Delayed liver regeneration, increased injury and mortality in heterozyogous or homozygous obmutant mice

Abstract

Background: Hepatic steatosis is thought to contribute to primary nonfunction (PNF)after orthotopic liver transplantation (OLT). Since ischemiareperfusion injury is inevitable during OLT, recovery requires hepatic regeneration. Thus, PNF may develop in fatty livers because regeneration is impaired. Aim: To determine if regeneration is inhibited in fatty livers. Methods: Regeneration after 70% partial hepatectomy (PH) in male C57BU 6 obese (ob/ob) mice with fatty livers was compared to ageand sex-matched lean, heterozygous (-lob) litter mates and wild-type (WT) C57BU6 mice. Both control groups had normal basal liver histology. Results: WT mice had < 10% mortality during the first 48h after PH. BrdV pulse-labeling demonstrated replicating hepatocytes at various times after PH: 2% BrdV(+) hepatocytes at 6 and l2h, 8% at 24h, 33% at 36h, and 25% at 48h. Almost 60% of the initial liver weight was regained by 48h. In contrast, PH mortality was increased in lean, -lob mice (33% by 48h) and in obese, oblob mice (68% by 48h), ps .OOI. Liver regeneration was delayed in -lob mice (2:!:1% BrdV(+ )hepatocytes at 24h and 29:!:3% at 48h) and never occurred in oblob mice. Liver mass restoration also was decreased in -lob (l 4::!: 5%)and oblob (-2:!:6%) groups. FACS analysis of propidium iodide-stained liver nuclei not only confirmed the BrdV results but also demonstrated a basal shift in the cell cycle distribution of oblob hepatocytes. In oblob livers, 46:!:6% hepatocytes were in GO-GI and 52:!:6% in G2; however, in -lob livers, 71:!:6% hepatocytes were in GO-G I and 27:!:6% in G2 (psO.05 for both). After PH, in oblob fatty livers after PH, there were extensive areas of hemorrhage, dead hepatocytes, and inflammation. Heterozygous, -lob, mice developed severe microvesicular steatosis, with islands of dead hepatocytes (without much associated hemorrhage or inflammation) by 24-48h after PH. In WT mice after PH, mild microvesicular steatosis occurred at 6-12h, and minor focal liver injury rarely was noted at 24-48h. Conclusions: After PH, obese, oblob mice with fatty livers do not regenerate their livers and develop extensive liver injury with high mortality. Delayed regeneration and increased liver injury also occur post-PH in lean, -lob mice. Although these heterozygotes have non-fatty livers pre-PH, they develop severe steatosis post-PH. The inverse relationship between hepatic steatosis and regeneration supports the concept that inhibited regeneration contributes to PNF of fatty allografts after OLT.