PMID- 32094147
OWN - NLM
STAT- MEDLINE
DCOM- 20210610
LR  - 20240229
IS  - 1754-8411 (Electronic)
IS  - 1754-8403 (Print)
IS  - 1754-8403 (Linking)
VI  - 13
IP  - 4
DP  - 2020 Apr 29
TI  - Novel defatting strategies reduce lipid accumulation in primary human culture 
      models of liver steatosis.
LID - 10.1242/dmm.042663 [doi]
LID - dmm042663
AB  - Normothermic perfusion provides a means to rescue steatotic liver grafts, 
      including by pharmacological defatting. In this study, we tested the potential of 
      new drug combinations to trigger defatting in three human culture models, primary 
      hepatocytes with induced steatosis, primary hepatocytes isolated from steatotic 
      liver, and precision-cut liver slices (PCLS) of steatotic liver. Forskolin, 
      L-carnitine and a PPARalpha agonist were all combined with rapamycin, an 
      immunosuppressant that induces autophagy, in a D-FAT cocktail. D-FAT was tested 
      alone or in combination with necrosulfonamide, an inhibitor of mixed lineage 
      kinase domain like pseudokinase involved in necroptosis. Within 24 h, in all 
      three models, D-FAT induced a decrease in triglyceride content by 30%, 
      attributable to an upregulation of genes involved in free fatty acid beta-oxidation 
      and autophagy, and a downregulation of those involved in lipogenesis. Defatting 
      was accompanied by a decrease in endoplasmic reticulum stress and in the 
      production of reactive oxygen species. The addition of necrosulfonamide increased 
      the efficacy of defatting by 8%-12% in PCLS, with a trend towards increased 
      autophagy. In conclusion, culture models, notably PCLS, are insightful to design 
      strategies for liver graft rescue. Defatting can be rapidly achieved by 
      combinations of drugs targeting mitochondrial oxidative metabolism, 
      macro-autophagy and lipogenesis.
CI  - (c) 2020. Published by The Company of Biologists Ltd.
FAU - Aoudjehane, Lynda
AU  - Aoudjehane L
AUID- ORCID: 0000-0003-4191-0564
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France lynda.aoudjehane@inserm.fr.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
FAU - Gautheron, Jeremie
AU  - Gautheron J
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
FAU - Le Goff, Wilfried
AU  - Le Goff W
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
FAU - Goumard, Claire
AU  - Goumard C
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
AD  - Department of Hepatobiliary and Liver Transplantation Surgery, Pitie-Salpetriere 
      Hospital, Assistance Publique-Hopitaux de Paris, Paris 75013, France.
FAU - Gilaizeau, Julia
AU  - Gilaizeau J
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
FAU - Nget, Chan Sonavine
AU  - Nget CS
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
FAU - Savier, Eric
AU  - Savier E
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
AD  - Department of Hepatobiliary and Liver Transplantation Surgery, Pitie-Salpetriere 
      Hospital, Assistance Publique-Hopitaux de Paris, Paris 75013, France.
FAU - Atif, Muhammad
AU  - Atif M
AD  - Centre d'immunologie et maladies infectieuses, Sorbonne Universite, INSERM, 
      U1135, Paris 75013, France.
FAU - Lesnik, Philippe
AU  - Lesnik P
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
FAU - Morichon, Romain
AU  - Morichon R
AD  - Production et Analyse des donnees en Sciences de la vie et en Sante (PASS), 
      Sorbonne Universite, INSERM, UMS 37, Paris 75013, France.
FAU - Chretien, Yves
AU  - Chretien Y
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
FAU - Calmus, Yvon
AU  - Calmus Y
AD  - Department of Medical Liver Transplantation, Pitie-Salpetriere Hospital, 
      Assistance Publique-Hopitaux de Paris, Paris 75013, France.
FAU - Scatton, Olivier
AU  - Scatton O
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
AD  - Department of Hepatobiliary and Liver Transplantation Surgery, Pitie-Salpetriere 
      Hospital, Assistance Publique-Hopitaux de Paris, Paris 75013, France.
FAU - Housset, Chantal
AU  - Housset C
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
AD  - Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and 
      Autoimmune Hepatitis, Saint-Antoine Hospital, Assistance Publique-Hopitaux de 
      Paris, Paris 75012, France.
FAU - Conti, Filomena
AU  - Conti F
AD  - Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universite, INSERM, 
      Paris 75012, France.
AD  - Centre de Recherche Saint-Antoine (CRSA), Sorbonne Universite, INSERM, Paris 
      75013, France.
AD  - Department of Medical Liver Transplantation, Pitie-Salpetriere Hospital, 
      Assistance Publique-Hopitaux de Paris, Paris 75013, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200429
PL  - England
TA  - Dis Model Mech
JT  - Disease models & mechanisms
JID - 101483332
RN  - 0 (Acrylamides)
RN  - 0 (Fatty Acids)
RN  - 0 
      (N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide)
RN  - 0 (Sulfonamides)
SB  - IM
MH  - Acrylamides
MH  - Cells, Cultured
MH  - Fatty Acids
MH  - Fatty Liver/*metabolism/*pathology
MH  - Female
MH  - Hepatocytes/metabolism/pathology
MH  - Humans
MH  - *Lipid Metabolism
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Signal Transduction
MH  - Sulfonamides
PMC - PMC7197711
OTO - NOTNLM
OT  - Defatting
OT  - Human hepatocytes
OT  - Human precision-cut liver slices
OT  - Liver transplantation
OT  - Steatosis
OT  - Triglycerides
COIS- Competing interestsThe authors declare no competing or financial interests.
EDAT- 2020/02/26 06:00
MHDA- 2021/06/11 06:00
PMCR- 2020/04/29
CRDT- 2020/02/26 06:00
PHST- 2019/10/04 00:00 [received]
PHST- 2020/02/13 00:00 [accepted]
PHST- 2020/02/26 06:00 [pubmed]
PHST- 2021/06/11 06:00 [medline]
PHST- 2020/02/26 06:00 [entrez]
PHST- 2020/04/29 00:00 [pmc-release]
AID - dmm.042663 [pii]
AID - DMM042663 [pii]
AID - 10.1242/dmm.042663 [doi]
PST - epublish
SO  - Dis Model Mech. 2020 Apr 29;13(4):dmm042663. doi: 10.1242/dmm.042663.