Age‐related sensitivity to endotoxin‐induced liver inflammation: Implication of inflammasome/IL‐1β for steatohepatitis
Open accessAbstract
Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide (LPS)-induced upregulation of the inflammasome/IL-1β pathway is accompanied with an increased inflammatory response and abnormal lipid accumulation in livers of aged rats. To monitor the effects of aging on LPS-induced inflammation, we administered LPS (2 mg kg(-1) ) to young (6-month old) and aged (24-month old) rats and found abnormal lipid metabolism in only aged rats with increased lipid accumulation in the liver. This lipid accumulation in the liver was due to the dysregulation of PPARα and SREBP1c. We also observed severe liver inflammation in aged rats as indicated by increased ALT levels in serum and increased Kupffer cells in the liver. Importantly, among many inflammation-associated factors, the aged rat liver showed chronically increased IL-1β production. Increased levels of IL-1β were caused by the upregulation of caspase-1 activity and inflammasome activation. In vitro studies with HepG2 cells demonstrated that treatment with IL-1β significantly induced lipid accumulation in hepatocytes through the regulation of PPARα and SREBP1c. In summary, we demonstrated that LPS-induced liver inflammation and lipid accumulation were associated with a chronically overactive inflammasome/IL-1β pathway in aged rat livers. Based on the present findings, we propose a mechanism of aging-associated progression of steatohepatitis induced by endotoxin, delineating a pathogenic role of the inflammasome/IL-1β pathway involved in lipid accumulation in the liver.
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Chronically overactive inflammasome activity and production of IL-1β is associated with abnormal lipid accumulation in old rat liver resulting in steatohepatitis.
“Moreover, chronically overactive inflammasome activity and production of IL-1β has been associated with the abnormal lipid accumulation in old rat liver resulting in steatohepatitis (Chung et al., 2015).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Chung et al., 2015
Chronically overactive inflammasome activity and production of IL-1β have been associated with abnormal lipid accumulation in old rat liver resulting in steatohepatitis.
“chronically overactive inflammasome activity and production of IL-1β has been associated with the abnormal lipid accumulation in old rat liver resulting in steatohepatitis (Chung et al., 2015).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Chung et al., 2015
Inflammasome activity has been associated with dysregulation of PPARα and SREBP1c.
“The activity of inflammasome has been associated with dysregulation of PPARα and SREBP1c (Chung et al., 2015).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Chung et al., 2015
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Cites
Changes of Intestinal Functions in Liver Cirrhosis
Fukui, H., & Wiest, R. (2016) · Inflammatory Intestinal Diseases · doi:10.1159/000444436 · Cited by 6,820 · see citing works
Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis
Tilg, H., & Moschen, A. R. (2010) · Hepatology · doi:10.1002/hep.24001 · Cited by 2,548 · see citing works
Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease
Miele, L., Valenza, V., La Torre, G., Montalto, M., Cammarota, G., Ricci, R., Mascianà, R., Forgione, A., Gabrieli, M. L., Perotti, G., et al. (2009) · Hepatology · doi:10.1002/hep.22848 · Cited by 1,434 · see citing works
The effect of age on the development and outcome of adult sepsis*
Martin, G. S., Mannino, D. M., & Moss, M. M. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000194535.82812.ba · Cited by 1,040 · see citing works
Wree, A., Eguchi, A., McGeough, M. D., Pena, C. A., Johnson, C. D., Canbay, A., Hoffman, H. M., & Feldstein, A. E. (2014) · Hepatology · doi:10.1002/hep.26592 · Cited by 945 · see citing works
Inflammation and Lipid Signaling in the Etiology of Insulin Resistance
Glass, C. K., & Olefsky, J. M. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.001 · Cited by 942 · see citing works
Regulation of inflammasome signaling
Rathinam, V. A. K., Vanaja, S. K., & Fitzgerald, K. A. (2012) · Nature Immunology · doi:10.1038/ni.2237 · Cited by 927 · see citing works
