Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease
Open accessAbstract
Background & Aims To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD. Methods As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD + ), we hypothesized that overactivation of PARPs drives NAD + depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD + and activate NAD + -dependent sirtuins, hence improving hepatic fatty acid oxidation. To do this, we examined the preventive and therapeutic benefits of the PARP inhibitor (PARPi), olaparib, in different models of NAFLD. Results The induction of NAFLD in C57BL/6J mice using a high-fat high-sucrose (HFHS)-diet increased PARylation of proteins by PARPs. As such, increased PARylation was associated with reduced NAD + levels and mitochondrial function and content, which was concurrent with elevated hepatic lipid content. HFHS diet supplemented with PARPi reversed NAFLD through repletion of NAD + , increasing mitochondrial biogenesis and β-oxidation in liver. Furthermore, PARPi reduced reactive oxygen species, endoplasmic reticulum stress and fibrosis. The benefits of PARPi treatment were confirmed in mice fed with a methionine- and choline-deficient diet and in mice with lipopolysaccharide-induced hepatitis; PARP activation was attenuated and the development of hepatic injury was delayed in both models. Using Sirt1 hep−/− mice, the beneficial effects of a PARPi-supplemented HFHS diet were found to be Sirt1-dependent. Conclusions Our study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies. Lay summary Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the Western world and has no approved pharmacological therapy. PARP inhibitors given as a treatment in two different mouse models of NAFLD confer a protection against its development. PARP inhibitors may therefore represent a novel and practical pharmacological approach for treating NAFLD.
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Inhibition of NAD+-consuming enzymes is a promising approach to treat mitochondrial dysfunction in age-related metabolic dysfunction.
“Additionally, inhibition of NAD+-consuming enzymes has been shown to be a promising approach to treat mitochondrial dysfunction in age-related metabolic dysfunction261.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [261]
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“The protective effects of Olaparib and other PAPR inhibitors against NAFLD and AFLD have been intensively reported during recent several months [135-138].”
BackgroundInfluentialRepairing mitochondrial dysfunction in disease
Sorrentino, V., Menzies, K. J., & Auwerx, J. (2018) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104908 · Cited by 337 · see citing works
Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies
Wu, X., Xu, M., Geng, M., Chen, S., Little, P. J., Xu, S., & Weng, J. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01439-y · Cited by 290 · see citing works
“A PARP inhibitor olaparib reversed NAFLD by NAD elevation, increasing mitochondrial biogenesis and β-oxidation in liver under HFHS diet.(366)”
BackgroundTan, Z., Xiao, L., Tang, M., Bai, F., Li, J., Li, L., Shi, F., Li, N., Li, Y., Du, Q., et al. (2018) · Theranostics · doi:10.7150/thno.21451 · Cited by 272 · see citing works
“FAO is relatively more active in energy-consuming tissues such as muscle tissues and some tumor tissues [23-28].”
BackgroundSelf-citationPleiotropic effects of mitochondria in aging
de Lima, T. I., Li, T. Y., Mottis, A., & Auwerx, J. H. (2022) · Nature Aging · doi:10.1038/s43587-022-00191-2 · Cited by 242 · see citing works
Self-citationModulating NAD+ metabolism, from bench to bedside
Katsyuba, E., & Auwerx, J. H. (2017) · The EMBO Journal · doi:10.15252/embj.201797135 · Cited by 224 · see citing works
“NAD + boosting was also efficient to improve glucose homeostasis in obese, prediabetic, and T2DM animals (Barbosa et al , 2007; Bai et al , 2011; Yoshino et al , 2011; Canto et al , 2012; Kraus et al , 2014; Gariani et al , 2016, 2017; Trammell et al , 2016b).”
InfluentialSelf-citationPazzaglia, S., & Pioli, C. (2019) · Cells · doi:10.3390/cells9010041 · Cited by 223 · see citing works
“Studies include results relevant to stroke, neurodegeneration, neuroinflammation and blood brain barrier function [148,149], sepsis [150], liver diseases [151,152], and asthma [112].”
