Fructose leads to hepatic steatosis in zebrafish that is reversed by mTOR inhibition

Sapp, V., Gaffney, L., EauClaire, S.F., Matthews, R.P.
Hepatology (Baltimore, Md.)   60(5): 1581-92 (Journal)
Registered Authors
EauClaire, Steven, Matthews, Randy
MeSH Terms
  • Animals
  • Antibiotics, Antineoplastic/pharmacology
  • Antibiotics, Antineoplastic/therapeutic use
  • Disease Models, Animal*
  • Endoplasmic Reticulum Stress
  • Fatty Liver/drug therapy
  • Fatty Liver/etiology*
  • Fatty Liver/metabolism
  • Fructose/adverse effects*
  • Humans
  • Male
  • Multiprotein Complexes/metabolism
  • Sirolimus/pharmacology
  • Sirolimus/therapeutic use
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • TOR Serine-Threonine Kinases/metabolism*
  • Up-Regulation
  • Zebrafish*
25043405 Full text @ Hepatology
Background: Non-Alcoholic 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 upregulation in the development of steatohepatitis in fructose-treated larval zebrafish. Methods: 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 qPCR and western blot analysis. We performed immunostaining on samples from patients with NAFLD and non-alcoholic steatohepatitis (NASH). Results: 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. Rapamcyin 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;).
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes