Metabolic and lipidomic profiling of steatotic human livers during ex situ normothermic machine perfusion guides resuscitation strategies
There continues to be a significant shortage of donor livers for transplantation. One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best...
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| creator | Raigani, Siavash Karimian, Negin Huang, Viola Zhang, Anna M Beijert, Irene Geerts, Sharon Nagpal, Sonal Hafiz, Ehab O A Fontan, Fermin M Aburawi, Mohamed M Mahboub, Paria Markmann, James F Porte, Robert J Uygun, Korkut Yarmush, Martin Yeh, Heidi |
| description | There continues to be a significant shortage of donor livers for transplantation. One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best to improve the quality of steatotic livers is lacking. Herein, we use normothermic (37°C) machine perfusion in combination with metabolic and lipidomic profiling to elucidate deficiencies in metabolic pathways in steatotic livers, and to inform strategies for improving their function. During perfusion, energy cofactors increased in steatotic livers to a similar extent as non-steatotic livers, but there were significant deficits in anti-oxidant capacity, efficient energy utilization, and lipid metabolism. Steatotic livers appeared to oxidize fatty acids at a higher rate but favored ketone body production rather than energy regeneration via the tricyclic acid cycle. As a result, lactate clearance was slower and transaminase levels were higher in steatotic livers. Lipidomic profiling revealed ω-3 polyunsaturated fatty acids increased in non-steatotic livers to a greater extent than in steatotic livers. The novel use of metabolic and lipidomic profiling during ex situ normothermic machine perfusion has the potential to guide the resuscitation and rehabilitation of steatotic livers for transplantation. |
| doi_str_mv | 10.1371/journal.pone.0228011 |
| format | Article |
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One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best to improve the quality of steatotic livers is lacking. Herein, we use normothermic (37°C) machine perfusion in combination with metabolic and lipidomic profiling to elucidate deficiencies in metabolic pathways in steatotic livers, and to inform strategies for improving their function. During perfusion, energy cofactors increased in steatotic livers to a similar extent as non-steatotic livers, but there were significant deficits in anti-oxidant capacity, efficient energy utilization, and lipid metabolism. Steatotic livers appeared to oxidize fatty acids at a higher rate but favored ketone body production rather than energy regeneration via the tricyclic acid cycle. As a result, lactate clearance was slower and transaminase levels were higher in steatotic livers. Lipidomic profiling revealed ω-3 polyunsaturated fatty acids increased in non-steatotic livers to a greater extent than in steatotic livers. The novel use of metabolic and lipidomic profiling during ex situ normothermic machine perfusion has the potential to guide the resuscitation and rehabilitation of steatotic livers for transplantation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0228011</identifier><identifier>PMID: 31978172</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine triphosphate ; Adenosine Triphosphate - biosynthesis ; Antioxidants ; Bile Acids and Salts - metabolism ; Biology and Life Sciences ; Cofactors ; Cold storage ; Consent ; Criminal investigation ; Energy metabolism ; Energy utilization ; Engineering ; Fatty acids ; Fatty Acids - metabolism ; Fatty Liver - metabolism ; Fatty Liver - pathology ; Fatty Liver - physiopathology ; Glucose - metabolism ; Hemodynamics ; Histology ; Hospitals ; Humans ; Ischemia ; Lactates ; Lactic acid ; Lipid metabolism ; Lipidomics ; Lipids ; Liver - pathology ; Liver - physiopathology ; Liver diseases ; Liver Function Tests ; Liver transplantation ; Liver transplants ; Medical schools ; Medicine ; Medicine and Health Sciences ; Metabolic pathways ; Metabolism ; Metabolomics ; Novels ; Oxidants ; Oxidation-Reduction ; Oxidative Stress ; Oxidizing agents ; Perfusion ; Physiological aspects ; Polyunsaturated fatty acids ; Regeneration ; Rehabilitation ; Reperfusion ; Reperfusion injury ; Resuscitation ; Surgery ; Temperature ; Transaminase ; Transplantation ; Transplants & implants ; Unsaturated fatty acids ; Vascular Resistance</subject><ispartof>PloS one, 2020-01, Vol.15 (1), p.e0228011-e0228011</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Raigani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best to improve the quality of steatotic livers is lacking. Herein, we use normothermic (37°C) machine perfusion in combination with metabolic and lipidomic profiling to elucidate deficiencies in metabolic pathways in steatotic livers, and to inform strategies for improving their function. During perfusion, energy cofactors increased in steatotic livers to a similar extent as non-steatotic livers, but there were significant deficits in anti-oxidant capacity, efficient energy utilization, and lipid metabolism. Steatotic livers appeared to oxidize fatty acids at a higher rate but favored ketone body production rather than energy regeneration via the tricyclic acid cycle. As a result, lactate clearance was slower and transaminase levels were higher in steatotic livers. Lipidomic profiling revealed ω-3 polyunsaturated fatty acids increased in non-steatotic livers to a greater extent than in steatotic livers. The novel use of metabolic and lipidomic profiling during ex situ normothermic machine perfusion has the potential to guide the resuscitation and rehabilitation of steatotic livers for transplantation.