A novel non-alcoholic steatohepatitis animal model featured with insulin resistance, hepatic inflammation and fibrosis.
OBJECTIVE
There is no animal model that displays the features of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance (IR) and fibrosing steatohepatitis. This study aimed to develop a novel IR-associated rat model of NASH.


METHODS
Male Sprague-Dawley rats were fed with the high-fat diet (HFD) supplemented with 0.25% propylthiouracil for 2, 4, 6, 8 and 12 weeks. The IR-associated metabolic parameters, histological assessment and the expression of key insulin signaling molecules were determined. The circulating and tissue pro-inflammatory factors and adipocytokines were examined.


RESULTS
In the HFD-fed rats, the systemic and multiple-organ IR was developed after 4 weeks, whereas the histological changes characterized by steatohepatitis, inflammatory response in the visceral adipose tissue and proliferative pancreatic islet β-cells appeared after 6 weeks, concomitant with altered expression of key insulin signaling molecules. In addition, the elevated levels of serum tumor necrosis factor α (TNF-α), soluble TNF receptor2, interleukin (IL)-6, CC-chemokine ligand (CCL)2 and resistin were parallel with the severity of hepatic inflammation, while the levels of serum adiponectin, leptin and TNF-α, but not resistin, were correlated with IR.


CONCLUSIONS
We have developed a systemic IR-associated NASH model of rats, with impaired insulin signaling, systemic inflammation and appropriate pathology characterized by human NASH, and provided a realistic experimental model for elucidating the association between IR and the pathogenesis of NASH.
Zhao
Jingmin
J
Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China. jmzhao302@163.com
Zhou
Guangde
G
Li
Meirong
M
Li
Wenshu
W
Lü
Jiyun
J
Xiong
Lu
L
Liang
Li
L
Zhao
Yulai
Y
Xu
Dongping
D
Yu
Jun
J
D052242:Adiponectin / Q000097:blood* / Q000235:genetics; D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood* / Q000235:genetics; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000378:metabolism; D012720:Severity of Illness Index
D052242:Adiponectin; D018925:Chemokines; D020738:Leptin; D052243:Resistin; D012313:RNA