Insulin in UW solution exacerbates hepatic ischemia / reperfusion injury by energy depletion through the IRS-2 / SREBP-1c pathway.
Ischemia / reperfusion (I / R) injury is related to tissue graft energy status. Insulin, which is currently used in the University of Wisconsin (UW) preservation solution with insulin (UWI), is an anabolic hormone and was shown to exacerbate the hepatic I / R injury in our previous study. In this study, the energy status and regulation of metabolism genes by insulin were investigated in liver grafts preserved by UW solution. Insulin could significantly decrease adenosine triphosphate (ATP) level after 3 hours of preservation, as well as total adenine nucleotides (TANs) and energy charge (EC) levels. Energy regeneration deteriorated in the grafts preserved by insulin in terms of ATP and EC levels at 24 hours after transplantation. The insulin signal was transduced through the insulin receptor substrate-2 (IRS-2) pathway and the activity of IRS-2 was decreased gradually at the messenger ribonucleic acid (mRNA) level during cold preservation. Downstream targeting genes such as sterol regulatory element-binding protein-1c (SREBP-1c), glucokinase (GKC), and fatty acid synthase (FAS) genes, as well as phospho-glycogen synthase kinase-3beta (GSK-3beta) were activated and they showed the similar expression profiles during cold preservation. Lipoprotein metabolism was accelerated by insulin through upregulation of the activity of apolipoprotein C-III (Apo C-III) during cold preservation. The insulin-like growth factor-binding protein-1 pathway was inhibited during cold preservation. In conclusion, insulin in UW solution exacerbates hepatic I / R injury by energy depletion as the graft maintains its anabolic activity. The key enzyme activities of the energy-consuming process of glycogen and fatty acid synthesis as well as lipoprotein metabolism were accelerated by insulin through the IRS-2 / SREBP-1c pathway.
Li
Xian Liang
XL
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Hong Kong, China.
Man
Kwan
K
Ng
Kevin T
KT
Lee
Terence K
TK
Lo
Chung Mau
CM
Fan
Sheung Tat
ST
D000241:Adenosine / Q000737:chemistry*; D000493:Allopurinol / Q000737:chemistry*; D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000378:metabolism; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D005978:Glutathione / Q000737:chemistry*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000737:chemistry* / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D009926:Organ Preservation; D019188:Organ Preservation Solutions / Q000737:chemistry*; D010750:Phosphoproteins / Q000502:physiology*; D011887:Raffinose / Q000737:chemistry*; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D019188:Organ Preservation Solutions; D010750:Phosphoproteins; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose