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Background & aims

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."xsd:string
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http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/author"Field J."xsd:string
http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/author"Farrell G.C."xsd:string
http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/author"Leclercq I.A."xsd:string
http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/date"2003"xsd:gYear
http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/name"Gastroenterology"xsd:string
http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/pages"1451-1464"xsd:string
http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/title"Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury."xsd:string
http://purl.uniprot.org/citations/12730884http://purl.uniprot.org/core/volume"124"xsd:string
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