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High‐fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis
Author(s) -
Kohli Rohit,
Kirby Michelle,
Xanthakos Stavra A.,
Softic Samir,
Feldstein Ariel E.,
Saxena Vijay,
Tang Peter H.,
Miles Lili,
Miles Michael V.,
Balistreri William F.,
Woods Stephen C.,
Seeley Randy J.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23797
Subject(s) - medicine , endocrinology , fibrosis , steatohepatitis , triglyceride , fructose , oxidative stress , fatty liver , biology , chemistry , cholesterol , biochemistry , disease
Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 ( ox CoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high‐fat (HF), or high‐fat high‐carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin‐resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol ( P < 0.001), histological hepatic fibrosis, liver hydroxyproline content ( P = 0.006), collagen 1 messenger RNA ( P = 0.003), CD11b‐F4/80+Gr1+ monocytes ( P < 0.0001), transforming growth factor β1 mRNA ( P = 0.04), and α‐smooth muscle actin messenger RNA ( P = 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression ( P = 0.002), 4‐hydroxynonenal, and plasma ox CoQ9 ( P < 0.001) levels, was highest in HFHC mice. Conclusion: These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH‐like phenotype with significant fibrosis. Plasma ox CoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor β1–signaled collagen deposition and histologically visible hepatic fibrosis. (H EPATOLOGY 2010)