Abnormal lipid processing but normal long-term repopulation potential of myc-/- hepatocytes

// Lia R. Edmunds 1,2 , P. Anthony Otero 3 , Lokendra Sharma 1,13 , Sonia D’Souza 1 , James M. Dolezal 1 , Sherin David 2 , Jie Lu 1 , Lauren Lamm 1 , Mahesh Basantani 4 , Pili Zhang 5 , Ian J. Sipula 4 , Lucy Li 5 , Xuemei Zeng 6 , Ying Ding 7 , Fei Ding 7 , Megan E. Beck 8 , Jerry Vockley 8 , Satdarshan P. S. Monga 9 , Erin E. Kershaw 4 , Robert M. O’Doherty 4 , Lisa E. Kratz 10 , Nathan A. Yates 6,11 , Eric P. Goetzman 8 , Donald Scott 5 , Andrew W. Duncan 3 and Edward V. Prochownik 1,2,12 1 Division of Hematology/Oncology, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA 2 Department of Molecular Genetics and Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA 3 Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA 4 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA 5 Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Mt. Sinai School of Medicine, New York, NY, USA 6 Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA, USA 7 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA 8 Division of Medical Genetics, Children’s Hospital of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA 9 Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, PA, USA 10 Laboratory of Biochemical Genetics Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA 11 Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 12 The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA 13 Biotechnology Program, Center for Biological Sciences, Central University of Bihar, Bihar, India Correspondence to: Edward V. Prochownik, email: // Keywords : hereditary tyrosinemia, cytochrome p450, electron transport chain, NAFLD, NASH Received : March 30, 2016 Accepted : April 09, 2016 Published : April 20, 2016 Abstract 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 CO 2 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.