|
|
核受体PPAR在肝纤维化中的作用
|
Abstract:
肝纤维化是反复肝损伤和炎症导致肝脏形成纤维瘢痕，主要由非酒精性脂肪肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)、慢性毒性损伤、代谢相关损伤等引起，可导致肝衰竭、肝硬化等，甚至可能会导致肝癌。目前，临床上对肝纤维化的发病机制和治疗进行了许多研究，并取得了一些进展。其中，临床前研究表明，过氧化物酶体增殖物激活受体(PPAR)参与炎症、能量平衡、脂质代谢、葡萄糖稳态的转录调节，在防治肝纤维化的发展中起到十分重要的作用。在本文中我们概述过氧化物酶体增殖物激活受体在肝纤维化中发展中的机制，并讨论以过氧化物酶体增殖物激活受体为靶点的抗纤维化药物的发展潜力。
Liver fibrosis is the formation of fibrotic scars in the liver due to repeated liver injury and inflammation, mainly caused by non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty hepatitis (NASH), chronic toxic injury, metabolic related injury, etc. It can lead to liver failure, cirrhosis, and even liver cancer. At present, there have been many studies on the pathogenesis and treatment of liver fibrosis in clinical practice, and some progress has been made. Among them, preclinical studies have shown that peroxisome proliferator activated receptor (PPAR) is involved in transcriptional regulation of inflammation, energy balance, lipid metabolism, and glucose homeostasis, and plays a crucial role in preventing and treating the development of liver fibrosis. In this article, we outline the mechanisms underlying the development of peroxisome proliferator activated receptors in liver fibrosis and discuss the potential for the development of anti fibrotic drugs targeting peroxisome proliferator activated receptors.
| [1] | Parola, M. and Pinzani, M. (2019) Liver Fibrosis: Pathophysiology, Pathogenetic Targets and Clinical Issues. Molecular Aspects of Medicine, 65, 37-55. https://doi.org/10.1016/j.mam.2018.09.002 |
| [2] | Zheng, Y., Sun, W., Wang, Z., Liu, J., Shan, C., He, C., et al. (2022) Activation of Pancreatic Acinar FXR Protects against Pancreatitis via Osgin1-Mediated Restoration of Efficient Autophagy. Research, 2022, Article ID: 9784081. https://doi.org/10.34133/2022/9784081 |
| [3] | Lamas Bervejillo, M. and Ferreira, A.M. (2019) Understanding Peroxisome Proliferator-Activated Receptors: From the Structure to the Regulatory Actions on Metabolism. In: Trostchansky, A. and Rubbo, H., Eds., Advances in Experimental Medicine and Biology, Springer International Publishing, 39-57. https://doi.org/10.1007/978-3-030-11488-6_3 |
| [4] | Linghu, L., Zong, W., Liao, Y., Chen, Q., Meng, F., Wang, G., et al. (2023) Herpetrione, a New Type of PPARα Ligand as a Therapeutic Strategy against Nonalcoholic Steatohepatitis. Research, 6, Article ID: 0276. https://doi.org/10.34133/research.0276 |
| [5] | Kisseleva, T. and Brenner, D. (2020) Molecular and Cellular Mechanisms of Liver Fibrosis and Its Regression. Nature Reviews Gastroenterology & Hepatology, 18, 151-166. https://doi.org/10.1038/s41575-020-00372-7 |
| [6] | Fritzen, A.M., Lundsgaard, A. and Kiens, B. (2020) Tuning Fatty Acid Oxidation in Skeletal Muscle with Dietary Fat and Exercise. Nature Reviews Endocrinology, 16, 683-696. https://doi.org/10.1038/s41574-020-0405-1 |
| [7] | Tahri-Joutey, M., Andreoletti, P., Surapureddi, S., Nasser, B., Cherkaoui-Malki, M. and Latruffe, N. (2021) Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPAR. International Journal of Molecular Sciences, 22, Article 8969. https://doi.org/10.3390/ijms22168969 |
| [8] | Reddy, J.K. (2004) Peroxisome Proliferators and Peroxisome Proliferator-Activated Receptor α. The American Journal of Pathology, 164, 2305-2321. https://doi.org/10.1016/s0002-9440(10)63787-x |
| [9] | Zhang, X., Gao, T., Deng, S., Shang, L., Chen, X., Chen, K., et al. (2021) Fasting Induces Hepatic Lipid Accumulation by Stimulating Peroxisomal Dicarboxylic Acid Oxidation. Journal of Biological Chemistry, 296, Article 100622. https://doi.org/10.1016/j.jbc.2021.100622 |
