Lipotoxicity and steatohepatitis in an overfed mouse model for non-alcoholic fatty liver disease

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Gaemers, Ingrid C.¹  Stallen, Jan M.¹  Kunne, Cindy¹  Wallner, Christian²  van Werven, Jochem²  Nederveen, Aart²  Lamers, Wouter H.¹ 

[1] Univ Amsterdam, Acad Med Ctr, Tytgat Inst Liver & Intestinal Res, NL-1105 BK Amsterdam, Netherlands

[2] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands

关键词: Non-alcoholic fatty liver disease;    Steatohepatitis;    Liver;    Overnutrition;    High-fat diet;    Endoplasmatic reticulum stress;    Adipose tissue;   

DOI  :  10.1016/j.bbadis.2011.01.003

来源: Elsevier

【 摘 要 】

The major risk factors for non-alcoholic fatty liver disease (NAFLD) are obesity, insulin resistance and dyslipidemia. The cause for progression from the steatosis stage to the inflammatory condition (non-alcoholic steatohepatitis (NASH)) remains elusive at present. Aim of this study was to test whether the different stages of NAFLD as well as the associated metabolic abnormalities can be recreated in time in an overfed mouse model and study the mechanisms underlying the transition from steatosis to NASH. Male C57BI/6J mice were subjected to continuous intragastric overfeeding with a high-fat liquid diet (HFLD) for different time periods. Mice fed a solid high-fat diet (HFD) ad libitum served as controls. Liver histology and metabolic characteristics of liver, white adipose tisue (WAT) and plasma were studied. Both HFD-fed and HFLD-overfed mice initially developed liver steatosis, but only the latter progressed in time to NASH. NASH coincided with obesity, hyperinsulinemia, loss of liver glycogen and hepatic endoplasmatic reticulum stress. Peroxisome proliferator-activated receptor gamma (Ppary), fibroblast growth factor 21 (Fgf21), fatty acid binding protein (Fabp) and fatty acid translocase (CD36) were induced exclusively in the livers of the HFLD-overfed mice. Inflammation, reduced adiponectin expression and altered expression of genes that influence adipogenic capacity were only observed in WAT of HFLD-overfed mice. In conclusion: this dietary mouse model displays the different stages and the metabolic settings often found in human NAFLD. Lipotoxicity due to compromised adipose tissue function is likely associated with the progression to NASH, but whether this is cause or consequence remains to be established. (C) 2011 Elsevier B.V. All rights reserved.

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