Na (2016) Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune Pax6 Gene in Neuronal Differentiation. Stem Cells 34:114-23

Showing the most recent 10 out of 100 publications