Abnormal lipid processing but normal long-term repopulation potential of myc-/- hepatocytes.
Abnormal lipid processing but normal long-term repopulation potential of myc-/- hepatocytes.
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DOI：
10.18632/oncotarget.8856
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Prochownik EV
中科院分区：
文献类型：
--
作者：
Edmunds LR;Otero PA;Sharma L;D'Souza S;Dolezal JM;David S;Lu J;Lamm L;Basantani M;Zhang P;Sipula IJ;Li L;Zeng X;Ding Y;Ding F;Beck ME;Vockley J;Monga SP;Kershaw EE;O'Doherty RM;Kratz LE;Yates NA;Goetzman EP;Scott D;Duncan AW;Prochownik EV
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.
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影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
影响因子：
3.7
作者：
Graves JA;Wang Y;Sims-Lucas S;Cherok E;Rothermund K;Branca MF;Elster J;Beer-Stolz D;Van Houten B;Vockley J;Prochownik EV
通讯作者：
Prochownik EV
影响因子：
30.8
作者：
GROMPE, M;LINDSTEDT, S;FINEGOLD, M
通讯作者：
FINEGOLD, M
影响因子：
3.7
作者：
Edmunds LR;Sharma L;Wang H;Kang A;d'Souza S;Lu J;McLaughlin M;Dolezal JM;Gao X;Weintraub ST;Ding Y;Zeng X;Yates N;Prochownik EV
通讯作者：
Prochownik EV
影响因子：
2.6
作者：
Baena, Esther;Ortiz, Maitane;de Alboran, Ignacio Moreno
通讯作者：
de Alboran, Ignacio Moreno