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A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.
Am J Physiol Gastrointest Liver Physiol. 2017 Jun 01; 312(6):G666-G680.AJ

Abstract

The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s-1·ml-1 per unit citrate synthase) than SC mice (17-394 pmol·s-1·ml-1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH.NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.

Authors+Show Affiliations

Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota.Indian Institute of Integrative Medicine, Council of Scientific and Industrial Research, Jammu and Kashmir, India.Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota.Division of Immunology, Mayo Clinic, Rochester, Minnesota.Division of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota.Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota.Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and.Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and.Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota; mcharlton@medicine.bsd.uchicago.edu michael.charlton@imail.org. Division of Hepatology, Intermountain Healthcare, Salt Lake City, Utah.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28232454

Citation

Krishnan, Anuradha, et al. "A Longitudinal Study of Whole Body, Tissue, and Cellular Physiology in a Mouse Model of Fibrosing NASH With High Fidelity to the Human Condition." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 312, no. 6, 2017, pp. G666-G680.
Krishnan A, Abdullah TS, Mounajjed T, et al. A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2017;312(6):G666-G680.
Krishnan, A., Abdullah, T. S., Mounajjed, T., Hartono, S., McConico, A., White, T., LeBrasseur, N., Lanza, I., Nair, S., Gores, G., & Charlton, M. (2017). A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition. American Journal of Physiology. Gastrointestinal and Liver Physiology, 312(6), G666-G680. https://doi.org/10.1152/ajpgi.00213.2016
Krishnan A, et al. A Longitudinal Study of Whole Body, Tissue, and Cellular Physiology in a Mouse Model of Fibrosing NASH With High Fidelity to the Human Condition. Am J Physiol Gastrointest Liver Physiol. 2017 Jun 1;312(6):G666-G680. PubMed PMID: 28232454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition. AU - Krishnan,Anuradha, AU - Abdullah,Tasduq Sheikh, AU - Mounajjed,Taofic, AU - Hartono,Stella, AU - McConico,Andrea, AU - White,Thomas, AU - LeBrasseur,Nathan, AU - Lanza,Ian, AU - Nair,Sreekumaran, AU - Gores,Gregory, AU - Charlton,Michael, Y1 - 2017/02/23/ PY - 2016/06/08/received PY - 2017/02/14/revised PY - 2017/02/14/accepted PY - 2017/2/25/pubmed PY - 2017/8/12/medline PY - 2017/2/25/entrez KW - fatty liver KW - hepatic fibrosis KW - inflammation metabolic function KW - insulin resistance KW - mitochondrial respiration SP - G666 EP - G680 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 312 IS - 6 N2 - The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s-1·ml-1 per unit citrate synthase) than SC mice (17-394 pmol·s-1·ml-1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH.NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/28232454/A_longitudinal_study_of_whole_body_tissue_and_cellular_physiology_in_a_mouse_model_of_fibrosing_NASH_with_high_fidelity_to_the_human_condition_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00213.2016?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -