Metabolic Remodeling during Liver Regeneration

被引：99

作者：

Caldez, Matias J. ^{[1
,2
]}

Van Hul, Noemi ^{[1
]}

Koh, Hiromi W. L. ^{[3
]}

Teo, Xing Qi ^{[4
]}

Fan, Jun Jun ^{[5
,6
,7
]}

Tan, Peck Yean ^{[8
]}

Dewhurst, Matthew R. ^{[1
,9
]}

Too, Peh Gek ^{[8
]}

Talib, S. Zakiah A. ^{[1
]}

Chiang, Beatrice E. ^{[1
]}

Stunkel, Walter ^{[8
]}

Yu, Hanry ^{[5
,11
,12
,13
]}

Lee, Philip ^{[4
]}

Fuhrer, Tobias ^{[10
]}

Choi, Hyungwon ^{[1
,3
]}

Bjorklund, Mikael ^{[14
]}

Kaldis, Philipp ^{[1
]}

机构：

[1] ASTAR, IMCB, 61 Biopolis Dr,Proteos 3-09, Singapore 138673, Singapore

[2] NUS, Dept Biochem, Singapore 117597, Singapore

[3] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, 12 Sci Dr 2, Singapore 117549, Singapore

[4] ASTAR, Singapore Bioimaging Consortium, Singapore, Singapore

[5] ASTAR, Inst Bioengn & Nanotechnol, Nanos 04-01,31 Biopolis Way, Singapore 138669, Singapore

[6] Singapore MIT Alliance Res & Technol, 1 CREATE Way,10-01 CREATE Tower, Singapore 138602, Singapore

[7] Fourth Mil Med Univ, Xi Jing Hosp, Dept Orthopaed Surg, 88 Jiefang Rd, Xian 710032, Shaanxi, Peoples R China

[8] ASTAR, Singapore Inst Clin Sci, Singapore, Singapore

[9] Univ Manchester, Fac Biol Med & Hlth, AV Hill Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England

[10] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland

[11] Yong Loo Lin Sch Med, Dept Physiol, MD9-04-11,2 Med Dr, Singapore 117597, Singapore

[12] Natl Univ Singapore, Mechanobiol Inst, 5A Engn Dr 1, Singapore 117411, Singapore

[13] Southern Med Univ, Gastroenterol Dept, Guangzhou 510515, Guangdong, Peoples R China

[14] Zhejiang Univ, Sch Med, Univ Edinburgh, ZJU UoE Inst, Int Campus,718 East Haizhou Rd, Haining 314400, Zhejiang, Peoples R China

来源：

DEVELOPMENTAL CELL | 2018年 / 47卷 / 04期

基金：

英国生物技术与生命科学研究理事会;

关键词：

MITOCHONDRIAL BIOENERGETICS; OXIDATIVE-PHOSPHORYLATION; PARTIAL-HEPATECTOMY; CELL-DIVISION; HYPERTROPHY; CDK1; MASS; GLUCONEOGENESIS; PROLIFERATION; HEPATOCYTES;

D O I：

10.1016/j.devcel.2018.09.020

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Liver disease is linked to a decreased capacity of hepatocytes to divide. In addition, cellular metabolism is important for tissue homeostasis and regeneration. Since metabolic changes are a hallmark of liver disease, we investigated the connections between metabolism and cell division. We determined global metabolic changes at different stages of liver regeneration using a combination of integrated transcriptomic and metabolomic analyses with advanced functional redox in vivo imaging. Our data indicate that blocking hepatocyte division during regeneration leads to mitochondrial dysfunction and downregulation of oxidative pathways. This resulted in an increased redox ratio and hyperactivity of alanine transaminase allowing the production of alanine and alpha-ketoglutarate from pyruvate when mitochondrial functions are impaired. Our data suggests that during liver regeneration, cell division leads to hepatic metabolic remodeling. Moreover, we demonstrate that hepatocytes are equipped with a flexible metabolic machinery able to adapt dynamically to changes during tissue regeneration.