Transcriptional Regulation of Metabolism
Desvergne, B., Michalik, L., & Wahli, W. (2006) · Physiological Reviews · doi:10.1152/physrev.00025.2005 · Cited by 889 · see citing works
Lipid Metabolism and Liver Inflammation. II. Fatty liver disease and fatty acid oxidation
Reddy, J. K., & Rao, M. S. (2006) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00521.2005 · Cited by 860 · see citing works
Protein blotting: Principles and applications
Gershoni, J. M., & Palade, G. E. (1983) · Analytical Biochemistry · doi:10.1016/0003-2697(83)90128-8 · Cited by 853 · see citing works
Toll-Like Receptor 9 Promotes Steatohepatitis by Induction of Interleukin-1β in Mice
Miura, K., Kodama, Y., Inokuchi, S., Schnabl, B., Aoyama, T., Ohnishi, H., Olefsky, J. M., Brenner, D. A., & Seki, E. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.03.052 · Cited by 741 · see citing works
IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice
Petrasek, J., Bala, S., Csak, T., Lippai, D., Kodys, K., Menashy, V., Barrieau, M., Min, S.-Y., Kurt-Jones, E. A., & Szabo, G. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60777 · Cited by 735 · see citing works
Yecies, J. L., Zhang, H., Menon, S., Liu, S., Yecies, D. W., Lipovsky, A. I., Görgün, C. Z., Kwiatkowski, D. J., Hotamışlıgil, G. S., Lee, C., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.06.002 · Cited by 655 · see citing works
From NAFLD to NASH to cirrhosis—new insights into disease mechanisms
Wree, A., Broderick, L., Canbay, A. E., Hoffman, H. M., & Feldstein, A. E. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.149 · Cited by 608 · see citing works
Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome
Imaeda, A. B., Watanabe, A., Sohail, M. A., Mahmood, S., Mohamadnejad, M., Sutterwala, F. S., Flavell, R. A., & Mehal, W. Z. (2009) · Journal of Clinical Investigation · doi:10.1172/jci35958 · Cited by 604 · see citing works
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Vuppalanchi, R., & Chalasani, N. (2008) · Hepatology · doi:10.1002/hep.22603 · Cited by 562 · see citing works
Inflammasomes in liver diseases
Szabó, G., & Csák, T. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.03.035 · Cited by 498 · see citing works
The Immunopathogenesis of Sepsis in Elderly Patients
Opal, S. M., Girard, T. D., & Ely, E. W. (2005) · Clinical Infectious Diseases · doi:10.1086/432007 · Cited by 461 · see citing works
Negash, A. A., Ramos, H. J., Crochet, N., Lau, D., Doehle, B., Papić, N., Delker, D. A., Jo, J., Bertoletti, A., Hagedorn, C. H., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003330 · Cited by 416 · see citing works
The ageing immune system: is it ever too old to become young again?
Dorshkind, K. A., Montecino‐Rodriguez, E., & Signer, R. A. J. (2008) · Nature reviews. Immunology · doi:10.1038/nri2471 · Cited by 412 · see citing works
Feingold, K., Staprãns, I., Memon, R., Moser, A. H., Shigenaga, J. K., Doerrler, W. T., Dinarello, C. A., & Grünfeld, C. (1992) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)41334-3 · Cited by 346 · see citing works
Effects of endotoxin and cytokines on lipid metabolism
Harðardóttir, I., Grünfeld, C., & Feingold, K. R. (1994) · Current Opinion in Lipidology · doi:10.1097/00041433-199405030-00008 · Cited by 305 · see citing works
Clinical review: The liver in sepsis
Nesseler, N., Launey, Y., Aninat, C., Morel, F., Mallédant, Y., & Séguin, P. (2012) · Critical Care · doi:10.1186/cc11381 · Cited by 288 · see citing works
Non-Alcoholic Fatty Liver Disease in Older People
Frith, J., Day, C. P., Henderson, E., Burt, A. D., & Newton, J. L. (2009) · Gerontology · doi:10.1159/000235677 · Cited by 280 · see citing works
Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response
Gustot, T. (2011) · Current Opinion in Critical Care · doi:10.1097/mcc.0b013e328344b446 · Cited by 250 · see citing works
Ma, K. L., Ruan, X. Z., Powis, S. H., Chen, Y., Moorhead, J. F., & Varghese, Z. (2008) · Hepatology · doi:10.1002/hep.22423 · Cited by 246 · see citing works
Saitō, H., Sherwood, E. R., Varma, T. K., & Evers, B. M. (2003) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2003.08.002 · Cited by 173 · see citing works
Kamo, N., Ke, B., Ghaffari, A. A., Shen, X., Busuttil, R. W., Cheng, G., & Kupiec‐Weglinski, J. W. (2013) · Hepatology · doi:10.1002/hep.26320 · Cited by 170 · see citing works
