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Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice.
J Transl Med 2015; 13:193JT

Abstract

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is becoming a pandemic. While multiple 'hits' have been reported to contribute to NAFLD progression to non-alcoholic steatohepatitis (NASH), fibrosis and liver cancer, understanding the natural history of the specific molecular signals leading to hepatocyte damage, inflammation and fibrosis, is hampered by the lack of suitable animal models that reproduce disease progression in humans. The purpose of this study was first, to develop a mouse model that closely mimics progressive NAFLD covering the spectrum of immune, metabolic and histopathologic abnormalities present in human disease; and second, to characterize the temporal relationship between sterile/exogenous danger signals, inflammation, inflammasome activation and NAFLD progression.

METHODS

Male C57Bl/6 mice were fed a high fat diet with high cholesterol and a high sugar supplement (HF-HC-HSD) for 8, 27, and 49 weeks and the extent of steatosis, liver inflammation, fibrosis and tumor development were evaluated at each time point.

RESULTS

The HF-HC-HSD resulted in liver steatosis at 8 weeks, progressing to steatohepatitis and early fibrosis at 27 weeks, and steatohepatitis, fibrosis, and tumor development at 49 weeks compared to chow diet. Steatohepatitis was characterized by increased levels of MCP-1, TNFα, IL-1β and increased liver NASH histological score. We found increased serum levels of sterile danger signals, uric acid and HMGB1, as early as 8 weeks, while endotoxin and ATP levels increased only after 49 weeks. Increased levels of these sterile and microbial danger signals paralleled upregulation and activation of the multiprotein complex inflammasome. At 27, 49 weeks of HF-HC-HSD, activation of M1 macrophages and loss of M2 macrophages as well as liver fibrosis were present. Finally, similar to human NASH, liver tumors occurred in 41% of mice in the absence of cirrhosis and livers expressed increased p53 and detectable AFP.

CONCLUSIONS

HF-HC-HSD over 49 weeks induces the full spectrum of liver pathophysiologic changes that characterizes the progression of NAFLD in humans. NAFLD progression to NASH, fibrosis and liver tumor follows progressive accumulation of sterile and microbial danger signals, inflammasome activation, altered M1/M2 cell ratios that likely contribute to NASH progression and hepatic tumor formation.

Authors+Show Affiliations

Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. mganz1@gmail.com.Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. terence.bukong@umassmed.edu.Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. timea.csak@umassmed.edu.Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. banishree.saha@umassmed.edu.Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. jin-kyu.park@yale.edu.Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. aditya.ambade@umassmed.edu.Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. karen.kodys@umassmed.edu.Department of Medicine, University of Massachusetts Medical School, 364 Plantation St, LRB-208, Worcester, MA, 01605, USA. gyongyi.szabo@umassmed.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26077675

Citation

Ganz, Michal, et al. "Progression of Non-alcoholic Steatosis to Steatohepatitis and Fibrosis Parallels Cumulative Accumulation of Danger Signals That Promote Inflammation and Liver Tumors in a High Fat-cholesterol-sugar Diet Model in Mice." Journal of Translational Medicine, vol. 13, 2015, p. 193.
Ganz M, Bukong TN, Csak T, et al. Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice. J Transl Med. 2015;13:193.
Ganz, M., Bukong, T. N., Csak, T., Saha, B., Park, J. K., Ambade, A., ... Szabo, G. (2015). Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice. Journal of Translational Medicine, 13, p. 193. doi:10.1186/s12967-015-0552-7.
Ganz M, et al. Progression of Non-alcoholic Steatosis to Steatohepatitis and Fibrosis Parallels Cumulative Accumulation of Danger Signals That Promote Inflammation and Liver Tumors in a High Fat-cholesterol-sugar Diet Model in Mice. J Transl Med. 2015 Jun 16;13:193. PubMed PMID: 26077675.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice. AU - Ganz,Michal, AU - Bukong,Terence N, AU - Csak,Timea, AU - Saha,Banishree, AU - Park,Jin-Kyu, AU - Ambade,Aditya, AU - Kodys,Karen, AU - Szabo,Gyongyi, Y1 - 2015/06/16/ PY - 2014/12/11/received PY - 2015/05/28/accepted PY - 2015/6/17/entrez PY - 2015/6/17/pubmed PY - 2016/3/5/medline SP - 193 EP - 193 JF - Journal of translational medicine JO - J Transl Med VL - 13 N2 - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a pandemic. While multiple 'hits' have been reported to contribute to NAFLD progression to non-alcoholic steatohepatitis (NASH), fibrosis and liver cancer, understanding the natural history of the specific molecular signals leading to hepatocyte damage, inflammation and fibrosis, is hampered by the lack of suitable animal models that reproduce disease progression in humans. The purpose of this study was first, to develop a mouse model that closely mimics progressive NAFLD covering the spectrum of immune, metabolic and histopathologic abnormalities present in human disease; and second, to characterize the temporal relationship between sterile/exogenous danger signals, inflammation, inflammasome activation and NAFLD progression. METHODS: Male C57Bl/6 mice were fed a high fat diet with high cholesterol and a high sugar supplement (HF-HC-HSD) for 8, 27, and 49 weeks and the extent of steatosis, liver inflammation, fibrosis and tumor development were evaluated at each time point. RESULTS: The HF-HC-HSD resulted in liver steatosis at 8 weeks, progressing to steatohepatitis and early fibrosis at 27 weeks, and steatohepatitis, fibrosis, and tumor development at 49 weeks compared to chow diet. Steatohepatitis was characterized by increased levels of MCP-1, TNFα, IL-1β and increased liver NASH histological score. We found increased serum levels of sterile danger signals, uric acid and HMGB1, as early as 8 weeks, while endotoxin and ATP levels increased only after 49 weeks. Increased levels of these sterile and microbial danger signals paralleled upregulation and activation of the multiprotein complex inflammasome. At 27, 49 weeks of HF-HC-HSD, activation of M1 macrophages and loss of M2 macrophages as well as liver fibrosis were present. Finally, similar to human NASH, liver tumors occurred in 41% of mice in the absence of cirrhosis and livers expressed increased p53 and detectable AFP. CONCLUSIONS: HF-HC-HSD over 49 weeks induces the full spectrum of liver pathophysiologic changes that characterizes the progression of NAFLD in humans. NAFLD progression to NASH, fibrosis and liver tumor follows progressive accumulation of sterile and microbial danger signals, inflammasome activation, altered M1/M2 cell ratios that likely contribute to NASH progression and hepatic tumor formation. SN - 1479-5876 UR - https://www.unboundmedicine.com/medline/citation/26077675/Progression_of_non_alcoholic_steatosis_to_steatohepatitis_and_fibrosis_parallels_cumulative_accumulation_of_danger_signals_that_promote_inflammation_and_liver_tumors_in_a_high_fat_cholesterol_sugar_diet_model_in_mice_ L2 - https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-015-0552-7 DB - PRIME DP - Unbound Medicine ER -