</description><subject>Adenosine triphosphate</subject><subject>Adenosine Triphosphate - biosynthesis</subject><subject>Antioxidants</subject><subject>Bile Acids and Salts - metabolism</subject><subject>Biology and Life Sciences</subject><subject>Cofactors</subject><subject>Cold storage</subject><subject>Consent</subject><subject>Criminal investigation</subject><subject>Energy metabolism</subject><subject>Energy utilization</subject><subject>Engineering</subject><subject>Fatty acids</subject><subject>Fatty Acids - metabolism</subject><subject>Fatty Liver - metabolism</subject><subject>Fatty Liver - pathology</subject><subject>Fatty Liver - physiopathology</subject><subject>Glucose - metabolism</subject><subject>Hemodynamics</subject><subject>Histology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Ischemia</subject><subject>Lactates</subject><subject>Lactic acid</subject><subject>Lipid metabolism</subject><subject>Lipidomics</subject><subject>Lipids</subject><subject>Liver - pathology</subject><subject>Liver - physiopathology</subject><subject>Liver diseases</subject><subject>Liver Function Tests</subject><subject>Liver transplantation</subject><subject>Liver transplants</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolic pathways</subject><subject>Metabolism</subject><subject>Metabolomics</subject><subject>Novels</subject><subject>Oxidants</subject><subject>Oxidation-Reduction</subject><subject>Oxidative Stress</subject><subject>Oxidizing agents</subject><subject>Perfusion</subject><subject>Physiological aspects</subject><subject>Polyunsaturated fatty 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Raigani, Siavash</au><au>Karimian, Negin</au><au>Huang, Viola</au><au>Zhang, Anna M</au><au>Beijert, Irene</au><au>Geerts, Sharon</au><au>Nagpal, Sonal</au><au>Hafiz, Ehab O A</au><au>Fontan, Fermin M</au><au>Aburawi, Mohamed M</au><au>Mahboub, Paria</au><au>Markmann, James F</au><au>Porte, Robert J</au><au>Uygun, Korkut</au><au>Yarmush, Martin</au><au>Yeh, Heidi</au><au>Strnad, Pavel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolic and lipidomic profiling of steatotic human livers during ex situ normothermic machine perfusion guides resuscitation strategies</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-01-24</date><risdate>2020</risdate><volume>15</volume><issue>1</issue><spage>e0228011</spage><epage>e0228011</epage><pages>e0228011-e0228011</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>There continues to be a significant shortage of donor livers for transplantation. One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best to improve the quality of steatotic livers is lacking. Herein, we use normothermic (37°C) machine perfusion in combination with metabolic and lipidomic profiling to elucidate deficiencies in metabolic pathways in steatotic livers, and to inform strategies for improving their function. During perfusion, energy cofactors increased in steatotic livers to a similar extent as non-steatotic livers, but there were significant deficits in anti-oxidant capacity, efficient energy utilization, and lipid metabolism. Steatotic livers appeared to oxidize fatty acids at a higher rate but favored ketone body production rather than energy regeneration via the tricyclic acid cycle. As a result, lactate clearance was slower and transaminase levels were higher in steatotic livers. Lipidomic profiling revealed ω-3 polyunsaturated fatty acids increased in non-steatotic livers to a greater extent than in steatotic livers. The novel use of metabolic and lipidomic profiling during ex situ normothermic machine perfusion has the potential to guide the resuscitation and rehabilitation of steatotic livers for transplantation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31978172</pmid><doi>10.1371/journal.pone.0228011</doi><tpages>e0228011</tpages><orcidid>https://orcid.org/0000-0003-2762-7287</orcidid><orcidid>https://orcid.org/0000-0002-7379-0600</orcidid><orcidid>https://orcid.org/0000-0002-1551-4309</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2020-01, Vol.15 (1), p.e0228011-e0228011 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2344549069 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine triphosphate Adenosine Triphosphate - biosynthesis Antioxidants Bile Acids and Salts - metabolism Biology and Life Sciences Cofactors Cold storage Consent Criminal investigation Energy metabolism Energy utilization Engineering Fatty acids Fatty Acids - metabolism Fatty Liver - metabolism Fatty Liver - pathology Fatty Liver - physiopathology Glucose - metabolism Hemodynamics Histology Hospitals Humans Ischemia Lactates Lactic acid Lipid metabolism Lipidomics Lipids Liver - pathology Liver - physiopathology Liver diseases Liver Function Tests Liver transplantation Liver transplants Medical schools Medicine Medicine and Health Sciences Metabolic pathways Metabolism Metabolomics Novels Oxidants Oxidation-Reduction Oxidative Stress Oxidizing agents Perfusion Physiological aspects Polyunsaturated fatty acids Regeneration Rehabilitation Reperfusion Reperfusion injury Resuscitation Surgery Temperature Transaminase Transplantation Transplants & implants Unsaturated fatty acids Vascular Resistance |
| title | Metabolic and lipidomic profiling of steatotic human livers during ex situ normothermic machine perfusion guides resuscitation strategies |
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