Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(-/-) mice

Eur J Pharmacol. 2015 Sep 5;762:247-55. doi: 10.1016/j.ejphar.2015.06.008. Epub 2015 Jun 6.

Abstract

Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury.

Keywords: Apoptosis; Cholestasis; Hepatic fibrosis; Necrosis; Vitamin C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ascorbic Acid / pharmacology*
  • Cell Line
  • Cholestasis / complications
  • Cholestasis / pathology*
  • Cytoprotection / drug effects*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Lithocholic Acid / adverse effects*
  • Liver / drug effects*
  • Liver / injuries*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / complications
  • Male
  • Mice
  • Mice, Knockout
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Lithocholic Acid
  • Ascorbic Acid