| [10] | Ranea-Robles, P. and Houten, S.M. (2023) The Biochemistry and Physiology of Long-Chain Dicarboxylic Acid Metabolism. Biochemical Journal, 480, 607-627. https://doi.org/10.1042/bcj20230041 |
| [11] | Christofides, A., Konstantinidou, E., Jani, C. and Boussiotis, V.A. (2021) The Role of Peroxisome Proliferator-Activated Receptors (PPAR) in Immune Responses. Metabolism, 114, Article 154338. https://doi.org/10.1016/j.metabol.2020.154338 |
| [12] | Devchand, P.R., Keller, H., Peters, J.M., Vazquez, M., Gonzalez, F.J. and Wahli, W. (1996) The PPARα-Leukotriene B4 Pathway to Inflammation Control. Nature, 384, 39-43. https://doi.org/10.1038/384039a0 |
| [13] | Gallucci, G.M., Alsuwayt, B., Auclair, A.M., Boyer, J.L., Assis, D.N. and Ghonem, N.S. (2022) Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-Inflammatory Cytokine Secretion in Human THP-1 Macrophages and during Primary Biliary Cholangitis. Inflammation, 45, 2570-2581. https://doi.org/10.1007/s10753-022-01713-1 |
| [14] | Crisafulli, C. and Cuzzocrea, S. (2009) The Role of Endogenous and Exogenous Ligands for the Peroxisome Proliferator-Activated Receptor Alpha (PPAR-Α) in the Regulation of Inflammation in Macrophages. Shock, 32, 62-73. https://doi.org/10.1097/shk.0b013e31818bbad6 |
| [15] | Kleemann, R., Gervois, P.P., Verschuren, L., Staels, B., Princen, H.M.G. and Kooistra, T. (2003) Fibrates Down-Regulate Il-1-Stimulated C-Reactive Protein Gene Expression in Hepatocytes by Reducing Nuclear P50-NFκB-C/EBP-β Complex Formation. Blood, 101, 545-551. https://doi.org/10.1182/blood-2002-06-1762 |
| [16] | Hill, M.R., Clarke, S., Rodgers, K., Thornhill, B., Peters, J.M., Gonzalez, F.J., et al. (1999) Effect of Peroxisome Proliferator-Activated Receptor Alpha Activators on Tumor Necrosis Factor Expression in Mice during Endotoxemia. Infection and Immunity, 67, 3488-3493. https://doi.org/10.1128/iai.67.7.3488-3493.1999 |
| [17] | Wigg, A.J. (2001) The Role of Small Intestinal Bacterial Overgrowth, Intestinal Permeability, Endotoxaemia, and Tumour Necrosis Factor Alpha in the Pathogenesis of Non-Alcoholic Steatohepatitis. Gut, 48, 206-211. https://doi.org/10.1136/gut.48.2.206 |
| [18] | Wagner, N. and Wagner, K. (2020) The Role of PPARs in Disease. Cells, 9, Article 2367. https://doi.org/10.3390/cells9112367 |
| [19] | Tailleux, A., Wouters, K. and Staels, B. (2012) Roles of PPARs in NAFLD: Potential Therapeutic Targets. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1821, 809-818. https://doi.org/10.1016/j.bbalip.2011.10.016 |
| [20] | Flowers, M.T. and Ntambi, J.M. (2008) Role of Stearoyl-Coenzyme a Desaturase in Regulating Lipid Metabolism. Current Opinion in Lipidology, 19, 248-256. https://doi.org/10.1097/mol.0b013e3282f9b54d |
| [21] | Zarei, M., Barroso, E., Palomer, X., Dai, J., Rada, P., Quesada-López, T., et al. (2018) Hepatic Regulation of VLDL Receptor by PPARβ/δ and FGF21 Modulates Non-Alcoholic Fatty Liver Disease. Molecular Metabolism, 8, 117-131. https://doi.org/10.1016/j.molmet.2017.12.008 |
| [22] | Wang, Y., Nakajima, T., Gonzalez, F.J. and Tanaka, N. (2020) PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice. International Journal of Molecular Sciences, 21, Article 2061. https://doi.org/10.3390/ijms21062061 |
| [23] | Sanderson, L.M., Boekschoten, M.V., Desvergne, B., Müller, M. and Kersten, S. (2010) Transcriptional Profiling Reveals Divergent Roles of PPARα and PPARβ/δ in Regulation of Gene Expression in Mouse Liver. Physiological Genomics, 41, 42-52. https://doi.org/10.1152/physiolgenomics.00127.2009 |
| [24] | Vázquez-Carrera, M. and Wahli, W. (2024) Ppars as Key Transcription Regulators at the Crossroads of Metabolism and Inflammation. International Journal of Molecular Sciences, 25, Article 4467. https://doi.org/10.3390/ijms25084467 |
