Ablation of Tumor Necrosis Factor Alpha Receptor 1 Signaling Blunts Steatohepatitis in Peroxisome Proliferator Activated Receptor α-Deficient Mice
Main Article Content
Abstract
Tumor necrosis factor -alpha (TNFa) is strongly associated with fatty liver disease (i.e, hepatosteatosis). Cytokine production has been thought of as a consequence of hepatic lipid accumulation which becomes a critical factor in the development of chronic liver pathologies as well as insulin resistance. The purpose of this study was to test the hypothesis that TNFa directly regulates lipid metabolism in liver in the mutant peroxisome-proliferator activated receptor-alpha (PPARa-/-) mouse model with robust hepatic lipid accumulation. At 10 weeks of age, TNFa and TNF receptor 1 expression are increased in livers of PPARa-/- mice compared to wild type. PPARa-/- mice were then crossed with mice lacking the receptor for TNFa receptor 1 (TNFR1-/-). Wild type, PPARa-/-, TNFR1-/-, PPARa-/- x TNFR1-/- mice were housed on ad-libitum standard chow diet for up to 40 weeks. Increases in hepatic lipid and liver injury and metabolic disruption associated with PPARa ablation were largely blunted when PPARa-/- mice were crossed with TNFR1-/- mice. These data support the hypothesis that TNFR1 signaling is critical for accumulation of lipid in liver. Therapies that reduce pro-inflammatory responses, namely TNFa, could have important clinical implications to reduce hepatosteatosis and progression of severe liver disease.
Keywords:
liver, inflammation, immune cell, cytokine
Article Details
How to Cite
HINES, Ian N. et al.
Ablation of Tumor Necrosis Factor Alpha Receptor 1 Signaling Blunts Steatohepatitis in Peroxisome Proliferator Activated Receptor α-Deficient Mice.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3082>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i9.3082.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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24. Dreyer C, Keller H, Mahfoudi A, Laudet V, Krey G, Wahli W. Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR). Biol Cell. 1993;77(1):67-76. doi: 10.1016/s0248-4900(05)80176-5 [doi].
25. Neschen S, Morino K, Hammond LE, et al. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:Glycerol-sn-3-phosphate acyltransferase 1 knockout mice. Cell Metab. 2005;2(1):55-65. doi: S1550-4131(05)00171-3 [pii].
26. Perpinan E, Perez-Del-Pulgar S, Londono MC, et al. Cirrhosis hampers early and rapid normalization of natural killer cell phenotype and function in hepatitis C patients undergoing interferon-free therapy. Front Immunol. 2020;11:129. doi: 10.3389/fimmu.2020.00129 [doi].
27. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183-190. https://pubmed.ncbi.nlm.nih.gov/15685173 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440292/. doi: 10.1038/nm1166.
28. Arkan MC, Hevener AL, Greten FR, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med. 2005;11(2):191-198. doi: nm1185 [pii].
29. Hong GQ, Cai D, Gong JP, Lai X. Innate immune cells and their interaction with T cells in hepatocellular carcinoma. Oncol Lett. 2021;21(1):57. doi: 10.3892/ol.2020.12319 [doi].
30. Lee JY, Plakidas A, Lee WH, et al. Differential modulation of toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res. 2003;44(3):479-486. doi: 10.1194/jlr.M200361-JLR200 [doi].
31. dela Peña A, Leclercq I, Field J, George J, Jones B, Farrell G. NF-κB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology. 2005;129(5):1663-1674. https://www.sciencedirect.com/science/article/pii/S0016508505017889. doi: https://doi.org/10.1053/j.gastro.2005.09.004.
32. Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37(2):343-350. doi: 10.1053/jhep.2003.50048 [doi].
33. Deng QG, She H, Cheng JH, et al. Steatohepatitis induced by intragastric overfeeding in mice. Hepatology. 2005;42(4):905-914. doi: 10.1002/hep.20877 [doi].
34. Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T, et al. Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. Hepatology. 2006;44(3):581-591. doi: 10.1002/hep.21313 [doi].
35. Memon RA, Grunfeld C, Feingold KR. TNF-alpha is not the cause of fatty liver disease in obese diabetic mice. Nat Med. 2001;7(1):2-3. doi: 10.1038/83316 [doi].