BackgroundOpportunities for the repurposing of PARP inhibitors for the therapy of non‐oncological diseases
Berger, N. A., Besson, V. C., Boulares, A. H., Bürkle, A., Chiarugi, A., Clark, R. S. B., Curtin, N. J., Cuzzocrea, S., Dawson, T. M., Dawson, V. L., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13748 · Cited by 212 · see citing works
“Gariani et al., 2017 Ovalbumin exposure in ovalbumin-sensitized mice: pulmonary inflammation and airway hyperreactivity in mice Asthma bronchiale 1, 5 and 10 mg·kg 1, single intraperitoneal dosing At all doses tested, olaparib afforded a dose-dependent reduction in ovalbumin-specific IgE production…”
InfluentialRelevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease
de Gregorio, E., Colell, A., Morales, A., & Marı́, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113858 · Cited by 202 · see citing works
“Antrodan, together with adiponectin, induced conversion of AMPK into pAMPK, which, in turn, increased the ratio of NAD+/NADH and upregulated SIRT1.”
BackgroundMethodInfluentialZhao, W., Bian, Y., Wang, Q., Yin, F., Yin, L., Zhang, Y.-L., & Liu, J. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00681-w · Cited by 198 · see citing works
PARPs in lipid metabolism and related diseases
Szántó, M., Gupte, R., Kraus, W. L., Pacher, P., & Bai, P. (2021) · Progress in Lipid Research · doi:10.1016/j.plipres.2021.101117 · Cited by 184 · see citing works
Human hepatic 3D spheroids as a model for steatosis and insulin resistance
Kozyra, M., Johansson, I., Nordling, Å., Ullah, S., Lauschke, V. M., & Ingelman‐Sundberg, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-32722-6 · Cited by 173 · see citing works
PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis
Mukhopadhyay, P., Horváth, B., Rajesh, M., Varga, Z. V., Gariani, K., Ryu, D., Cao, Z., Holovac, E., Park, O., Zhou, Z., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.10.023 · Cited by 168 · see citing works
Self-citationThe role of NAD+ metabolism and its modulation of mitochondria in aging and disease
Yusri, K., Jose, S., Vermeulen, K. S., Tan, T. C. M., & Sorrentino, V. (2025) · npj Metabolic Health and Disease · doi:10.1038/s44324-025-00067-0 · Cited by 171 · see citing works
Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights
Stephenson, K., Kennedy, L. L., Hargrove, L. A., Demieville, J., Thomson, J., Alpini, G. D., & Francis, H. (2017) · Gene Expression · doi:10.3727/105221617x15093707969658 · Cited by 142 · see citing works
Graphene Oxide Quantum Dots as Novel Nanozymes for Alcohol Intoxication
Sun, A., Li, M., & Hu, X. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b00306 · Cited by 121 · see citing works
Hou, T., Tian, Y., Cao, Z., Zhang, J., Feng, T., Tao, W., Sun, H., Wen, H., Lu, X., Zhu, Q., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.09.018 · Cited by 106 · see citing works
Jokinen, R., Pirnes-Karhu, S., Pietiläinen, K. H., & Pirinen, E. (2017) · Redox Biology · doi:10.1016/j.redox.2017.02.011 · Cited by 103 · see citing works
Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule
Elhassan, Y., Philp, A., & Lavery, G. G. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2017-00092 · Cited by 92 · see citing works
“PARP inhibition in mice with NAFLD can correct NAD+ deficiency, augmenting mitochondrial function and insulin sensitivity and allaying hepatic lipid accumulation and transaminitis [197].”
BackgroundSIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice
Li, M., Hong, W., Hao, C., Li, L., Wu, D., Shen, A., Lu, J. L., Zheng, Y., Li, P., & Xu, Y. (2017) · The FASEB Journal · doi:10.1096/fj.201700612r · Cited by 91 · see citing works
“In addition, inhibition of SIRT1 activity by depleting intracellular NAD, mediated by the poly (ADP-ribose) polymerase, has been implicated as a potential mechanism underlying high-fat-diet–induced liver injury and fibrosis (35, 36).”