| [25] | Qiu, Y., Zhang, J., Zeng, F. and Zhu, Y.Z. (2023) Roles of the Peroxisome Proliferator-Activated Receptors (PPARs) in the Pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD). Pharmacological Research, 192, Article 106786. https://doi.org/10.1016/j.phrs.2023.106786 |
| [26] | Jackson, S.M., Parhami, F., Xi, X., Berliner, J.A., Hsueh, W.A., Law, R.E., et al. (1999) Peroxisome Proliferator—Activated Receptor Activators Target Human Endothelial Cells to Inhibit Leukocyte-Endothelial Cell Interaction. Arteriosclerosis, Thrombosis, and Vascular Biology, 19, 2094-2104. https://doi.org/10.1161/01.atv.19.9.2094 |
| [27] | Yoo, J., Jeong, I., Ahn, K.J., Chung, H.Y. and Hwang, Y. (2021) Fenofibrate, a PPARα Agonist, Reduces Hepatic Fat Accumulation through the Upregulation of TFEB-Mediated Lipophagy. Metabolism, 120, Article 154798. https://doi.org/10.1016/j.metabol.2021.154798 |
| [28] | Lawitz, E.J., Bhandari, B.R., Ruane, P.J., Kohli, A., Harting, E., Ding, D., et al. (2023) Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated with Cilofexor/Firsocostat. Clinical Gastroenterology and Hepatology, 21, 143-152.E3. https://doi.org/10.1016/j.cgh.2021.12.044 |
| [29] | Mahmoudi, A., Jamialahmadi, T., Johnston, T.P. and Sahebkar, A. (2022) Impact of Fenofibrate on NAFLD/NASH: A Genetic Perspective. Drug Discovery Today, 27, 2363-2372. https://doi.org/10.1016/j.drudis.2022.05.007 |
| [30] | Ginsberg, H.N., Hounslow, N.J., Senko, Y., Suganami, H., Bogdanski, P., Ceska, R., et al. (2022) Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy. Diabetes Care, 45, 898-908. https://doi.org/10.2337/dc21-1288 |
| [31] | Nakajima, A., Eguchi, Y., Yoneda, M., Imajo, K., Tamaki, N., Suganami, H., et al. (2021) Randomised Clinical Trial: Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor Α Modulator (SPPARMα), versus Placebo in Patients with Non-Alcoholic Fatty Liver Disease. Alimentary Pharmacology & Therapeutics, 54, 1263-1277. https://doi.org/10.1111/apt.16596 |
| [32] | Yamashita, S., Masuda, D. and Matsuzawa, Y. (2020) Pemafibrate, a New Selective PPARα Modulator: Drug Concept and Its Clinical Applications for Dyslipidemia and Metabolic Diseases. Current Atherosclerosis Reports, 22, Article No. 5. https://doi.org/10.1007/s11883-020-0823-5 |
| [33] | de Vries, E., Bolier, R., Goet, J., Parés, A., Verbeek, J., de Vree, M., et al. (2021) Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial. Gastroenterology, 160, 734-743.e6. https://doi.org/10.1053/j.gastro.2020.10.001 |
| [34] | Rudic, J.S., Poropat, G., Krstic, M.N., Bjelakovic, G. and Gluud, C. (2012) Bezafibrate for Primary Biliary Cirrhosis. Cochrane Database of Systematic Reviews, 2012, CD009145. https://doi.org/10.1002/14651858.cd009145.pub2 |
| [35] | Sanyal, A., Charles, E.D., Neuschwander-Tetri, B.A., Loomba, R., Harrison, S.A., Abdelmalek, M.F., et al. (2018) Pegbelfermin (BMS-986036), a PEGylated Fibroblast Growth Factor 21 Analogue, in Patients with Non-Alcoholic Steatohepatitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2a Trial. The Lancet, 392, 2705-2717. https://doi.org/10.1016/s0140-6736(18)31785-9 |
| [36] | Harrison, S.A., Ruane, P.J., Freilich, B.L., Neff, G., Patil, R., Behling, C.A., et al. (2021) Efruxifermin in Non-Alcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Trial. Nature Medicine, 27, 1262-1271. https://doi.org/10.1038/s41591-021-01425-3 |
| [37] | Haczeyni, F., Wang, H., Barn, V., Mridha, A.R., Yeh, M.M., Haigh, W.G., et al. (2017) The Selective Peroxisome Proliferator-Activated Receptor-Delta Agonist Seladelpar Reverses Nonalcoholic Steatohepatitis Pathology by Abrogating Lipotoxicity in Diabetic Obese Mice. Hepatology Communications, 1, 663-674. https://doi.org/10.1002/hep4.1072 |