36. Czaja MJ. JNK regulation of hepatic manifestations of the metabolic syndrome. Trends Endocrinol Metab. 2010;21(12):707-713. doi: 10.1016/j.tem.2010.08.010 [doi].
37. Seki E, Brenner DA, Karin M. A liver full of JNK: Signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 2012;143(2):307-320. doi: 10.1053/j.gastro.2012.06.004 [doi].
38. Abdelmegeed MA, Yoo SH, Henderson LE, Gonzalez FJ, Woodcroft KJ, Song BJ. PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver. J Nutr. 2011;141(4):603-610. doi: 10.3945/jn.110.135210 [doi].
2. Tilg H, Adolph TE, Dudek M, Knolle P. Non-alcoholic fatty liver disease: The interplay between metabolism, microbes and immunity. Nat Metab. 2021;3(12):1596-1607. doi: 10.1038/s42255-021-00501-9 [doi].
3. Mitra S, De A, Chowdhury A. Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Translational gastroenterology and hepatology. 2020;5:16. https://pubmed.ncbi.nlm.nih.gov/32258520 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063528/. doi: 10.21037/tgh.2019.09.08.
4. Maurice J, Manousou P. Non-alcoholic fatty liver disease. Clin Med (Lond). 2018;18(3):245-250. doi: 10.7861/clinmedicine.18-3-245 [doi].
5. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47(4):571-579. doi: S0168-8278(07)00301-7 [pii].
6. Miyoshi H, Moriya K, Tsutsumi T, et al. Pathogenesis of lipid metabolism disorder in hepatitis C: Polyunsaturated fatty acids counteract lipid alterations induced by the core protein. J Hepatol. 2011;54(3):432-438. doi: 10.1016/j.jhep.2010.07.039 [doi].
7. Perez-Carreras M, Del Hoyo P, Martin MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38(4):999-1007. doi: 10.1053/jhep.2003.50398 [doi].
8. Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302(11):1310. doi: 10.1152/ajpgi.00365.2011 [doi].
9. Liu TF, Brown CM, El Gazzar M, et al. Fueling the flame: Bioenergy couples metabolism and inflammation. J Leukoc Biol. 2012;92(3):499-507. doi: 10.1189/jlb.0212078 [doi].
10. Chen Z, Tian R, She Z, Cai J, Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med. 2020;152:116-141. doi: S0891-5849(19)31515-1 [pii].
11. Rada P, Gonzalez-Rodriguez A, Garcia-Monzon C, Valverde AM. Understanding lipotoxicity in NAFLD pathogenesis: Is CD36 a key driver? Cell Death Dis. 2020;11(9):802-w. doi: 10.1038/s41419-020-03003-w [doi].
12. Ventre J, Doebber T, Wu M, et al. Targeted disruption of the tumor necrosis factor-alpha gene: Metabolic consequences in obese and nonobese mice. Diabetes. 1997;46(9):1526-1531. doi: 10.2337/diab.46.9.1526 [doi].
13. Spencer NY, Zhou W, Li Q, et al. Hepatocytes produce TNF-alpha following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-src-dependent manner. Am J Physiol Gastrointest Liver Physiol. 2013;305(1):84. doi: 10.1152/ajpgi.00430.2012 [doi].
14. Holbrook J, Lara-Reyna S, Jarosz-Griffiths H, McDermott M. Tumour necrosis factor signalling in health and disease. F1000Res. 2019;8:10.12688/f1000research.17023.1. eCollection 2019. doi: F1000 Faculty Rev-111 [pii].
15. Yin M, Wheeler MD, Kono H, et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999;117(4):942-952. doi: S0016508599003625 [pii].
16. Beutler B, Greenwald D, Hulmes JD, et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature. 2014;316(6028):552-554. doi: 10.1038/316552a0 [doi].
17. Davizon-Castillo P, McMahon B, Aguila S, et al. TNF-alpha-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging. Blood. 2019;134(9):727-740. doi: 10.1182/blood.2019000200 [doi].
18. Russell AE, Doll DN, Sarkar SN, Simpkins JW. TNF-alpha and beyond: Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity. J Clin Cell Immunol. 2016;7(6):10.4172/2155-9899.1000467. Epub 2016 Nov 14. doi: 467 [pii].
