Metabolic and lipidomic profiling of steatotic human livers during ex situ normothermic machine perfusion guides resuscitation strategies

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Raigani S.; Karimian N.; Huang V.; Zhang A.M.; Beijert I.; Geerts S.; Nagpal S.; Hafiz E.O.A.; Fontan F.M.; Aburawi M.M.; Mahboub P.; Markmann J.F.; Porte R.J.; Uygun K.; Yarmush M.; Yeh H.

Journal: PLoS ONE

Publisher: Public Library of Science

Publication Date: 24 January 2020

Volume / Issue: Volume 15 / Issue 1

Article No.: e0228011

ISSN: 19326203

DOI: 10.1371/journal.pone.0228011

Scopus: View on Scopus

PubMed: 31978172

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Raigani S., Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; Karimian N., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Huang V., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Zhang A.M., Tufts University School of Medicine, Boston, MA, United States; Beijert I., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States, Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Geerts S., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States, Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Nagpal S., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Hafiz E.O.A., Electron Microscopy Research Division, Theodor Bilharz Research Institute, Giza, Egypt; Fontan F.M., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Aburawi M.M., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Mahboub P., Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Markmann J.F., Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; Porte R.J., Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Uygun K., Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Yarmush M., Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA, United States; Yeh H., Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

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. © 2020 Raigani et al.

Keywords

Adenosine Triphosphate; Bile Acids and Salts; Fatty Acids; Fatty Liver; Glucose; Hemodynamics; Humans; Lipidomics; Liver; Liver Function Tests; Metabolomics; Oxidation-Reduction; Oxidative Stress; Perfusion; Resuscitation; Temperature; Vascular Resistance; aminotransferase; ketone; omega 3 fatty acid; tricyclic acid; unclassified drug; bile acid; fatty acid; adult; antioxidant activity; Article; clinical article; controlled study; disease association; energy consumption; energy recovery; fatty acid oxidation; female; human; human tissue; lactate blood level; lipid fingerprinting; lipid metabolism; liver function; liver perfusion; liver transplantation; male; metabolic disorder; metabolic fingerprinting; biosynthesis; liver function test; metabolism; oxidation reduction reaction; pathology; pathophysiology

Citation Information

Scopus Citations: 23

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