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.
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 beta1 mRNA (P = 0.04), and alpha-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.


CONCLUSIONS
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 beta1-signaled collagen deposition and histologically visible hepatic fibrosis.
Kohli
Rohit
R
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. rohit.kohli@cchmc.org
Kirby
Michelle
M
Xanthakos
Stavra A
SA
Softic
Samir
S
Feldstein
Ariel E
AE
Saxena
Vijay
V
Tang
Peter H
PH
Miles
Lili
L
Miles
Michael V
MV
Balistreri
William F
WF
Woods
Stephen C
SC
Seeley
Randy J
RJ
D000818:Animals; D001823:Body Composition; D003094:Collagen / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000009:adverse effects*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044242:Trans Fatty Acids / Q000008:administration & dosage / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014451:Ubiquinone / Q000097:blood*
D004040:Dietary Carbohydrates; D004041:Dietary Fats; D017382:Reactive Oxygen Species; D044242:Trans Fatty Acids; D016212:Transforming Growth Factor beta; D014451:Ubiquinone; D005632:Fructose; D003094:Collagen; C030571:ubiquinone 9