Affò, S., Morales‐Ibanez, O., Rodrigo‐Torres, D., Altamirano, J., Blaya, D., Dapito, D. H., Millán, C., Coll, M., Caviglia, J. M., Arroyo, V., et al. (2014) · Gut · doi:10.1136/gutjnl-2013-306098 · Cited by 147 · see citing works
Cellular energetic metabolism in sepsis: The need for a systems approach
Carré, J. E., & Singer, M. (2008) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.04.024 · Cited by 147 · see citing works
Role of interleukins in obesity: implications for metabolic disease
Febbraio, M. A. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.02.004 · Cited by 130 · see citing works
Effects of aging on the immunopathologic response to sepsis
Turnbull, I. R., Clark, A. T., Stromberg, P. E., Dixon, D. J., Woolsey, C. A., Davis, C. G., Hotchkiss, R. S., Buchman, T. G., & Coopersmith, C. M. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181968f3a · Cited by 127 · see citing works
Aging promotes the development of diet-induced murine steatohepatitis but not steatosis
Fontana, L., Zhao, E., Amir, M., Dong, H., Tanaka, K. E., & Czaja, M. J. (2012) · Hepatology · doi:10.1002/hep.26099 · Cited by 127 · see citing works
Petrasek, J., Dolganiuc, A., Csák, T., Kurt‐Jones, E. A., & Szabó, G. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.08.020 · Cited by 111 · see citing works
Chen, X., Zhang, C., Zhao, M., Shi, C.-E., Zhu, R.-M., Wang, H., Zhao, H., Wei, W., Li, J., & Xu, D. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00905.x · Cited by 64 · see citing works
Septic shock in older people: a prospective cohort study
da Silva, F. P., Zampieri, F. G., Barbeiro, D. F., Barbeiro, H. V., Goulart, A. C., Filho, F. T., Velasco, I. T., Neto, L. M. D. C., de Souza, H. P., & Machado, M. C. C. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-21 · Cited by 30 · see citing works
Nichtalkoholische Fettleber und Steatohepatitis
Wiegand, J., Mössner, J., & Tillmann, H. L. (2007) · Der Internist · doi:10.1007/s00108-006-1796-3 · Cited by 20 · see citing works
The effect of lipopolysaccharide on enhanced inflammatory process with age: Modulation of NF-κB
Kwon, H. J., Sung, B. K., Kim, J. W., Lee, J., Kim, N. D., Yoo, M. A., Kang, H. S., Baek, H. S., Bae, S.-J., Choi, J. S., et al. (2001) · AGE · doi:10.1007/s11357-001-0017-1 · Cited by 12 · see citing works
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Do, M. H., Lee, E., Oh, M.-J., Kim, Y., & Park, H.-Y. (2018) · Nutrients · doi:10.3390/nu10060761 · Cited by 441 · see citing works
Self-citationMitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity
López-Lluch, G. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.12.005 · Cited by 103 · see citing works
“Moreover, chronically overactive inflammasome activity and production of IL-1β has been associated with the abnormal lipid accumulation in old rat liver resulting in steatohepatitis (Chung et al., 2015).”
Background
- Authors
- Chung, K. W., Lee, E. K., Kim, D. H., An, H. J., Kim, N. D., Im, D. S., Lee, J., Yu, B. P., & Chung, H. Y.
- Affiliations
- Pusan National University (KR)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Chung, Hae Young
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2015-04-07
- Volume
- 14
- Issue
- 4
- Pages
- 524-533
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC4531067
- OpenAlex
- W1970030711
- Cited by
- 41
- References
- 38
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 9 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 1
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Aging Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ministry of Science, ICT and Future Planning (No. 2009-0083538)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- aging, steatohepatitis, endotoxin, lipopolysaccharide, liver inflammation, inflammasome, IL-1β, caspase-1, hepatic lipid accumulation, PPARα, SREBP-1c, Kupffer cells, hepatocytes, metabolic inflammation
- MeSH terms
- Age Factors, Aging, Alanine Transaminase, Animals, Fatty Liver, Gene Expression Regulation, Humans, Kupffer Cells, Lipopolysaccharides, Liver, Male, Signal Transduction, Rats, Sprague-Dawley, Caspase 1, PPAR alpha, Lipid Metabolism, Rats, Sterol Regulatory Element Binding Protein 1, Interleukin-1beta, Hep G2 Cells, Inflammasomes
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