Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver.
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.
Honda
Hajime
H
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
Ikejima
Kenichi
K
Hirose
Miyoko
M
Yoshikawa
Mutsuko
M
Lang
Tie
T
Enomoto
Nobuyuki
N
Kitamura
Tsuneo
T
Takei
Yoshiyuki
Y
Sato
Nobuhiro
N
D000199:Actins / Q000032:analysis; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D020738:Leptin / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013853:Thioacetamide / Q000008:administration & dosage*; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics
D000199:Actins; D020738:Leptin; D011347:Procollagen; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D013853:Thioacetamide