Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury.
OBJECTIVE
Profound impairment of liver regeneration in rodents with dysfunctional leptin signaling has been attributed to non-alcohol-induced fatty liver disorders (NAFLD). Our aim was to establish whether defective liver regeneration in ob/ob mice is a direct consequence of leptin-dependent, intracellular signaling mechanisms controlling cell-cycle regulation in hepatocytes.


METHODS
After exposure to a single hepatotoxic dose of (CCl(4)), the regenerative response to hepatic injury was studied in leptin-deficient ob/ob and control mice. The effects of leptin supplementation (100 microg x kg(-1) x day(-1)) were examined. We assessed entry into and progression through the cell cycle and activation of key signaling intermediates and transcriptional regulators.


RESULTS
CCl(4)-induced liver injury was equally severe in ob/ob and control mice. In leptin-deficient mice, it was associated with exaggerated activation of NF-kappa B and STAT3 during the priming phase, abrogation of tumor necrosis factor (TNF) and interleukin (IL)-6 release at the time of G1/S transition, and failure of hepatocyte induction of cyclin D1 and cell cycle entry. Leptin replacement corrected these defects in ob/ob mice by restoring TNF and IL-6 release and inducing cyclin D1. Hepatocytes entered S phase and progressed, as in wild-type mice, to vigorous mitosis and normal hepatic regenerative response. In ob/ob mice, low doses of TNF before CCl(4) also were associated with restitution of TNF release and proliferative capabilities.


CONCLUSIONS
Impaired liver regeneration in ob/ob mice is caused by leptin deficiency. We propose that altered cytokine production in ob/ob mice is part of the mechanisms responsible for impaired proliferation in response to hepatic injury.
Leclercq
Isabelle A
IA
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, Australia. isabelle_leclerq@wmi.usyd.edu.au
Field
Jacqueline
J
Farrell
Geoffrey C
GC
D000818:Animals; D002251:Carbon Tetrachloride; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics; D005234:Fatty Liver / Q000188:drug therapy / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D020738:Leptin / Q000172:deficiency / Q000235:genetics* / Q000494:pharmacology*; D008099:Liver / Q000473:pathology / Q000502:physiology; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009336:Necrosis; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D020738:Leptin; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D002251:Carbon Tetrachloride