Potential conflict of interest: Nothing to report.
Steatohepatitis/Metabolic Liver Disease
Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition
Article first published online: 1 OCT 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 5, pages 1581–1592, November 2014
How to Cite
Sapp, V., Gaffney, L., EauClaire, S. F. and Matthews, R. P. (2014), Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition. Hepatology, 60: 1581–1592. doi: 10.1002/hep.27284
Supported by a pilot award from the Diabetes Research Center at the University of Pennsylvania (NIH DK19525), and by the Children's Hospital of Philadelphia Research Institute (Fred and Suzanne Biesecker Pediatric Liver Center and a Foerderer award).
- Issue published online: 23 OCT 2014
- Article first published online: 1 OCT 2014
- Accepted manuscript online: 4 JUL 2014 09:10PM EST
- Manuscript Accepted: 27 JUN 2014
- Manuscript Received: 24 FEB 2014
Nonalcoholic fatty liver disease (NAFLD), the accumulation of lipid within hepatocytes, is increasing in prevalence. Increasing fructose consumption correlates with this increased prevalence, and rodent studies directly support fructose leading to NAFLD. The mechanisms of NAFLD and in particular fructose-induced lipid accumulation remain unclear, although there is evidence for a role for endoplasmic reticulum (ER) stress and oxidative stress. We have evidence that NAFLD models demonstrate activation of the target of rapamycin complex 1 (Torc1) pathway. We set out to assess the contribution of ER stress, oxidative stress, and Torc1 up-regulation in the development of steatohepatitis in fructose-treated larval zebrafish. Zebrafish were treated with fructose or glucose as a calorie-matched control. We also treated larvae with rapamycin, tunicamycin (ER stress), or valinomycin (oxidative stress). Fish were stained with oil red O to assess hepatic lipid accumulation, and we also performed quantitative polymerase chain reaction (qPCR)and western blot analysis. We performed immunostaining on samples from patients with NAFLD and nonalcoholic steatohepatitis (NASH). Treatment with fructose induced hepatic lipid accumulation, mitochondrial abnormalities, and ER defects. In addition, fructose-treated fish showed activation of inflammatory and lipogenic genes. Treatment with tunicamycin or valinomycin also induced hepatic lipid accumulation. Expression microarray studies of zebrafish NAFLD models showed an elevation of genes downstream of Torc1 signaling. Rapamycin treatment of fructose-treated fish prevented development of hepatic steatosis, as did treatment of tunicamycin- or valinomycin-treated fish. Examination of liver samples from patients with hepatic steatosis demonstrated activation of Torc1 signaling. Conclusion: Fructose treatment of larval zebrafish induces hepatic lipid accumulation, inflammation, and oxidative stress. Our results indicate that Torc1 activation is required for hepatic lipid accumulation across models of NAFLD, and in patients. (Hepatology 2014;60:1581–1592)