Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 308, Issue 4, Pages G298-G312Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00346.2014
Keywords
nonalcoholic fatty liver disease; ob/ob; NF-kappa B; SMAD7; SMAD2/3 colocalization; transforming growth factor-beta
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Funding
- NIH [4R00ES019875-02, P20GM103641, R01AT006888, R01ES019313]
- NIH R01 [R01DK053792]
- Intramural Research Program of the National Institutes of Health
- National Institute of Environmental Health Sciences
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Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-beta signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-kappa B activation, and increased miR21 levels. These mice and human livers showed increased TGF-beta, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1 alpha, and alpha-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-kappa B and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-kappa B-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-beta signaling and fibrogenesis in experimental and human NASH.
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