TY - JOUR
T1 - The impact of diet-induced hepatic steatosis in a murine model of hepatic ischemia/reperfusion injury
AU - Liss, Kim H.H.
AU - McCommis, Kyle S.
AU - Chambers, Kari T.
AU - Pietka, Terri A.
AU - Schweitzer, George G.
AU - Park, Sara L.
AU - Nalbantoglu, Ilke
AU - Weinheimer, Carla J.
AU - Hall, Angela M.
AU - Finck, Brian N.
N1 - Funding Information:
Work in the authors’ laboratory was supported by National Institutes of Health (NIH) grants R01 DK078187 and R01 DK104735 to Brian N. Finck and several core laboratories of Washington University (P30 DK052574; P30 DK20579; P30 DK56341). Kim H. H. Liss is a Pediatric Gastroenterology Training Grant Fellow supported by T32 DK0077653. Angela M. Hall is supported by the American Diabetes Association Innovative Basic Science Award 1-17-IBS-109. Kyle S. McCommis is supported by NIH grant K99 HL136658. Carla J. Weinheimer is supported by NIH R01 HL107594.
Funding Information:
Work in the authors' laboratory was supported by National Institutes of Health (NIH) grants R01 DK078187 and R01 DK104735 to Brian N. Finck and several core laboratories of Washington University (P30 DK052574; P30 DK20579; P30 DK56341). Kim H. H. Liss is a Pediatric Gastroenterology Training Grant Fellow supported by T32 DK0077653. Angela M. Hall is supported by the American Diabetes Association Innovative Basic Science Award 1‐17‐IBS‐109. Kyle S. McCommis is supported by NIH grant K99 HL136658. Carla J. Weinheimer is supported by NIH R01 HL107594.
Publisher Copyright:
© 2018 by the American Association for the Study of Liver Diseases.
PY - 2018/7
Y1 - 2018/7
N2 - The prevalence of obesity-associated nonalcoholic fatty liver disease has significantly increased over the past decade, and end-stage liver disease secondary to nonalcoholic steatohepatitis has become 1 of the most common indications for liver transplantation. This both increases the demand for organs and decreases the availability of donor livers deemed suitable for transplantation. Although in the past many steatotic livers were discarded due to concerns over enhanced susceptibility to ischemia/reperfusion injury (IRI) and organ failure, the discrepancy between supply and demand has resulted in increasing use of expanded criteria donor organs including steatotic livers. However, it remains controversial whether steatotic livers can be safely used for transplantation and how best to improve the performance of steatotic grafts. We aimed to evaluate the impact of diet-induced hepatic steatosis in a murine model of IRI. Using a diet of high trans-fat, fructose, and cholesterol (HTF-C) and a diet high in saturated fats, sucrose, and cholesterol (Western diet), we were able to establish models of mixed macrovesicular and microvesicular steatosis (HTF-C) and microvesicular steatosis (Western). We found that the presence of hepatic steatosis, whether it is predominantly macrovesicular or microvesicular, significantly worsens IRI as measured by plasma alanine aminotransferase levels and inflammatory cytokine concentration, and histological evaluation for necrosis. Additionally, we report on a novel finding in which hepatic IRI in the setting of steatosis results in the induction of the necroptosis factors, receptor interacting protein kinase (RIPK) 3, RIPK1, and mixed-lineage kinase domain-like. These data lay the groundwork for additional experimentation to test potential therapeutic approaches to limit IRI in steatotic livers by using a genetically tractable system. Liver Transplantation 24 908–921 2018 AASLD.
AB - The prevalence of obesity-associated nonalcoholic fatty liver disease has significantly increased over the past decade, and end-stage liver disease secondary to nonalcoholic steatohepatitis has become 1 of the most common indications for liver transplantation. This both increases the demand for organs and decreases the availability of donor livers deemed suitable for transplantation. Although in the past many steatotic livers were discarded due to concerns over enhanced susceptibility to ischemia/reperfusion injury (IRI) and organ failure, the discrepancy between supply and demand has resulted in increasing use of expanded criteria donor organs including steatotic livers. However, it remains controversial whether steatotic livers can be safely used for transplantation and how best to improve the performance of steatotic grafts. We aimed to evaluate the impact of diet-induced hepatic steatosis in a murine model of IRI. Using a diet of high trans-fat, fructose, and cholesterol (HTF-C) and a diet high in saturated fats, sucrose, and cholesterol (Western diet), we were able to establish models of mixed macrovesicular and microvesicular steatosis (HTF-C) and microvesicular steatosis (Western). We found that the presence of hepatic steatosis, whether it is predominantly macrovesicular or microvesicular, significantly worsens IRI as measured by plasma alanine aminotransferase levels and inflammatory cytokine concentration, and histological evaluation for necrosis. Additionally, we report on a novel finding in which hepatic IRI in the setting of steatosis results in the induction of the necroptosis factors, receptor interacting protein kinase (RIPK) 3, RIPK1, and mixed-lineage kinase domain-like. These data lay the groundwork for additional experimentation to test potential therapeutic approaches to limit IRI in steatotic livers by using a genetically tractable system. Liver Transplantation 24 908–921 2018 AASLD.
UR - http://www.scopus.com/inward/record.url?scp=85050498336&partnerID=8YFLogxK
U2 - 10.1002/lt.25189
DO - 10.1002/lt.25189
M3 - Article
C2 - 29729104
AN - SCOPUS:85050498336
VL - 24
SP - 908
EP - 921
JO - Liver Transplantation
JF - Liver Transplantation
SN - 1527-6465
IS - 7
ER -