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A Novel Multidrug Combination Mitigates Rat Liver Steatosis Through Activating AMPK Pathway During Normothermic Machine Perfusion.
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ABSTRACT: Background
Hepatic steatosis is now the leading cause of liver discards in deceased donors. Previous studies [Yarmush formula (Y) defatting] have successfully reduced the fat content by treating rat steatotic livers on extracorporeal normothermic machine perfusion (NMP) with a multidrug combination including the GW compounds that were linked to an increased risk of carcinogenesis.Methods
We developed a novel multidrug combination by replacing the GW compounds with 2 polyphenols, epigallocatechin-3-gallate (E) and resveratrol (R). Sixteen rat livers were placed on NMP and assigned to control, Y defatting, Y + E + R defatting, or Y'-GW + E + R defatting groups (Y'-GW = 90% dose-reduced Y defatting, n = 4/group).Results
All livers in defatting groups had significant decreases in hepatic triglyceride content at the end of the experiment. However, livers treated with our novel Y'-GW + E + R combination had evidence of increased metabolism and less hepatocyte damage and carcinogenic potential. Our Y'-GW + E + R combination had increased phosphorylation of AMP-activated protein kinase (P = 0.019) and acetyl-CoA carboxylase (P = 0.023) compared with control; these were not increased in Y + E + R group and actually decreased in the Y group. Furthermore, the Y'-GW + E + R group had less evidence of carcinogenic potential with no increase in AKT phosphorylation compared with control (P = 0.089); the Y (P = 0.031) and Y + E + R (P = 0.035) groups had striking increases in AKT phosphorylation. Finally, our Y'-GW + E + R showed less evidence of hepatocyte damage with significantly lower perfusate alanine aminotransferase (P = 0.007) and aspartate aminotransferase (P = 0.014) levels.Conclusions
We have developed a novel multidrug combination demonstrating promising defatting efficacy via activation of the AMP-activated protein kinase pathway with an optimized safety profile and reduced hepatotoxicity during ex vivo NMP.
SUBMITTER: Xu M
PROVIDER: S-EPMC8356968 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
Publications
A Novel Multidrug Combination Mitigates Rat Liver Steatosis Through Activating AMPK Pathway During Normothermic Machine Perfusion.
Transplantation 20211101 11
<h4>Background</h4>Hepatic steatosis is now the leading cause of liver discards in deceased donors. Previous studies [Yarmush formula (Y) defatting] have successfully reduced the fat content by treating rat steatotic livers on extracorporeal normothermic machine perfusion (NMP) with a multidrug combination including the GW compounds that were linked to an increased risk of carcinogenesis.<h4>Methods</h4>We developed a novel multidrug combination by replacing the GW compounds with 2 polyphenols, ...[more]
