PARP1-mediated PPARα poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease

Huang, Kun; Du, Meng; Tan, Xin; Yang, Ling; Li, Xiangrao; Jiang, Yuhan; Wang, Cheng; Zhang, Fengxiao; Zhu, Feng; Cheng, Min; Yang, Qinglin; Yu, Liqing; Wang, Lin; Huang, Dan

doi:10.1016/j.jhep.2016.11.020

Cited by 77 publications

(51 citation statements)

References 44 publications

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“…As is known to all, PAPR family is a cluster of NAD+ consuming enzymes that is responsible for DNA damage detection and repair (Bai & Canto, ). PARPs are capable of interacting with a variety of transcription factors and nuclear receptors, which modulate mitochondrial homeostasis and lipid oxidation process by PPAR (Huang et al, ), FOXO1 (Czapski et al, ), and so on. Pharmacological inhibition of PARP‐1 has been proved to be an effective approach to facilitate mitochondrial function (Pirinen et al, ).…”

Section: Discussionmentioning

confidence: 99%

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

Wang

Yang

Shang

et al. 2019

Phytotherapy Research

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As yet, there was no effective pharmacological therapy approved for non‐alcoholic fatty liver disease (NAFLD). Here, we aimed to evaluate the therapeutic potential of puerarin against NAFLD and explored the underlying mechanisms. C57BL/6J mice were fed with a high‐fat high‐sucrose (HFHS) diet with or without puerarin coadministration intragastrically. The levels of hepatocellular injury, steatosis, fibrosis, and mitochondrial and metabolism alteration were detected. First, puerarin ameliorated histopathologic abnormalities due to HFHS. We observed a marked increase in hepatic lipid content, inflammation, and fibrosis level, which were attenuated by puerarin. Possible mechanisms were related to puerarin‐mediated activation of PI3K/AKT pathway and further improvement in fatty acid metabolism. Puerarin restored the NAD+ content and beneficially affected the hepatic mitochondrial function, which attenuated HFHS‐induced steatosis and metabolic disturbances. Finally, hepatic PARP‐1 was activated due to excessive fat intake. Puerarin attenuated the PARP‐1 expression in HFHS‐fed mice, and PJ34, the PARP inhibitor, could mimic these protections of puerarin. However, pharmacological inhibition of PI3K disabled the protection of puerarin or PJ34 toward NAD+ refilling and mitochondrial homeostasis. In conclusion, our findings indicated that puerarin could be a promising and practical therapeutic strategy in NAFLD through modulating PARP‐1/PI3K/AKT signaling pathway and further facilitating mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

Wang

Yang

Shang

et al. 2019

Phytotherapy Research

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“…It may enhance or inhibit the DNA binding of different nuclear proteins by changing their respective structure. Studies have also reported that the nucleosome binding activity of transcription factors are regulated by poly(ADP-ribosyl)ation, such as PPARα, ERα, FXR 20 , 34 – 36 . In this study, we showed that PARP1-induced poly(ADP-ribosy)lation was required for starvation-induced FoxO3a nuclear accumulation through promoting FoxO3a dephosphorylation.…”

Section: Discussionmentioning

confidence: 99%

PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription

Wang

Zhang

et al. 2018

Cell Death Dis

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Autophagy is a key regulatory process in maintaining cellular homoeostasis via lysosome degradation. Growing evidence reveals that poly(ADP-ribose) polymerase-1 (PARP1) is involved in the progression of many cardiovascular diseases. This study was undertaken to discuss the role of PARP1 in cardiomyocyte autophagy. Our results demonstrated that PARP1 was activated in response to starvation-induced myocardial autophagy. We identified Forkhead box O (FoxO)3a as a substrate of PARP1. Upon PARP1 activation, poly(ADP-ribosyl)ation dissociated histone H1 from FoxO3a target gene promoter and promoted FoxO3a nuclear accumulation and binding activity to the target promoters, resulting in increased expression of autophagy related genes. Activated autophagy by PARP1 impaired mitochondrial metabolism and promoted cardiomyocyte death. And PARP1 silencing or specific inhibitors alleviated the promotion of FoxO3 activity upon starvation or myocardial ischemia, thus suppressing cardiac apoptosis and fibrosis. Together, these data indicate that PARP1-mediated poly(ADP-ribosyl)ation of FoxO3a plays a key role in cardiomyocyte autophagy. The utilization of PARP1 as a therapeutic target for related cardiovascular diseases would be desirable.

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“…Various publications show that PARP has been gaining recognition as a central regular signaling molecule in numerous diseases, including cancer, energetic metabolism, inflammation, shock, cardiovascular diseases, diabetes, and fatty liver disease (Sistigu et al, 2015;Huang et al, 2017;Islam et al, 2017;Vida et al, 2017). High-fat high-sucrose (HFHS) diets lead to insulin resistance, oxidative stress, steatosis, and inflammation and lower hepatic NAD 1 levels, driving reductions in hepatic mitochondrial dysfunction and increases in hepatic lipid content in mice (Verbeek et al, 2015;Gariani et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Attenuated Hepatic Triglyceride Accumulation in Alcoholic Fatty Liver Disease in Mice

Huang

Zhang

Chen

et al. 2018

J Pharmacol Exp Ther

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Poly(ADP-ribose) polymerase (PARP) is an NAD-consuming enzyme and its specific role in the pathogenesis of alcoholic fatty liver disease (AFLD) remains elusive. In this study, we applied PJ34 [-(5,6-dihydro-6-oxo-2-phenanthridinyl)-2-acetamide hydrochloride] to inhibit hepatic PARP activity to examine the corresponding pathologic alteration in AFLD in mice and the underlying molecular mechanism. We found that PJ34 decreased the intracellular triglyceride (TG) content in hepatocytes. Moreover, PJ34 suppressed the gene expression of diglyceride acyltransferases DGAT1 and DGAT2 and elevated intracellular NAD levels in hepatocytes. These mechanistic observations were validated in alcohol-fed mice injected with PJ34 intraperitoneally. Our results indicate that the PJ34 injection attenuated hepatic TG accumulation in alcohol-fed mice. Furthermore, PJ34 injection lowered the gene expression of hepatic sterol regulatory element binding protein 1c, DGAT1, and DGAT2, whereas PJ34 injection augmented hepatic NAD levels in alcohol-fed mice. Finally, nicotinamide riboside supplementation alleviated hepatic TG accumulation in alcohol-fed mice. These data indicate that applying PARP-specific inhibitor PJ34 by intraperitoneal injection attenuated hepatic NAD depletion and TG accumulation in alcohol-fed mice and may be a potential candidate for use in AFLD therapy.

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PARP1-mediated PPARα poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease

Cited by 77 publications

References 44 publications

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Attenuated Hepatic Triglyceride Accumulation in Alcoholic Fatty Liver Disease in Mice

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