BackgroundMitochondrial Dysfunction in the Transition from NASH to HCC
Léveillé, M., & Estall, J. L. (2019) · Metabolites · doi:10.3390/metabo9100233 · Cited by 93 · see citing works
Wang, S., Yang, F., Shang, L., Zhang, Y., Zhou, Y., & Shi, X. (2019) · Phytotherapy Research · doi:10.1002/ptr.6417 · Cited by 91 · see citing works
Szántó, M., & Bai, P. (2020) · Genes & Development · doi:10.1101/gad.334284.119 · Cited by 88 · see citing works
“…role of PARP1 concerningwhether the genetic ablation ofPARP1 exacerbates NAFLD (Erener et al. 2012b) or pharmacological PARP inhibition protects against steatosis, inflammation, and liver tissue injury in NAFLD (Bai et al. 2011b; Gariani et al. 2017; Mukhopadhyay et al. 2017; Huang et al. 2018).”
BackgroundUddin, G. M., Youngson, N. A., Doyle, B. M., Sinclair, D. A., & Morris, M. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-14866-z · Cited by 82 · see citing works
“WAT (mg) Gonadal 141 ± 8 601 ± 89*** 231 ± 22 1348 ± 164†††/*** F(1,51) = 22.”
BackgroundFlavonoids-mediated SIRT1 signaling activation in hepatic disorders
Sayed, A. M. M., Hassanein, E. H. M., Salem, S. H., Hussein, O. E., & Mahmoud, A. M. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118173 · Cited by 75 · see citing works
Excessive Gluconeogenesis Causes the Hepatic Insulin Resistance Paradox and Its Sequelae
Onyango, A. N. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e12294 · Cited by 79 · see citing works
Youngson, N. A., Morris, M. J., & Ballard, J. W. O. (2017) · Seizure · doi:10.1016/j.seizure.2017.09.005 · Cited by 75 · see citing works
Niacin: an old lipid drug in a new NAD+ dress
Romani, M., Hofer, D., Katsyuba, E., & Auwerx, J. H. (2019) · Journal of Lipid Research · doi:10.1194/jlr.s092007 · Cited by 74 · see citing works
“Interestingly, NAD-consuming enzymes, including the poly(ADP-ribose)-polymerase (PARP) family, can be overactivated in some diseases by lipid overload and, hence, could be responsible for NAD depletion, as observed in steatotic livers (57).”
BackgroundSelf-citationPham, T. X., Bae, M., Kim, M., Lee, Y., Hu, S., Kang, H., Park, Y., & Lee, J. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.06.009 · Cited by 73 · see citing works
“In fact, it has been demonstrated that genetic deletion and pharmacological inhibition of PARP1 can significantly attenuate the reduction of liver NAD + induced by a high-fat diet [52, 53].”
BackgroundKeeping the balance in NAD metabolism
Strømland, Ø., Niere, M., Nikiforov, A. A., VanLinden, M. R., Heiland, I., & Ziegler, M. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180417 · Cited by 72 · see citing works
The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks
Demény, M. Á., & Virág, L. (2021) · Cancers · doi:10.3390/cancers13092042 · Cited by 70 · see citing works
Wang, X. X., Xie, C., Libby, A. E., Ranjit, S., Levi, J., Myakala, K., Bhasin, K., Jones, B. A., Orlicky, D. J., Takahashi, S., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102530 · Cited by 66 · see citing works
“mitochondrial function per se may mediate anti-inflammatory, anti-oxidative, and antifibrotic effects (47-50).”
