title: Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway.
abstract: 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.
authors.affiliation: Laboratory of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Selzner
authors.forename: P A
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D005234:Fatty Liver / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D016193:G1 Phase; D006498:Hepatectomy; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000494:pharmacology; D008115:Liver Regeneration; D009336:Necrosis; D009765:Obesity / Q000150:complications; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011924:Rats, Zucker; D011994:Recombinant Proteins / Q000494:pharmacology; D016196:S Phase
chemical_list: D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins