*Purpose: Donor livers with moderate-to-severe steatosis are not generally used for transplantation because of poor post-transplant function. Ex situ normothermic machine perfusion (ENMP) provides an opportunity to decrease fat content and assess functional improvement. We evaluated the ability of a 7-component defatting cocktail to decrease macrosteatosis (MaS) and improve perfusion parameters in rat fatty livers.

*Methods: 6 each of lean Zucker rat livers (NL) and steatotic livers (SL) from obese Zucker rats underwent 6 hours of ENMP with standard perfusion medium; an additional 6 SL were perfused with the addition of a defatting cocktail (SLD) containing visfatin, hypericin, forskolin, scoparone, L-carnitine, GW7647, and GW501516. Perfusion dynamics were recorded and perfusate samples collected hourly; macrosteatosis at the end of perfusion was determined in blinded fashion by a pathologist by H & E.

*Results: After 6 hours ENMP, SL livers retained 41.5% MaS (range 25-58%) while SLD had only 8.5% MaS (range 1-18%); NL were <2% MaS, as expected. At 6 hours, perfusate lactate content was significantly higher in SL (13.4 ±4.0 mg/dL) compared to LL (6.6 ±1.0 mg/dL, p=0.001) and SLD (8.2 ±1.7 mg/dL, p=0.01). Perfusate ketone content (as a proxy for fatty acid beta-oxidation) was significantly higher at 4 and 6 hours in SLD compared to SL (p<0.05 for both). Interestingly, perfusate triglyceride levels increased significantly more over 6 hours in SL (140 ng/uL) than SLD (43 ng/uL, p<0.001). Bicarbonate content in produced bile was significantly higher in SLD (42 mmol/L) than SL (26 mmol/L), and even NL (31 mmol/L, p<0.001), although cumulative bile volume remained higher in NL.

*Conclusions: Moderate-to-severe macrosteatosis can be reversed in rat fatty livers using a 7-component defatting cocktail during 6 hours of ENMP, resulting in significantly improved lactate clearance and bile quality. Further studies to test liver viability in a transplant model are planned.

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