Abnormal lipid processing but normal long-term repopulation potential of myc-/- hepatocytes.
Establishing c-Myc's (Myc) role in liver regeneration has proven difficult particularly since the traditional model of partial hepatectomy may provoke an insufficiently demanding proliferative stress. We used a model of hereditary tyrosinemia whereby the affected parenchyma can be gradually replaced by transplanted hepatocytes, which replicate 50-100-fold, over several months. Prior to transplantation, livers from myc-/- (KO) mice were smaller in young animals and larger in older animals relative to myc+/+ (WT) counterparts. KO mice also consumed more oxygen, produced more CO2 and generated more heat. Although WT and KO hepatocytes showed few mitochondrial structural differences, the latter demonstrated defective electron transport chain function. RNAseq revealed differences in transcripts encoding ribosomal subunits, cytochrome p450 members and enzymes for triglyceride and sterol biosynthesis. KO hepatocytes also accumulated neutral lipids. WT and KO hepatocytes repopulated recipient tyrosinemic livers equally well although the latter were associated with a pro-inflammatory hepatic environment that correlated with worsening lipid accumulation, its extracellular deposition and parenchymal oxidative damage. Our results show Myc to be dispensable for sustained in vivo hepatocyte proliferation but necessary for maintaining normal lipid homeostasis. myc-/- livers resemble those encountered in non-alcoholic fatty liver disease and, under sustained proliferative stress, gradually acquire the features of non-alcoholic steatohepatitis.
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.|Department of Molecular Genetics and Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Lia R
LR
Edmunds
Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
P Anthony
PA
Otero
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.|Biotechnology Program, Center for Biological Sciences, Central University of Bihar, Bihar, India.
Lokendra
L
Sharma
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Sonia
S
D'Souza
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
James M
JM
Dolezal
Department of Molecular Genetics and Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Sherin
S
David
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Jie
J
Lu
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Lauren
L
Lamm
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Mahesh
M
Basantani
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Mt. Sinai School of Medicine, New York, NY, USA.
Pili
P
Zhang
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Ian J
IJ
Sipula
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Mt. Sinai School of Medicine, New York, NY, USA.
Lucy
L
Li
Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA, USA.
Xuemei
X
Zeng
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Ying
Y
Ding
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Fei
F
Ding
Division of Medical Genetics, Children's Hospital of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Megan E
ME
Beck
Division of Medical Genetics, Children's Hospital of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Jerry
J
Vockley
Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
Satdarshan P S
SP
Monga
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Erin E
EE
Kershaw
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Robert M
RM
O'Doherty
Laboratory of Biochemical Genetics Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Lisa E
LE
Kratz
Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA, USA.|Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Nathan A
NA
Yates
Division of Medical Genetics, Children's Hospital of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Eric P
EP
Goetzman
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Mt. Sinai School of Medicine, New York, NY, USA.
Donald
D
Scott
Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Andrew W
AW
Duncan
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.|Department of Molecular Genetics and Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA.|The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Edward V
EV
Prochownik
D000818:Animals; D049109:Cell Proliferation; D048429:Cell Size; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008115:Liver Regeneration; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D024101:Mitochondrial Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014280:Triglycerides
NAFLD; NASH; cytochrome p450; electron transport chain; hereditary tyrosinemia