Dual PPARα/γ activation inhibitsSIRT1-PGC1α axis and causes cardiac dysfunction

Kalliora, Charikleia; Kyriazis, Ioannis D.; Oka, Sarang; Lieu, Melissa; Yue, Yujia; Area‐Gómez, Estela; Pol, Christine J.; Tian, Ying; Mizushima, Wataru; Chin, Adave; Scerbo, Diego; Schulze, P. Christian; Civelek, Mete; Sadoshima, Junichi; Madesh, Muniswamy; Goldberg, Ira J.; Drosatos, Konstantinos

doi:10.1172/jci.insight.129556

Cited by 62 publications

(60 citation statements)

References 80 publications

(106 reference statements)

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“…As discussed herein, PPARs not only impact liver, but also other organs. In particular, they can have both positive and negative effects on heart physiology, pathology and injury [416,417]. Therefore, it is of importance that the new potential NASH drugs are evaluated for potential beneficial as well as deleterious effects on cardiac functions.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

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Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.

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Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

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“…187,188 Furthermore, drugs causing dual PPARα/ϒ activation have been shown to induce cardiac dysfunction due to Sirt1-PGC1α inhibition and decreased mitochondrial number. 189 In the hearts of fructose-fed rats, Sirt1 activity decreased early in the progression to T2DM and was also associated with decreased in mitochondrial content and lower FAO capacity in the mitochondria. 106 Recent evidence suggests that the cardioprotective effect of CR in the diabetic heart operates via Sirt1 and PGC-1α, increasing OXPHOS capacity and reducing cardiomyocyte oxidative stress and inflammation.…”

Section: Dietary Interventionsmentioning

confidence: 94%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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“…PPARδ, but not PPARα, stimulates PGC-1α transcription, although both PPARδ and PPARα bind to the PPRE. PPARγ also stimulates PGC-1α transcription (77). Interestingly, PPARγ-induced PGC-1α transcription is inhibited by PPARα possibly through competition of the binding to PPRE (77).…”

Section: Transcriptional Regulation Of Pgc-1α Gene In the Heartmentioning

confidence: 99%

“…PPARγ also stimulates PGC-1α transcription (77). Interestingly, PPARγ-induced PGC-1α transcription is inhibited by PPARα possibly through competition of the binding to PPRE (77). Cardiac-specific PPARα overexpression inhibits PGC-1α transcription (78).…”

Section: Transcriptional Regulation Of Pgc-1α Gene In the Heartmentioning

confidence: 99%

Multiple Levels of PGC-1α Dysregulation in Heart Failure

Oka

Sabry

Cawley

et al. 2020

Front. Cardiovasc. Med.

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Metabolic adaption is crucial for the heart to sustain its contractile activity under various physiological and pathological conditions. At the molecular level, the changes in energy demand impinge on the expression of genes encoding for metabolic enzymes. Among the major components of an intricate transcriptional circuitry, peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) plays a critical role as a metabolic sensor, which is responsible for the fine-tuning of transcriptional responses to a plethora of stimuli. Cumulative evidence suggests that energetic impairment in heart failure is largely attributed to the dysregulation of PGC-1α. In this review, we summarize recent studies revealing how PGC-1α is regulated by a multitude of mechanisms, operating at different regulatory levels, which include epigenetic regulation, the expression of variants, post-transcriptional inhibition, and post-translational modifications. We further discuss how the PGC-1α regulatory cascade can be impaired in the failing heart.

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Dual PPARα/γ activation inhibitsSIRT1-PGC1α axis and causes cardiac dysfunction

Cited by 62 publications

References 80 publications

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Altered mitochondrial metabolism in the insulin‐resistant heart

Multiple Levels of PGC-1α Dysregulation in Heart Failure

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