A Novel Multidrug Combination Mitigates Rat Liver Steatosis Through Activating AMPK Pathway During Normothermic Machine Perfusion

Abstract

Supplemental Digital Content is available in the text.

Normothermic liver machine perfusion as a dynamic platform for regenerative purposes: What does the future have in store for us?

“…An often studied defatting cocktail is the combination of forskolin, scoparone, nuclear receptor ligands GW7647 and GW501516, hypericin, and visfatin, which all play a role in fat metabolism, uptake, or accumulation. 33 This cocktail led to a 4fold faster decrease in macrovesicular steatosis in isolated rat hepatocytes and a triglyceride content reduction of 65% in rat livers after only 3 h NMP, compared to a 30% reduction with a control perfusate. 34,35 Histology showed a significant decrease in lipid vesicles in hepatocytes, especially in the periportal area (zone 1), and a restored hepatocellular cytoplasmic volume.…”

“…35 The addition of L-carnitine to this cocktail led to even better results, by increasing fatty acid transportation to the mitochondria. 33,36 Reductions in tissue triglyceride levels and macrovesicular steatosis were seen in discarded human steatotic livers after 6 h NMP. The addition of L-carnitine also decreased IRI, expression of oxidative injury markers, activation of immune cells, and inflammatory cytokines in the perfusate.…”

“…The first mentioned defatting cocktail has been reported to increase lactic dehydrogenase activity, and the GWcompounds are associated with hepatic carcinogenesis and mitochondrial dysfunction. 33,40 For this reason, other agents have also been tested, with success. The replacement of the GW-compounds with 2 polyphenols, epigallocatechin-3-gallate, and resveratrol, led to less hepatotoxicity in rat livers, and glial cell line-derived neurotrophic factor led to no alteration in lactic dehydrogenase activity in steatotic mouse livers after 4 h NMP, while both were still effective.…”

“…The replacement of the GW-compounds with 2 polyphenols, epigallocatechin-3-gallate, and resveratrol, led to less hepatotoxicity in rat livers, and glial cell line-derived neurotrophic factor led to no alteration in lactic dehydrogenase activity in steatotic mouse livers after 4 h NMP, while both were still effective. 33,40 In summary, in experimental studies, defatting cocktails can decrease steatosis in livers in just a few hours. However, with long-term NMP, it might become possible to defat livers without extra medication because a "spontaneous" decrease in hepatic triglyceride content and steatosis is also seen without defatting cocktails.…”

NRF2 assessment in discarded liver allografts: A role in allograft function and salvage

“…We used a modified NMP system based on the previously reported Harvard Apparatus 21 . Livers were placed on NMP using our previously described approach with whole‐blood perfusate and cannulation of the portal vein 22 . An NRF2 agonist (Oltipraz, ab141957; Abcam; 150 mg/kg) was delivered at the initial 1‐hour time point when the system temperature was stabilized, 22 and perfusion was maintained at 37°C for an additional 3 h. Perfusate samples were collected at baseline (0 h) and 4‐h of NMP for blood gas and biochemical testing.…”