BackgroundMusso, G., Saba, F., Cassader, M., & Gambino, R. (2023) · Progress in Lipid Research · doi:10.1016/j.plipres.2023.101238 · Cited by 67 · see citing works
Metabolic roles of poly(ADP-ribose) polymerases
Vida, A., Márton, J., Mikó, E., & Bai, P. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.12.009 · Cited by 66 · see citing works
Chen, L., Li, Y., Bai, M., Huang, Y., Yang, H., Liu, L., Wang, S., Yu, C., Song, Z., Bao, Y., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104657 · Cited by 60 · see citing works
Zheng, X., Zhao, M., Jiang, C., Sheng, X., Yang, H., Liu, Y., Yao, X.-M., Zhang, J., & Yin, Z. (2019) · Phytomedicine · doi:10.1016/j.phymed.2019.153130 · Cited by 60 · see citing works
NAD+ and NAFLD – caution, causality and careful optimism
Dall, M., Hassing, A. S., & Treebak, J. T. (2021) · The Journal of Physiology · doi:10.1113/jp280908 · Cited by 57 · see citing works
“…and reverses NAFLD induced by high-fat high fructose diet NR elevates hepatic NAD+ content, decreases triglyceride accumulation and fibrosis markers Gariani et al. 2017 Olaparip (PARP inhibitor, 50 mg/kg/day added to diet) 5, 9 and 18 weeks Mice (male C57BL/6J, 7 weeks of age) PARP inhibition…”
BackgroundWang, X., Zhang, Z.-F., Zheng, G., Wang, A., Sun, C., Qin, S., Zhuang, J., Lu, J. L., Ma, D., & Zheng, Y. (2017) · Molecules · doi:10.3390/molecules22081315 · Cited by 55 · see citing works
“Accumulated evidence reveals that PARP1 is largely promoted by oxidative stress under various pathological conditions, resulting in NAD+ depletion [31,32].”
BackgroundRole of PARP-1 in mitochondrial homeostasis
Kadam, A. A., Jubin, T., Roychowdhury, R., & Begum, R. (2020) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2020.129669 · Cited by 55 · see citing works
NAD+: A key metabolic regulator with great therapeutic potential
Sultani, G., Samsudeen, A., Osborne, B., & Turner, N. A. (2017) · Journal of Neuroendocrinology · doi:10.1111/jne.12508 · Cited by 54 · see citing works
NAD+ Deficits in Age-Related Diseases and Cancer
Garrido, A., & Djouder, N. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.06.001 · Cited by 52 · see citing works
Xu, X., Wang, W., Lin, L., & Chen, P. (2020) · Tissue and Cell · doi:10.1016/j.tice.2020.101382 · Cited by 52 · see citing works
Targeting organ-specific mitochondrial dysfunction to improve biological aging
Madreiter‐Sokolowski, C. T., Hiden, U., Krstić, J., Panzitt, K., Wagner, M., Enzinger, C., Khalil, M., Abdellatif, M., Malle, E., Madl, T., et al. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108710 · Cited by 54 · see citing works
Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage
Sambeat, A., Ratajczak, J., Joffraud, M., Sanchez-Garcia, J. L., Giner, M. P., Valsesia, A., Giroud‐Gerbetant, J., Valera‐Alberni, M., Cercillieux, A., Boutant, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12262-x · Cited by 51 · see citing works
Emerging strategies, applications and challenges of targeting NAD+ in the clinic
Zhang, J., Wang, H., Lautrup, S., Nilsen, H. L., Treebak, J. T., Watne, L. O., Selbæk, G., Wu, L. E., Omland, T., Pirinen, E., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00947-6 · Cited by 58 · see citing works
“Specifically, NAD + depletion, probably due to PARylation driven by oxidative stress and DNA damage, emerged as a critical factor in MASLD progression 124–127 .”
A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis
Lu, R., Jiang, Y.-N., Lai, X., Liu, S., Sun, L., & Zhou, Z. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168898 · Cited by 49 · see citing works
“It has been reported that inhibition of PARP1 can increase the expression of GPX4 in mouse livers and PC12 cells [27,28].”
BackgroundA Double-Edged Sword: The Two Faces of PARylation
Kang, M., Park, S., Park, S., Lee, H. G., & Park, J. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179826 · Cited by 46 · see citing works
“Pharmacological inhibition of PARylation has protective effects against non-alcoholic and alcoholic hepatic steatosis induced by a high-fat diet [66].”
