Hepatocyte proliferation in health and in liver failure.
Mammalian liver possesses an extraordinary capacity for compensatory growth in response to conditions that induce cell loss by physical, infectious, or toxic injury. In normal animals and humans, it is a tightly regulated process of both hypertrophy and hyperplasia involving different liver cell populations and a finely tuned interplay between growth factors, cytokines, extracellular matrix components and other regulators. The regeneration response is maximal when two-thirds of the liver is resected. When a lesser amount of parenchyma is removed, residual liver grows more slowly. Resections exceeding two-thirds of the liver mass also retard and diminish both DNA synthesis and mitotic activity and subtotal (90%) hepatectomy invariably results in the death of rats without regeneration. The underlying mechanisms of liver growth inhibition are poorly understood. In particular, only a few studies exist that provide insight into the mechanisms that control regeneration after extensive hepatocyte loss. In this regard, the role of growth-regulatory factors and other compounds that accumulate in the blood circulation as a result of hepatic insufficiency and liver cell death remains unclear. We have initiated studies of these mechanisms and demonstrated that in rats with low (10%) hepatocyte mass, a marked and sustained elevation of blood IL-6, HGF and TGF-b1 levels was associated with lack of hepatocyte proliferation and suppression of Stat3 DNA binding. While searching for the possible cause of inhibited IL-6/Stat3 signaling, we found that IL-6 receptor (IL-6R & gp130) was preserved, that nuclear Stat3 protein content was lowered, and that IL-6/Stat3 pathway inhibitors (SOCS-1, PIAS3) were induced during the pre-replicative Go-G1 period.
Rozga
Jacek
J
Liver Support Research Laboratory, Department of Surgery, Cedars-Sinai Medical Center and UCLA School of Medicine, 8700 Beverly Blvd., D-0418, Los Angeles, CA 90048, USA. Jacek.Rozga@cshs.org
D000818:Animals; D002455:Cell Division; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D017093:Liver Failure / Q000473:pathology*; D008115:Liver Regeneration