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      RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

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          Abstract

          The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. ROR α specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.

          Abstract

          Hepatic steatosis development may result from dysregulation of lipid metabolism, which is finely tuned by several transcription factors including the PPAR family. Here Kim et al. show that the nuclear receptor RORα inhibits PPARγ-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes.

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          Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.

          Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.
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            Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network.

            In multicellular organisms, the ability to regulate reproduction, development, and nutrient utilization coincided with the evolution of nuclear receptors (NRs), transcription factors that utilize lipophilic ligands to mediate their function. Studying the expression profile of NRs offers a simple, powerful way to obtain highly relational information about their physiologic functions as individual proteins and as a superfamily. We surveyed the expression of all 49 mouse NR mRNAs in 39 tissues, representing diverse anatomical systems. The resulting data set uncovers several NR clades whose patterns of expression indicate their ability to coordinate the transcriptional programs necessary to affect distinct physiologic pathways. Remarkably, this regulatory network divides along the following two physiologic paradigms: (1) reproduction, development, and growth and (2) nutrient uptake, metabolism, and excretion. These data reveal a hierarchical transcriptional circuitry that extends beyond individual tissues to form a meganetwork governing physiology on an organismal scale.
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              A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.

              The mammalian circadian clock plays an integral role in timing rhythmic physiology and behavior, such as locomotor activity, with anticipated daily environmental changes. The master oscillator resides within the suprachiasmatic nucleus (SCN), which can maintain circadian rhythms in the absence of synchronizing light input. Here, we describe a genomics-based approach to identify circadian activators of Bmal1, itself a key transcriptional activator that is necessary for core oscillator function. Using cell-based functional assays, as well as behavioral and molecular analyses, we identified Rora as an activator of Bmal1 transcription within the SCN. Rora is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN. These results suggest that opposing activities of the orphan nuclear receptors Rora and Rev-erb alpha, which represses Bmal1 expression, are important in the maintenance of circadian clock function.
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                Author and article information

                Contributors
                sfang@yuhs.ac
                sbaek@snu.ac.kr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                31 July 2017
                31 July 2017
                2017
                : 8
                : 162
                Affiliations
                [1 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Department of Biological Sciences, , Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University, ; Seoul, 08826 South Korea
                [2 ]ISNI 0000 0004 0628 9810, GRID grid.410914.9, Graduate School of Cancer Science and Policy, , Research Institute, National Cancer Center, ; Gyeonggi-do, 10408 South Korea
                [3 ]ISNI 0000 0004 0438 6721, GRID grid.417736.0, Department of New Biology and Center for Plant Aging Research, , Institute for Basic Science, DGIST, ; Daegu, 42988 South Korea
                [4 ]ISNI 0000 0001 0729 3748, GRID grid.412670.6, Department of Biological Sciences, , Sookmyung Women’s University, ; Seoul, 04310 South Korea
                [5 ]ISNI 0000 0001 0669 3109, GRID grid.412091.f, Department of Physiology, , Keimyung University School of Medicine, ; Daegu, 42601 South Korea
                [6 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Laboratory of Developmental Biology and Genomics, , College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, ; Seoul, 08826 South Korea
                [7 ]Korea Mouse Phenotyping Center, Seoul, 08826 South Korea
                [8 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, BK21 Plus Program for Creative Veterinary Science Research, , BIO-MAX institute, Interdisciplinary Program for Bioinformatics and Program for Cancer Biology, Seoul National University, ; Seoul, 08826 South Korea
                [9 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Severance Biomedical Science Institute, , BK21 Plus Project for Medical Science, Gangnam Severance Hospital, Yonsei University College of Medicine, ; Seoul, 06273 South Korea
                Author information
                http://orcid.org/0000-0002-9680-6230
                Article
                215
                10.1038/s41467-017-00215-1
                5534431
                28757615
                56815c70-ee92-4bfe-b490-14a3ec3e3639
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 October 2016
                : 9 June 2017
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