BackgroundRuan, Q., Ruan, J., Zhang, W., Qian, F., & Yu, Z. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.08.010 · Cited by 44 · see citing works
Lu, H., Wang, X., Li, M., Ji, D., Liang, D., Liang, C., Liu, Y., Zhang, Z., Cao, Y., & Zou, W. (2022) · Cells · doi:10.3390/cells12010020 · Cited by 44 · see citing works
“Studies on primary hepatocytes have shown that Hsp60 and CLPP expression are significantly downregulated in the absence of SIRT3 and then increase after NAD+ supplementation [30].”
NAD+ Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies
Chen, C., Yan, W., Tao, M., & Fu, Y. (2023) · Antioxidants · doi:10.3390/antiox12061230 · Cited by 44 · see citing works
Dall, M., Penke, M., Sulek, K., Matz‐Soja, M., Holst, B., Garten, A., Kieß, W., & Treebak, J. T. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.01.025 · Cited by 44 · see citing works
Yi, H. (2019) · Endocrinology and Metabolism · doi:10.3803/enm.2019.34.1.39 · Cited by 44 · see citing works
Self-citationZhang, X., Cheng, Q., Chen, J., Lam, A. T., Lu, Y., Dai, Z., Pei, H., Evdokimov, N. M., Louie, S. G., & Zhang, Y. (2019) · Nature Communications · doi:10.1038/s41467-019-12215-4 · Cited by 42 · see citing works
Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations
Cercillieux, A., Ciarlo, E., & Cantó, C. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04499-5 · Cited by 41 · see citing works
“This is consistent with increased PARP [49, 92] and CD38 [56] activities in tissues from HFD fed mice.”
BackgroundResultA systems-approach to NAD+ restoration
Conlon, N. J., & Ford, D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114946 · Cited by 40 · see citing works
Kors, L., Rampanelli, E., Stokman, G., Butter, L. M., Held, N. M., Claessen, N., Larsen, P. W. B., Verheij, J., Zuurbier, C. J., Liebisch, G., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.03.003 · Cited by 40 · see citing works
ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH
Liu, Y. J., Kimura, M., Li, X., Sulc, J., Wang, Q., Rodríguez-López, S., Scantlebery, A. M. L., Strotjohann, K., Gallart‐Ayala, H., Vijayakumar, A., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.08.009 · Cited by 37 · see citing works
Self-citationWu, Y., Tan, F., Zhang, T., Binglin, X., Ran, L., & Zhao, X. (2020) · Applied Biological Chemistry · doi:10.1186/s13765-020-00541-x · Cited by 36 · see citing works
Wasyluk, W., & Zwolak, A. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s300679 · Cited by 35 · see citing works
Pleiotropic role of PARP1: an overview
Kumar, V., Kumar, A., Mir, K. U. I., Yadav, V., & Chauhan, S. S. (2021) · 3 Biotech · doi:10.1007/s13205-021-03038-6 · Cited by 34 · see citing works
“The inhibition of PARP1 reduces endoplasmic reticulum stress (Gariani et al. 2017), leading to the downregulation of de novo lipid biosynthesis (Mukhopadhyay et al.”
BackgroundA Bifunctional NAD+ for Profiling Poly-ADP-Ribosylation-Dependent Interacting Proteins
Lam, A. T., Zhang, X., Courouble, V. V., Strutzenberg, T. S., Pei, H., Stiles, B. L., Louie, S. G., Griffin, P. R., & Zhang, Y. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.0c00937 · Cited by 33 · see citing works
PARPs and PARP inhibitors: molecular mechanisms and clinical applications
Wang, F., Zhuyi, G. U. O., Carr, M. J., & Shi, W. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00385-1 · Cited by 30 · see citing works
“For example, in non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), activation of PARP1 and PARP2 leads to increased fat accumulation in hepatocytes [195, 196], while PARP inhibition attenuates these pathological changes [190, 195].”
