Genetic differences in oxidative stress and inflammatory responses to diet-induced obesity do not alter liver fibrosis in mice.
OBJECTIVE
To determine how genetic factors might influence the progression of nonalcoholic fatty liver disease (NAFLD).


METHODS
Beginning in adolescence, male C57BL6 (BL6) and 129/SVJ mice were fed control (n=15/group) or high-fat (HF) diets (n=30/group) for 6 months.


METHODS
Assessed were body weight, insulin resistance, hepatic production of free radicals, expression of cytokines and fibrosis-related genes and severity of hepatic steatosis, injury and fibrosis.


RESULTS
High-fat diets induced comparable obesity, hepatic steatosis and insulin resistance in the two strains. Compared with BL6 mice, 129/SVJ mice had impaired induction of antioxidant genes, generated three- to four-fold more free radicals and exhibited two-fold greater induction of profibrogenic cytokines (interleukin-4 and transforming growth factor-beta1) and fibrosis-related genes (fibronectin and tissue inhibitor of metalloproteinase-1) (all P<0.05 for 129 vs BL6). Surprisingly, however, induction of collagen I alpha1 mRNA and accumulation of Sirius red-stained fibrils and hepatic hydroxyproline were similar in BL6 and 129/SVJ mice, and although patchy sinusoidal fibrosis emerged in both strains, neither developed bridging fibrosis.


CONCLUSIONS
Although BL6 and 129/SVJ mice with diet-induced obesity, insulin resistance and steatosis differed with respect to several factors that are thought to influence human NAFLD progression, they developed comparable liver fibrosis. Moreover, none of the risk factors for NAFLD-related cirrhosis in humans, including obesity, insulin resistance, chronic inflammatory and oxidant stress, steatohepatitis or activation of fibrogenic genes, proved to be sufficient to cause cirrhosis in these mice, even when exposure to one or more of these insults was very prolonged.
Syn
Wing-Kin
WK
Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC 27710, USA.
Yang
Liu
L
Chiang
Dian Jung
DJ
Qian
Yue
Y
Jung
Youngmi
Y
Karaca
Gamze
G
Choi
Steve S
SS
Witek
Rafal P
RP
Omenetti
Alessia
A
Pereira
Thiago A
TA
Diehl
Anna Mae
AM
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005609:Free Radicals / Q000032:analysis; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity
D015415:Biomarkers; D004041:Dietary Fats; D005609:Free Radicals; D012333:RNA, Messenger