19. Stadler J, Bentz BG, Harbrecht BG, et al. Tumor necrosis factor alpha inhibits hepatocyte mitochondrial respiration. Ann Surg. 1992;216(5):539-546. doi: 10.1097/00000658-199211000-00003 [doi].
20. Kastl L, Sauer SW, Ruppert T, et al. TNF-alpha mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-kappaB activation in liver cells. FEBS Lett. 2014;588(1):175-183. doi: 10.1016/j.febslet.2013.11.033 [doi].
21. Kim MS, Sweeney TR, Shigenaga JK, et al. Tumor necrosis factor and interleukin 1 decrease RXRalpha, PPARalpha, PPARgamma, LXRalpha, and the coactivators SRC-1, PGC-1alpha, and PGC-1beta in liver cells. Metabolism. 2007;56(2):267-279. doi: S0026-0495(06)00372-6 [pii].
22. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389(6651):610-614. doi: 10.1038/39335 [doi].
23. Wang Y, Nakajima T, Gonzalez FJ, Tanaka N. PPARs as metabolic regulators in the liver: Lessons from liver-specific PPAR-null mice. International Journal of Molecular Sciences. 2020;21(6). doi: 10.3390/ijms21062061.
24. Dreyer C, Keller H, Mahfoudi A, Laudet V, Krey G, Wahli W. Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR). Biol Cell. 1993;77(1):67-76. doi: 10.1016/s0248-4900(05)80176-5 [doi].
25. Neschen S, Morino K, Hammond LE, et al. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:Glycerol-sn-3-phosphate acyltransferase 1 knockout mice. Cell Metab. 2005;2(1):55-65. doi: S1550-4131(05)00171-3 [pii].
26. Perpinan E, Perez-Del-Pulgar S, Londono MC, et al. Cirrhosis hampers early and rapid normalization of natural killer cell phenotype and function in hepatitis C patients undergoing interferon-free therapy. Front Immunol. 2020;11:129. doi: 10.3389/fimmu.2020.00129 [doi].
27. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183-190. https://pubmed.ncbi.nlm.nih.gov/15685173 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440292/. doi: 10.1038/nm1166.
28. Arkan MC, Hevener AL, Greten FR, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med. 2005;11(2):191-198. doi: nm1185 [pii].
29. Hong GQ, Cai D, Gong JP, Lai X. Innate immune cells and their interaction with T cells in hepatocellular carcinoma. Oncol Lett. 2021;21(1):57. doi: 10.3892/ol.2020.12319 [doi].
30. Lee JY, Plakidas A, Lee WH, et al. Differential modulation of toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res. 2003;44(3):479-486. doi: 10.1194/jlr.M200361-JLR200 [doi].
31. dela Peña A, Leclercq I, Field J, George J, Jones B, Farrell G. NF-κB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology. 2005;129(5):1663-1674. https://www.sciencedirect.com/science/article/pii/S0016508505017889. doi: https://doi.org/10.1053/j.gastro.2005.09.004.
32. Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37(2):343-350. doi: 10.1053/jhep.2003.50048 [doi].
33. Deng QG, She H, Cheng JH, et al. Steatohepatitis induced by intragastric overfeeding in mice. Hepatology. 2005;42(4):905-914. doi: 10.1002/hep.20877 [doi].
34. Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T, et al. Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. Hepatology. 2006;44(3):581-591. doi: 10.1002/hep.21313 [doi].
35. Memon RA, Grunfeld C, Feingold KR. TNF-alpha is not the cause of fatty liver disease in obese diabetic mice. Nat Med. 2001;7(1):2-3. doi: 10.1038/83316 [doi].
36. Czaja MJ. JNK regulation of hepatic manifestations of the metabolic syndrome. Trends Endocrinol Metab. 2010;21(12):707-713. doi: 10.1016/j.tem.2010.08.010 [doi].
37. Seki E, Brenner DA, Karin M. A liver full of JNK: Signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 2012;143(2):307-320. doi: 10.1053/j.gastro.2012.06.004 [doi].
38. Abdelmegeed MA, Yoo SH, Henderson LE, Gonzalez FJ, Woodcroft KJ, Song BJ. PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver. J Nutr. 2011;141(4):603-610. doi: 10.3945/jn.110.135210 [doi].