Abstract
Fatty livers have low tolerance to IRI and high risks of organ failure after transplantation. Impaired liver regeneration, often attributed to fatty livers, is a frequent feature in acute liver failure. The present study unveils mechanisms of hepatic regeneration in clinically relevant models of lean and steatotic hepatic IRI. Methods and Results: C57BL6 mice were fed with standard or high-fat (HF; 60% of total kilocalories) diets for up to 8 weeks. Mice fed with a standard diet had virtually no liver fat inclusions, whereas HF-diet-fed mice with about 29-33g and 40-45g of body weight were characterized by prevalence of liver microsteatosis (MiS) and macrosteatosis (MaS), respectively (assessed by H&E, Oil-red O staining, and triglyceride levels). Mice were submitted to partial warm ischemia for 60- or 90-min ischemia followed by reperfusion. In 60-min IRI, all lean, MiS, and MaS mice survived post-reperfusion. MaS mice had significantly higher serum AST (11632±3238 vs. 2123±1424 vs. 380±269) levels (U/L) compared with MiS (p<0.05) and lean (p<0.05) mice, respectively, at 24h after IRI. Cyclin D1 is one of the key regulatory proteins of the cell cycle; its expression is required for transition from the G1 into the S phase. The relatively well-preserved lean livers showed significantly increased Cyclin D1 expression (1.18±0.26 vs. 0.24±0.13 vs. 0.04±0.01), but reduced PCNA levels (0.03±0.003 vs. 0.86±0.14 vs. 0.29±0.03), compared with MiSand MaS livers (respectively, p<0.05) at 48h post-IRI. In 90-min IRI, all lean and MiS mice survived surgery, despite significant liver damage, while only 40% of the MaS mice were alive after the first two postoperative days. Here, lean mice showed significantly higher expression levels of both Cyclin D1 (0.47±0.01vs. 0.31±0.02 vs. 0.10±0.02) and PCNA (0.40±0.05 vs. 0.23±0.05 vs. 0.13±0.04), compared with MiS and MaS mice (respectively, p<0.05) at 48h post-IRI. PCNA protein expression levels correlated with the hepatocyte proliferation index in all evaluated tissues. Conclusion: This thorough study demonstrates distinct expression patterns of cell-cycle regulators in macrosteatotic, microsteatotic and lean livers after IRI. Moreover, it suggests that while Cyclin D1 levels reflect the capability of livers to regenerate post-reperfusion, PCNA levels represent their regenerative activity.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have