title: A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.
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-1per unit citrate synthase) than SC mice (17-394 pmol·s-1·ml-1per 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 & NOTEWORTHYThis study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include1) 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; and3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.
authors.affiliation: Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Indian Institute of Integrative Medicine, Council of Scientific and Industrial Research, Jammu and Kashmir, India.
authors.forename: Tasduq Sheikh
authors.initials: TS
authors.lastname: Abdullah
authors.affiliation: Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Taofic
authors.initials: T
authors.lastname: Mounajjed
authors.affiliation: Division of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stella
authors.initials: S
authors.lastname: Hartono
authors.affiliation: Division of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Andrea
authors.initials: A
authors.lastname: McConico
authors.affiliation: Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas
authors.initials: T
authors.lastname: White
authors.affiliation: Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nathan
authors.initials: N
authors.lastname: LeBrasseur
authors.affiliation: Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Ian
authors.initials: I
authors.lastname: Lanza
authors.affiliation: Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Sreekumaran
authors.initials: S
authors.lastname: Nair
authors.affiliation: Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gregory
authors.initials: G
authors.lastname: Gores
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Charlton
mesh_terms: D050154:Adiposity; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D013045:Species Specificity; D013997:Time Factors; D015430:Weight Gain
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D018836:Inflammation Mediators; D007328:Insulin; D008055:Lipids
keywords: fatty liver; hepatic fibrosis; inflammation metabolic function; insulin resistance; mitochondrial respiration