Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice

Am J Pathol. 2002 Dec;161(6):2003-10. doi: 10.1016/S0002-9440(10)64478-1.

Abstract

Carbon tetrachloride (CCl(4)) intoxification in rodents is a commonly used model of both acute and chronic liver injury. Recently, we showed that mice in which FGFR4 was ablated from the germline exhibited elevated cholesterol metabolism and bile acid synthesis coincident with unrepressed levels of cytochrome P450 7A (CYP7A), the rate-limiting enzyme in cholesterol disposal. Of the four fibroblast growth factor (FGF) receptor genes expressed in adult liver, FGFR4 is expressed specifically in mature hepatocytes. To determine whether FGFR4 plays a broader role in liver-specific metabolic functions, we examined the impact of both acute and chronic exposure to CCl(4) in FGFR4-deficient mice. Following acute CCl(4) exposure, the FGFR4-deficient mice exhibited accelerated liver injury, a significant increase in liver mass and delayed hepatolobular repair. Chronic CCl(4) exposure resulted in severe fibrosis in livers of FGFR4-deficient mice compared to normal mice. Analysis at both mRNA and protein levels indicated an 8-hour delay in FGFR4-deficient mice in the down-regulation of cytochrome P450 2E1 (CYP2E1) protein, the major enzyme whose products underlie CCl(4)-induced injury. These results show that hepatocyte FGFR4 protects against acute and chronic insult to the liver and prevents accompanying fibrosis. The results show that FGFR4 acts by promotion of processes that restore hepatolobular architecture rather than cellularity while limiting damage due to prolonged CYP2E1 activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Carbon Tetrachloride / administration & dosage
  • Carbon Tetrachloride / toxicity*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytochrome P-450 CYP2E1 / metabolism
  • Down-Regulation / physiology
  • Female
  • Hepatocytes / metabolism
  • Liver / injuries
  • Liver / pathology
  • Liver / physiology
  • Liver Cirrhosis / chemically induced*
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Knockout
  • Receptor, Fibroblast Growth Factor, Type 4
  • Receptors, Fibroblast Growth Factor / genetics*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Receptors, Fibroblast Growth Factor
  • Carbon Tetrachloride
  • Cytochrome P-450 CYP2E1
  • Alanine Transaminase
  • Fgfr4 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 4
  • Cyclic AMP-Dependent Protein Kinases
  • Urokinase-Type Plasminogen Activator