PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis

Partha Mukhopadhyay, Béla Horváth, Mohanraj Rajesh, Zoltán V. Varga, Karim Gariani, Dongryeol Ryu, Zongxian Cao, Eileen Holovac, Ogyi Park, Zhou Zhou, Ming Jiang Xu, Wei Wang, Grzegorz Godlewski, Janos Paloczi, Balazs Tamas Nemeth, Yuri Persidsky, Lucas Liaudet, György Haskó, Peter Bai, A. Hamid BoularesJohan Auwerx, Bin Gao, Pal Pacher

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background & Aims Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). Methods We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. Results PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1−/− animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH. Conclusion Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. Lay summary Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases.

Original languageEnglish
Pages (from-to)589-600
Number of pages12
JournalJournal of Hepatology
Volume66
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

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Poly(ADP-ribose) Polymerases
Fatty Liver
Liver
Alcoholic Fatty Liver
Pharmacology
Kupffer Cells
Fats
Alcohols
Inflammation
NAD
Liver Diseases
Oxidative Stress
Fibrosis
Sirtuins
Alcoholic Liver Diseases
Wounds and Injuries
Enzymes
Choline
Liver Cirrhosis
Methionine

Keywords

  • Alcohols
  • Fatty liver
  • Fatty liver
  • Inflammation
  • Kupffer cells
  • Mitochondria
  • NAD
  • NASH
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Hepatology

Cite this

Mukhopadhyay, P., Horváth, B., Rajesh, M., Varga, Z. V., Gariani, K., Ryu, D., ... Pacher, P. (2017). PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. Journal of Hepatology, 66(3), 589-600. https://doi.org/10.1016/j.jhep.2016.10.023

PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. / Mukhopadhyay, Partha; Horváth, Béla; Rajesh, Mohanraj; Varga, Zoltán V.; Gariani, Karim; Ryu, Dongryeol; Cao, Zongxian; Holovac, Eileen; Park, Ogyi; Zhou, Zhou; Xu, Ming Jiang; Wang, Wei; Godlewski, Grzegorz; Paloczi, Janos; Nemeth, Balazs Tamas; Persidsky, Yuri; Liaudet, Lucas; Haskó, György; Bai, Peter; Boulares, A. Hamid; Auwerx, Johan; Gao, Bin; Pacher, Pal.

In: Journal of Hepatology, Vol. 66, No. 3, 01.03.2017, p. 589-600.

Research output: Contribution to journalArticle

Mukhopadhyay, P, Horváth, B, Rajesh, M, Varga, ZV, Gariani, K, Ryu, D, Cao, Z, Holovac, E, Park, O, Zhou, Z, Xu, MJ, Wang, W, Godlewski, G, Paloczi, J, Nemeth, BT, Persidsky, Y, Liaudet, L, Haskó, G, Bai, P, Boulares, AH, Auwerx, J, Gao, B & Pacher, P 2017, 'PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis', Journal of Hepatology, vol. 66, no. 3, pp. 589-600. https://doi.org/10.1016/j.jhep.2016.10.023
Mukhopadhyay P, Horváth B, Rajesh M, Varga ZV, Gariani K, Ryu D et al. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. Journal of Hepatology. 2017 Mar 1;66(3):589-600. https://doi.org/10.1016/j.jhep.2016.10.023
Mukhopadhyay, Partha ; Horváth, Béla ; Rajesh, Mohanraj ; Varga, Zoltán V. ; Gariani, Karim ; Ryu, Dongryeol ; Cao, Zongxian ; Holovac, Eileen ; Park, Ogyi ; Zhou, Zhou ; Xu, Ming Jiang ; Wang, Wei ; Godlewski, Grzegorz ; Paloczi, Janos ; Nemeth, Balazs Tamas ; Persidsky, Yuri ; Liaudet, Lucas ; Haskó, György ; Bai, Peter ; Boulares, A. Hamid ; Auwerx, Johan ; Gao, Bin ; Pacher, Pal. / PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. In: Journal of Hepatology. 2017 ; Vol. 66, No. 3. pp. 589-600.
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T1 - PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis

AU - Mukhopadhyay, Partha

AU - Horváth, Béla

AU - Rajesh, Mohanraj

AU - Varga, Zoltán V.

AU - Gariani, Karim

AU - Ryu, Dongryeol

AU - Cao, Zongxian

AU - Holovac, Eileen

AU - Park, Ogyi

AU - Zhou, Zhou

AU - Xu, Ming Jiang

AU - Wang, Wei

AU - Godlewski, Grzegorz

AU - Paloczi, Janos

AU - Nemeth, Balazs Tamas

AU - Persidsky, Yuri

AU - Liaudet, Lucas

AU - Haskó, György

AU - Bai, Peter

AU - Boulares, A. Hamid

AU - Auwerx, Johan

AU - Gao, Bin

AU - Pacher, Pal

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Background & Aims Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). Methods We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. Results PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1−/− animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH. Conclusion Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. Lay summary Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases.

AB - Background & Aims Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). Methods We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. Results PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1−/− animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH. Conclusion Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. Lay summary Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases.

KW - Alcohols

KW - Fatty liver

KW - Fatty liver

KW - Inflammation

KW - Kupffer cells

KW - Mitochondria

KW - NAD

KW - NASH

KW - Oxidative stress

KW - Reactive oxygen species

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