引用

页码：425 / +

页数：19

共 55 条

[31] Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling [J].

McCommis, Kyle S. ;

Chen, Zhouji ;

Fu, Xiaorong ;

McDonald, William G. ;

Colca, Jerry R. ;

Kletzien, Rolf F. ;

Burgess, Shawn C. ;

Finck, Brian N. .

CELL METABOLISM, 2015, 22 (04) :682-694

[32] Cellular Allometry of Mitochondrial Functionality Establishes the Optimal Cell Size [J].

Miettinen, Teemu P. ;

Bjorklund, Mikael .

DEVELOPMENTAL CELL, 2016, 39 (03) :370-382

[33]

Minamishima YA, 2002, CANCER RES, V62, P995

[34] A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice [J].

Mitchell, Claudia ;

Willenbring, Holger .

NATURE PROTOCOLS, 2008, 3 (07) :1167-1170

[35] Hypertrophy and Unconventional Cell Division of Hepatocytes Underlie Liver Regeneration [J].

Miyaoka, Yuichiro ;

Ebato, Kazuki ;

Kato, Hidenori ;

Arakawa, Satoko ;

Shimizu, Shigeomi ;

Miyajima, Atsushi .

CURRENT BIOLOGY, 2012, 22 (13) :1166-1175

[36] Identification of Transcriptional and Metabolic Programs Related to Mammalian Cell Size [J].

Mlettinen, Teemu P. ;

Pessa, Heli K. J. ;

Caldez, Matias J. ;

Fuhrer, Tobias ;

Diril, M. Kasim ;

Sauer, Uwe ;

Kaldis, Philipp ;

Bjoerklund, Mikael .

CURRENT BIOLOGY, 2014, 24 (06) :598-608

[37] Reductive carboxylation supports growth in tumour cells with defective mitochondria [J].

Mullen, Andrew R. ;

Wheaton, William W. ;

Jin, Eunsook S. ;

Chen, Pei-Hsuan ;

Sullivan, Lucas B. ;

Cheng, Tzuling ;

Yang, Youfeng ;

Linehan, W. Marston ;

Chandel, Navdeep S. ;

DeBerardinis, Ralph J. .

NATURE, 2012, 481 (7381) :385-U171

[38] Cellular senescence drives age-dependent hepatic steatosis [J].

Ogrodnik, Mikolaj ;

Miwa, Satomi ;

Tchkonia, Tamar ;

Tiniakos, Dina ;

Wilson, Caroline L. ;

Lahat, Albert ;

Day, Christopher P. ;

Burt, Alastair ;

Palmer, Allyson ;

Anstee, Quentin M. ;

Grellscheid, Sushma Nagaraja ;

Hoeijmakers, Jan H. J. ;

Barnhoorn, Sander ;

Mann, Derek A. ;

Bird, Thomas G. ;

Vermeij, Wilbert P. ;

Kirkland, James L. ;

Passos, Joao F. ;

von Zglinicki, Thomas ;

Jurk, Diana .

NATURE COMMUNICATIONS, 2017, 8

[39] CDK1 Enhances Mitochondrial Bioenergetics for Radiation-Induced DNA Repair [J].

Qin, Lili ;

Fan, Ming ;

Candas, Demet ;

Jiang, Guochun ;

Papadopoulos, Stelios ;

Tian, Lin ;

Woloschak, Gayle ;

Grdina, David J. ;

Li, Jian Jian .

CELL REPORTS, 2015, 13 (10) :2056-2063

[40] Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation [J].

Quinn, Kyle P. ;

Sridharan, Gautham V. ;

Hayden, Rebecca S. ;

Kaplan, David L. ;

Lee, Kyongbum ;

Georgakoudi, Irene .

SCIENTIFIC REPORTS, 2013, 3

← 1 2 3 4 5 6 →