Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver

Hepatology. 2002 Jul;36(1):12-21. doi: 10.1053/jhep.2002.33684.


In this study, we investigated hepatic fibrogenesis caused by long-term thioacetamide (TAA) administration in ob/ob mice, a naturally occurring leptin deficient animal. In the lean littermates, prominent hepatic fibrosis, as well as positive staining for alpha smooth muscle actin (alpha-SMA), was induced by treatment with TAA (200 microg/g, IP, 3 times per week) for 4 to 8 weeks as expected. In sharp contrast, almost no hepatic fibrosis developed in ob/ob mice given the equivalent doses of TAA, where specific staining for alpha-SMA barely was detected. Induction of alpha1(I) procollagen mRNA caused by TAA also was prevented in ob/ob mice almost completely. Further, transforming growth factor beta (TGF-beta) mRNA was increased in the liver after TAA treatment for 4 weeks in lean littermates, which also was prevented in ob/ob mice. Interestingly, fibrotic septa in the hepatic lobules, as well as increases in alpha1(I) procollagen mRNA, was observed in ob/ob mice, when they were injected with recombinant murine leptin (1 microg/g daily) in combination with TAA treatment. Leptin per se did not cause any fibrotic changes in the liver in ob/ob mice. These findings clearly indicated that leptin deficiency is responsible for the resistance to TAA-induced profibrogenic responses in ob/ob mice. In conclusion, leptin appears to promote profibrogenic responses in the liver, in part, by up-regulation of TGF-beta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Animals
  • Cells, Cultured
  • Female
  • Gene Expression / drug effects
  • Immunohistochemistry
  • Leptin / deficiency
  • Leptin / pharmacology
  • Leptin / physiology*
  • Liver / chemistry
  • Liver / metabolism
  • Liver Cirrhosis / chemically induced*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Procollagen / genetics
  • RNA, Messenger / analysis
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thioacetamide / administration & dosage*
  • Transforming Growth Factor beta / blood
  • Transforming Growth Factor beta / genetics


  • Actins
  • Leptin
  • Procollagen
  • RNA, Messenger
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • Thioacetamide