Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway

Hepatology. 2000 Jan;31(1):35-42. doi: 10.1002/hep.510310108.


Hepatic resection or transplantation in patients with fatty liver is associated with increased morbidity and mortality. The regenerative capacity of fatty livers after major tissue loss is unknown. Interleukin 6 (IL-6) is a potent inducer of hepatic regeneration in normal and ischemic livers. Therefore, we studied hepatic regeneration at day 1, day 2, and day 4 in a model of 70% hepatectomy in obese and lean Zucker rats, and obese Zucker rats pretreated with recombinant interleukin 6 (rIL-6). The mitotic cycle in hepatocytes was investigated by 4 different markers of regeneration representing distinct phases of mitosis (proliferating cell nuclear antigen [PCNA] = G(1) phase, bromodeoxy uridine [BrdU] = S phase, mitotic index, and regenerated liver weight = M phase). Obese Zucker rats had significantly decreased regenerative capacity compared with lean Zucker rats (PCNA, BrdU, mitotic index, regenerated liver weight) at days 1 and 2 after surgery. Four days after resection fatty animals showed an increase in the mitotic index indicating a delay of regeneration in steatotic livers. Animal survival after 70% hepatectomy was significantly decreased in obese rats compared with lean animals. Pretreatment of obese animals with rIL-6 normalized PCNA expression (G(1) phase) in steatotic hepatocytes but failed to increase DNA synthesis (BrdU, S phase), mitosis (mitotic index and regenerated liver weight, M phase), and animal survival. These results indicate major impairment of hepatic regeneration in steatotic livers. Two different blockages of regeneration must be present, one rIL-6 sensitive, at the level of IL-6 or upstream, and a second, rIL-6 resistant, at the level of G(1)/S-phase transition.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle
  • Fatty Liver / pathology
  • Fatty Liver / physiopathology
  • Fatty Liver / surgery*
  • G1 Phase
  • Hepatectomy
  • Injections, Intraperitoneal
  • Interleukin-6 / pharmacology
  • Liver Regeneration*
  • Necrosis
  • Obesity / complications
  • Proliferating Cell Nuclear Antigen / analysis
  • Rats
  • Rats, Zucker
  • Recombinant Proteins / pharmacology
  • S Phase


  • Interleukin-6
  • Proliferating Cell Nuclear Antigen
  • Recombinant Proteins