Increased free fatty acids (FA) metabolism following partial hepatectomy (PH) is required to meet energy demands of liver regeneration (LR). Impact of dietary lipid intake on LR depends on composition: diets enriched in olive/fish oils increase, while high fat diets decrease hepatocyte proliferation after PH by causing steatosis and inflammation. We previously showed that overexpression of the NF-ΚB inhibitory and hepatoprotective protein A20 improves FA metabolism, through increased peroxisome proliferator activator receptor alpha (PPARΑ) expression. This culminates in decreased oxidative stress and increased energy production, thereby improving mouse survival following severe liver ischemia/ reperfusion injury, and lethal radical hepatectomy. In contrast, partial loss of A20 (heterozygous (HT) mice) delays LR and increases lethality (42%) following PH, through impaired lipid metabolism and increased inflammation.

In this study, we evaluated the impact of a fish oil (FO) diet on LR. A20 HT and wild type (WT) mice were fed 7% FO or soybean (SO) oil diets for 4 weeks prior to 2/3 PH. We noted significantly less proliferating (Ki67+) hepatocytes and heightened macrosteatosis (Oil Red-O staining) correlating with increased lethality (>15% vs. 0%) in SO fed HT, as compared to WT mice, 48h after PH. Remarkably, FO feeding of HT mice abrogated death post PH by improving hepatocyte proliferation and reducing steatosis. This benefit relates to FO correcting lower PPARΑ and higher Fatty Acid Synthase (FASN) baseline mRNA levels noted in SO fed HT mice, as compared to WT, thereby reducing liver inflammation (otherwise significantly higher in SO Fed HT vs. WT) after PH, as evaluated by mRNA levels of Serum Amyloid A1 (SAA1). WT mice faired similarly well, regardless of diet.

This is the first demonstration that dietary manipulation of lipid composition prior to PH restores hepatocyte proliferative ability, improving outcome in A20 HT mice. The clinical relevance of these findings is emphasized by recently described gene polymorphisms associated with A20’s decreased expression or function. We propose that FO rich diets offer a safe and inexpensive means to overcome genetic predisposition in patients with unfavorable A20 polymorphisms, allowing for better outcomes following liver transplantation, mainly living donor liver transplantation.

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