Implications of NAD + boosters in translational medicine
Kang, B. E., Choi, J., Stein, S., & Ryu, D. (2020) · European Journal of Clinical Investigation · doi:10.1111/eci.13334 · Cited by 32 · see citing works
Self-citationDiscovery of an NAD + analogue with enhanced specificity for PARP1
Zhang, X., Lam, A. T., Cheng, Q., Courouble, V. V., Strutzenberg, T. S., Li, J., Wang, Y., Pei, H., Stiles, B. L., Louie, S. G., et al. (2022) · Chemical Science · doi:10.1039/d1sc06256e · Cited by 30 · see citing works
He, S., Guo, W., Deng, F., Chen, K., Jiang, Y., Dong, M., Peng, L., & Chen, X. (2018) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2018.1453830 · Cited by 30 · see citing works
“Furthermore, the development of NAFLD is typically accompanied by a series of metabolic disorders [5,6].”
BackgroundCortesi, L., Piombino, C., & Toss, A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11040245 · Cited by 29 · see citing works
“In a murine model of non-alcoholic fatty liver disease, a methionine- and choline-deficient diet attenuated PARP activation, enhancing the benefits of olaparib [32].”
BackgroundKorkmaz‐Icöz, S., Szczęsny, B., Marcatti, M., Li, S., Ruppert, M., Lasitschka, F., Loganathan, S., Szabó, C., & Szabo, G. B. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13983 · Cited by 29 · see citing works
“, 2018), and (5) protective effects of olaparib in rodent models of acute and chronic liver failure (Gariani et al., 2017; Mukhopadhyay et al., 2017).”
BackgroundNicotinamide induces liver regeneration and improves liver function by activating SIRT1
Wan, H., Li, J., Liao, H., Liao, M., Luo, L., Xu, L., Yuan, K., & Zeng, Y. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9688 · Cited by 28 · see citing works
“It was additionally reported that Nam serves as a precursor of oxidized nicotinamide adenine dinucleotide (NAD+) during the metabolism of hepatocytes in liver tissue (17-20).”
BackgroundNAMPT overexpression alleviates alcohol-induced hepatic steatosis in mice
Xiong, X., Yu, J., Fan, R., Zhang, C., Xu, L., Sun, X., Huang, Y., Wang, Q., Ruan, H., & Qian, X. (2019) · PLoS ONE · doi:10.1371/journal.pone.0212523 · Cited by 28 · see citing works
Sirtuins, a key regulator of ageing and age-related neurodegenerative diseases
Bhatt, V., & Tiwari, A. K. (2022) · International Journal of Neuroscience · doi:10.1080/00207454.2022.2057849 · Cited by 26 · see citing works
“There are several other molecules such as Thiazoloquin [310], PJ34 [81, 311] that increases the NAD + level by inhibiting the CD38 and PARP1 respectively.”
BackgroundNicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions
Li, J., Sun, W.-D., Zhu, X., Mei, Y.-Z., Li, W.-S., & Li, J.-H. (2024) · Metabolites · doi:10.3390/metabo14060343 · Cited by 26 · see citing works
Existing Evidence for the Repurposing of PARP-1 Inhibitors in Rare Demyelinating Diseases
Mekhaeil, M., Dev, K. K., & Conroy, M. J. (2022) · Cancers · doi:10.3390/cancers14030687 · Cited by 25 · see citing works
Lu, J., Wang, M., Chen, Y., Song, H., Wen, D., Tu, J., Guo, Y., & Liu, Z. (2022) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2022.110294 · Cited by 25 · see citing works
Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity
Zhan, T., Xiong, H., Pang, J., Zhang, W., Ye, Y., Liang, Z., Huang, X., He, F., Jian, B., He, W., et al. (2021) · Toxicology Letters · doi:10.1016/j.toxlet.2021.05.013 · Cited by 24 · see citing works
Yu, J., Laybutt, D. R., Kim, L.-J., Quek, L.-E., Wu, L. E., Morris, M. J., & Youngson, N. A. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00446.2020 · Cited by 24 · see citing works
The Role of NAD+ in Regenerative Medicine
Conlon, N. J. (2021) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0000000000009673 · Cited by 22 · see citing works
“5 21 Improvements to muscle function and endurance 20 were also observed together with increased mitochondrial function, ATP production 14 and an increased number and quality of muscle stem cells.”
