About: MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet

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About: MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet
Creator	He, Jun Han, Yipin Sullivan, Jenyth Bain, James Clarke, Brian Faadiel Essop, M Grevengoed, Trisha Hill, Joseph Mapanga, Rudo Muehlbauer, Michael Newgard, Christopher Parry, Traci Quintana, Megan Schisler, Jonathan Stansfield, William Willis, Monte Yates, Cecelia
source	Medline; PMC
abstract	BACKGROUND: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy involves the enhanced activation of PPAR transcription factors, including PPARα, and to a lesser degree PPARβ and PPARγ1. How these transcription factors are regulated in the heart is largely unknown. Recent studies have described post-translational ubiquitination of PPARs as ways in which PPAR activity is inhibited in cancer. However, specific mechanisms in the heart have not previously been described. Recent studies have implicated the muscle-specific ubiquitin ligase muscle ring finger-2 (MuRF2) in inhibiting the nuclear transcription factor SRF. Initial studies of MuRF2−/− hearts revealed enhanced PPAR activity, leading to the hypothesis that MuRF2 regulates PPAR activity by post-translational ubiquitination. METHODS: MuRF2−/− mice were challenged with a 26-week 60% fat diet designed to simulate obesity-mediated insulin resistance and diabetic cardiomyopathy. Mice were followed by conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARβ, and PPARγ1-regulated mRNA expression. RESULTS: MuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high fat diet. Compared to littermate wildtype hearts, MuRF2−/− hearts exhibit an exaggerated diabetic cardiomyopathy, characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2−/− hearts had significantly increased PPARα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2’s regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARα and PPARγ1 in vitro, consistent with its non-degradatory role in diabetic cardiomyopathy. However, increasing MuRF2:PPARγ1 (>5:1) beyond physiological levels drove poly-ubiquitin-mediated degradation of PPARγ1 in vitro, indicating large MuRF2 increases may lead to PPAR degradation if found in other disease states. CONCLUSIONS: Mutations in MuRF2 have been described to contribute to the severity of familial hypertrophic cardiomyopathy. The present study suggests that the lack of MuRF2, as found in these patients, can result in an exaggerated diabetic cardiomyopathy. These studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARα and PPARγ1 activities in vivo via post-translational modification without degradation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12933-015-0252-x) contains supplementary material, which is available to authorized users.
has issue date	2015-08-05(xsd:dateTime)
bibo:doi	10.1186/s12933-015-0252-x
bibo:pmid	26242235
has license	cc-by
sha1sum (hex)	f29df5233e688dddd0286374e0993e43459fe04b
schema:url	https://doi.org/10.1186/s12933-015-0252-x
resource representing a document's title	MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet
has PubMed Central identifier	PMC4526192
has PubMed identifier	26242235
schema:publication	Cardiovasc Diabetol
resource representing a document's body	covid:f29df5233e688dddd0286374e0993e43459fe04b#body_text
is schema:about of	named entity 'MURF2' named entity 'DIABETIC CARDIOMYOPATHY' named entity 'Background' named entity 'degree' named entity 'transcription factors' named entity 'PPAR' named entity 'Recent' named entity 'TRANSLATIONAL' named entity 'LEADING' named entity 'DESCRIBED' named entity 'ACTIVATION' named entity 'PATHOGENESIS' named entity 'DIABETIC CARDIOMYOPATHY' named entity 'UBIQUITIN LIGASE' named entity 'HAVE' named entity 'MORBIDITY AND MORTALITY' named entity 'ENHANCED' named entity 'HEART' named entity 'DIABETES MELLITUS' named entity 'RECENT' named entity 'LARGELY' named entity 'INHIBITING' named entity 'PPAR' named entity 'MECHANISMS' named entity 'THESE' named entity 'POST' named entity 'HOW' named entity 'TRANSCRIPTION FACTOR' named entity 'DEGREE' named entity 'ACTIVITY' named entity 'MUSCLE' named entity 'TRANSCRIPTION FACTORS' named entity 'INHIBITED' named entity 'INCLUDING' named entity 'WEIGHT GAIN' named entity 'HYPOTHESIS' named entity 'PREVIOUSLY' named entity 'HIGH FAT DIET' named entity 'SPECIFIC' named entity 'HEART DISEASE' named entity 'RING FINGER' named entity 'ACTIVITY' named entity 'ENHANCE' named entity 'INDUCED' named entity 'PPAR' named entity 'REVEALED' named entity 'MECHANISM' named entity 'LESSER' named entity 'REGULATED' named entity 'INCREASED' named entity 'INDEPENDENT' named entity 'EXACERBATED' named entity 'CANCER' named entity 'SRF' named entity 'NUCLEAR' named entity 'UNKNOWN' named entity 'CARDIOVASCULAR DISEASE' named entity 'MURF2' named entity 'BACKGROUND' named entity 'IMPORTANT' named entity 'STUDIES' named entity 'INITIAL' named entity 'UBIQUITINATION' named entity 'PPAR' named entity 'enhanced'

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