Permeant cGMP analogs prevent the mitochondria permeability transition (MPT) in vitro. In this study, we explored whether
8-pCPT-cGMP prevents the MPT and decreases post-transplant damage to fatty partial liver grafts (FPG) in vivo. Rats were fed a control or high-fat, high-
fructose diet for 2-week. Lean and
fatty liver explants were reduced in size ex vivo to ~35% and stored in the University of Wisconsin
solution with and without
8-pCPT-cGMP (300 µM) for 2 h. After
transplantation,
alanine aminotransferase release (
indicator of hepatocellular injury),
hyperbilirubinemia (
indicator of poor liver function), and cell death were all higher in FPG than in lean partial grafts (LPG). Liver regeneration increased in LPG but was suppressed in FPG.
8-pCPT-cGMP blunted graft injury, improved liver regeneration and function, and increased survival of FPG. Hepatic mitochondrial depolarization detected by intravital multiphoton microscopy of
rhodamine 123 in living rats was ~3.5-fold higher in FPG than in LPG.
8-pCPT-cGMP decreased mitochondrial depolarization in FPG almost to the level of LPG. Activation of
mammalian target of rapamycin (mTOR), an energy sensitive
kinase that stimulates cell proliferation and growth, and p70S6
kinase, a downstream signaling molecule of mTOR, was increased in LPG but suppressed in FPG.
8-pCPT-cGMP restored the activity of mTOR and p70S6
kinase in FPG.
8-pCPT-cGMP also increased activation of
cAMP response element-binding protein (CREB) and expression of
cyclins D1 and E in FPG. Non-alcoholic steatosis increases injury and suppresses regeneration after partial
liver transplantation, at least in part, due to more severe
mitochondrial dysfunction. Protection of mitochondria with a cGMP analog effectively improves outcomes of FPG
transplantation.