Zhou, F., Shang, B., Liu, C., Fang, W.-W., Wen, S., Zeng, H., Huang, J.-A., & Liu, Z. (2025) · Food Research International · doi:10.1016/j.foodres.2025.115666 · Cited by 21 · see citing works
The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target
Wang, M., Zhao, J., Chen, J., Long, T., Xu, M., Luo, T., Che, Q., He, Y.-H., & Xu, D. (2024) · PeerJ · doi:10.7717/peerj.17094 · Cited by 20 · see citing works
“Notably, liver PARP levels, which can result in depletion of ATP and NAD and subsequent inhibition of SIRT1, progressively increase during the development of NAFLD ( Gariani et al., 2017 ).”
BackgroundSantos, S. S., Brunialti, M. K. C., Rodrigues, L. D. O. C. P., Liberatore, A. M. A., Koh, I. H. J., Martins, V., Soriano, F. G., Szabó, C., & Salomão, R. (2022) · Biomolecules · doi:10.3390/biom12060788 · Cited by 20 · see citing works
“In another study, olaparib protected against acute hepatitis by reducing overall protein PARylation, improving liver function, and reducing the expression of inflammatory genes in a liver injury model induced by endotoxin injection [33].”
BackgroundPurhonen, J., Rajendran, J., Tegelberg, S., Smolander, O., Pirinen, E., Kallijärvi, J., & Fellman, V. (2018) · The FASEB Journal · doi:10.1096/fj.201800090r · Cited by 20 · see citing works
Ferretti, L. P., Böhi, F., Pedrioli, D. M. L., Cheng, P. F., Ferrari, E., Baumgaertner, P., Alvarado-Diaz, A., Sella, F., Cereghetti, A., Turko, P., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-0485 · Cited by 20 · see citing works
Huang, S., Zhang, B., Chen, Y., Liu, H., Liu, Y., Li, X., Bao, Z., Song, Z., & Wang, Z. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.243105 · Cited by 18 · see citing works
“PARP inhibitor olaparib (4-[[3-[[4-(cyclopropylcarbonyl)-1piperazinyl]carbonyl]-4-fluorophenyl]methyl]-1(2H)-phthalazinone; C24H23FN4O3) improved hepatic fatty acid oxidation and NAFLD induced by a HFHS diet (Gariani et al., 2017).”
BackgroundMethodInfluential‘PARP’ing fibrosis: repurposing poly (ADP ribose) polymerase (PARP) inhibitors
Rao, P. D., Sankrityayan, H., Srivastava, A., Kulkarni, Y. A., Mulay, S. R., & Gaikwad, A. B. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.04.019 · Cited by 17 · see citing works
Martín‐Guerrero, S. M., Muñoz‐Gámez, J. A., Carrasco, M., Salmerón, J., Martín‐Estebané, M., Cuadros, M. Á., Navascués, J., & Martín‐Oliva, D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0187130 · Cited by 16 · see citing works
A comparison of rat models that best mimic immune-driven preeclampsia in humans
Jahan, F., Vasam, G., Cariaco, Y., Nik-Akhtar, A., Green, A. L., Menzies, K. J., & Bainbridge, S. A. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1219205 · Cited by 16 · see citing works
Self-citationShen, W., Wan, X., Hou, J., Liu, Z., Mao, G., Xu, X., Yu, C., Zhu, X., & Ju, Z. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac031 · Cited by 13 · see citing works
Hao, W., Jialong, Z., Jiuzhi, Y., Yang, Y. S., Lv, C., & Jin-cai, L. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102347 · Cited by 13 · see citing works
“In high fat and high sucrose-diet induced NAFLD mice, increasing PAR level is associated with elevating hepatic lipid content, and PARP inhibition ameliorates live injury and reverses NAFLD(Gariani et al., 2017).”