| [38] | Dhingra, S., Mahadik, J.D., Tarabishy, Y., May, S.B. and Vierling, J.M. (2022) Prevalence and Clinical Significance of Portal Inflammation, Portal Plasma Cells, Interface Hepatitis and Biliary Injury in Liver Biopsies from Patients with Non-Alcoholic Steatohepatitis. Pathology, 54, 686-693. https://doi.org/10.1016/j.pathol.2022.01.009 |
| [39] | Aithal, G.P., Thomas, J.A., Kaye, P.V., Lawson, A., Ryder, S.D., Spendlove, I., et al. (2008) Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects with Nonalcoholic Steatohepatitis. Gastroenterology, 135, 1176-1184. https://doi.org/10.1053/j.gastro.2008.06.047 |
| [40] | Gupte, A.A., Liu, J.Z., Ren, Y., Minze, L.J., Wiles, J.R., Collins, A.R., et al. (2010) Rosiglitazone Attenuates Age-and Diet-Associated Nonalcoholic Steatohepatitis in Male Low-Density Lipoprotein Receptor Knockout Mice. Hepatology, 52, 2001-2011. https://doi.org/10.1002/hep.23941 |
| [41] | Wei, Z., Zhao, D., Zhang, Y., Chen, Y., Zhang, S., Li, Q., et al. (2019) Rosiglitazone Ameliorates Bile Duct Ligation-Induced Liver Fibrosis by Down-Regulating NF-κB-TNF-α Signaling Pathway in a PPARγ-Dependent Manner. Biochemical and Biophysical Research Communications, 519, 854-860. https://doi.org/10.1016/j.bbrc.2019.09.084 |
| [42] | Ratziu, V., Giral, P., Jacqueminet, S., Charlotte, F., Hartemann-Heurtier, A., Serfaty, L., et al. (2008) Rosiglitazone for Nonalcoholic Steatohepatitis: One-Year Results of the Randomized Placebo-Controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology, 135, 100-110. https://doi.org/10.1053/j.gastro.2008.03.078 |
| [43] | Marra, F., Efsen, E., Romanelli, R.G., Caligiuri, A., Pastacaldi, S., Batignani, G., et al. (2000) Ligands of Peroxisome Proliferator-Activated Receptor Γ Modulate Profibrogenic and Proinflammatory Actions in Hepatic Stellate Cells. Gastroenterology, 119, 466-478. https://doi.org/10.1053/gast.2000.9365 |
| [44] | Francque, S.M., Bedossa, P., Ratziu, V., Anstee, Q.M., Bugianesi, E., Sanyal, A.J., et al. (2021) A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. New England Journal of Medicine, 385, 1547-1558. https://doi.org/10.1056/nejmoa2036205 |
| [45] | Kumar, D.P., Caffrey, R., Marioneaux, J., Santhekadur, P.K., Bhat, M., Alonso, C., et al. (2020) The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease. Scientific Reports, 10, Article No. 9330. https://doi.org/10.1038/s41598-020-66458-z |
| [46] | Wu, D., Eeda, V., Undi, R.B., Mann, S., Stout, M., Lim, H., et al. (2021) A Novel Peroxisome Proliferator-Activated Receptor Gamma Ligand Improves Insulin Sensitivity and Promotes Browning of White Adipose Tissue in Obese Mice. Molecular Metabolism, 54, Article 101363. https://doi.org/10.1016/j.molmet.2021.101363 |
| [47] | Harrison, S.A., Alkhouri, N., Davison, B.A., Sanyal, A., Edwards, C., Colca, J.R., et al. (2020) Insulin Sensitizer MSDC-0602K in Non-Alcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo-Controlled Phase IIb Study. Journal of Hepatology, 72, 613-626. https://doi.org/10.1016/j.jhep.2019.10.023 |
| [48] | Davison, B.A., Harrison, S.A., Cotter, G., Alkhouri, N., Sanyal, A., Edwards, C., et al. (2020) Suboptimal Reliability of Liver Biopsy Evaluation Has Implications for Randomized Clinical Trials. Journal of Hepatology, 73, 1322-1332. https://doi.org/10.1016/j.jhep.2020.06.025 |
| [49] | Boyer-Diaz, Z., Aristu-Zabalza, P., Andrés-Rozas, M., Robert, C., Ortega-Ribera, M., Fernández-Iglesias, A., et al. (2021) Pan-PPAR Agonist Lanifibranor Improves Portal Hypertension and Hepatic Fibrosis in Experimental Advanced Chronic Liver Disease. Journal of Hepatology, 74, 1188-1199. https://doi.org/10.1016/j.jhep.2020.11.045 |