Kim, H. Y., Hong, M. H., Kim, K. W., Yoon, J. J., Lee, J. E., Kang, D. G., & Lee, H. S. (2020) · Nutrients · doi:10.3390/nu12123859 · Cited by 13 · see citing works
“In the case of obesity, when fat accumulates in hepatocytes owing to dyslipidemia, liver weight increases and the entire liver becomes enlarged, resulting in further liver damage [45,46].”
BackgroundSelf-citationHuang, X., Yang, J., Hu, Y., Li, S., Cai, Z., Li, C., Qin, W., & Zhang, G. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s510937 · Cited by 13 · see citing works
NAD + depletion is central to placental dysfunction in an inflammatory subclass of preeclampsia
Jahan, F., Vasam, G., Cariaco, Y., Nik-Akhtar, A., Green, A. E., Menzies, K. J., & Bainbridge, S. A. (2024) · Life Science Alliance · doi:10.26508/lsa.202302505 · Cited by 12 · see citing works
“To avoid unnecessary delays in the acceptance and publication of your paper, please read the following information carefully.”
InfluentialSelf-citationThapa, K., Grewal, A. S., Kanojia, N., Rani, L., Sharma, N., & Singh, S. (2020) · Current Drug Discovery Technologies · doi:10.2174/1570163817666200121143959 · Cited by 12 · see citing works
Repurposing of Clinically Approved Poly-(ADP-Ribose) Polymerase Inhibitors for the Therapy of Sepsis
Santos, S. S., Brunialti, M. K. C., Soriano, F. G., Szabó, C., & Salomão, R. (2021) · Shock · doi:10.1097/shk.0000000000001820 · Cited by 11 · see citing works
“Olaparib treatment protected against acute hepatitis by reducing overall protein PARylation, improving liver function, and reducing the expression of inflammatory genes in a liver injury model induced by endotoxin injection (71).”
BackgroundA macrodomain-linked immunosorbent assay (MLISA) for mono-ADP-ribosyltransferases
Chen, J., Lam, A. T., & Zhang, Y. (2017) · Analytical Biochemistry · doi:10.1016/j.ab.2017.12.019 · Cited by 10 · see citing works
The Role of Stearoyl-coenzyme A Desaturase 1 in Liver Development, Function, and Pathogenesis
Mohammadzadeh, F., Hosseini, V., Alihemmati, A., Shaaker, M., Mosayebi, G., Darabi, M., & Mehdizadeh, A. (2019) · Journal of Renal and Hepatic Disorders · doi:10.15586/jrenhep.2019.49 · Cited by 10 · see citing works
“PARP-SCD1 interaction as a major mechanism in the induction of non-alcoholic fatty liver disease (33).”
Background
- Authors
- Gariani, K., Ryu, D., Menzies, K. J., Yi, H.-S., Stein, S., Zhang, H., Perino, A., Lemos, V., Katsyuba, E., Jha, P., Vijgen, S., Rubbia-Brandt, L., Kim, Y. K., Kim, J. T., Kim, K. S., Shong, M., Schoonjans, K., & Auwerx, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- University of Ottawa (CA)
- Chungnam National University (KR)
- University of Zurich (CH)
- University Hospital of Geneva (CH)
- Corresponding author
- Auwerx, Johan
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 66
- Issue
- 1
- Pages
- 132-141
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2521759723
- Cited by
- 167
- References
- 53
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 14 · 2023: 14 · 2022: 21 · 2021: 17 · 2020: 16 · 2019: 13 · 2018: 12 · 2017: 23 · 2016: 2
- FWCI
- 15.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (161521)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- non-alcoholic fatty liver disease, poly(ADP-ribosyl)ation, PARP inhibitors, olaparib, NAD+ depletion, sirtuins, SIRT1, hepatic fatty acid oxidation, mitochondrial biogenesis, fatty acid beta-oxidation, mitochondrial function, endoplasmic reticulum stress, liver fibrosis, reactive oxygen species, methionine-choline-deficient diet, high-fat high-sugar diet
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Disease Models, Animal, Liver, Oxidation-Reduction, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerases, Lipid Metabolism, Mice, Non-alcoholic Fatty Liver Disease
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