Fatty acid oxidation promotes reprogramming by enhancing oxidative phosphorylation and inhibiting protein kinase C

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Abstract

Background

Changes in metabolic pathway preferences are key events in the reprogramming process of somatic cells to induced pluripotent stem cells (iPSCs). The optimization of metabolic conditions can enhance reprogramming; however, the detailed underlying mechanisms are largely unclear. By comparing the gene expression profiles of somatic cells, intermediate-phase cells, and iPSCs, we found that carnitine palmitoyltransferase (Cpt)1b, a rate-limiting enzyme in fatty acid oxidation, was significantly upregulated in the early stage of the reprogramming process.

Methods

Mouse embryonic fibroblasts isolated from transgenic mice carrying doxycycline (Dox)-inducible Yamanaka factor constructs were used for reprogramming. Various fatty acid oxidation-related metabolites were added during the reprogramming process. Colony counting and fluorescence-activated cell sorting (FACS) were used to calculate reprogramming efficiency. Fatty acid oxidation-related metabolites were measured by liquid chromatography–mass spectrometry. Seahorse was used to measure the level of oxidative phosphorylation.

Results

We found that overexpression of cpt1b enhanced reprogramming efficiency. Furthermore, palmitoylcarnitine or acetyl-CoA, the primary and final products of Cpt1-mediated fatty acid oxidation, also promoted reprogramming. In the early reprogramming process, fatty acid oxidation upregulated oxidative phosphorylation and downregulated protein kinase C activity. Inhibition of protein kinase C also promoted reprogramming.

Conclusion

We demonstrated that fatty acid oxidation promotes reprogramming by enhancing oxidative phosphorylation and inhibiting protein kinase C activity in the early stage of the reprogramming process. This study reveals that fatty acid oxidation is crucial for the reprogramming efficiency.

Electronic supplementary material

The online version of this article (10.1186/s13287-018-0792-6) contains supplementary material, which is available to authorized users.

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Most cited references 24

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The Lin28/let-7 axis regulates glucose metabolism.

Hao Zhu, Ng Shyh-Chang, Ayellet V. Segrè … (2011)

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. Copyright © 2011 Elsevier Inc. All rights reserved.

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Direct cell reprogramming is a stochastic process amenable to acceleration

Jacob Hanna, Krishanu Saha, Bernardo Pando … (2009)

Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming is a continuous stochastic process where almost all donor cells eventually give rise to iPSCs upon continued growth and transcription factor expression. Additional inhibition the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPSC formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell division rate independent manner. Quantitative analyses define distinct cell division rate dependent and independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.

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Metabolic plasticity in stem cell homeostasis and differentiation.

Clifford D L Folmes, Petras Dzeja, Timothy Nelson … (2012)

Plasticity in energy metabolism allows stem cells to match the divergent demands of self-renewal and lineage specification. Beyond a role in energetic support, new evidence implicates nutrient-responsive metabolites as mediators of crosstalk between metabolic flux, cellular signaling, and epigenetic regulation of cell fate. Stem cell metabolism also offers a potential target for controlling tissue homeostasis and regeneration in aging and disease. In this Perspective, we cover recent progress establishing an emerging relationship between stem cell metabolism and cell fate control. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Zhaoyu Lin:

ORCID: http://orcid.org/0000-0003-2095-7814

86-25-58641511 , Linzy@nju.edu.cn

Fei Liu: feiliu@nju.edu.cn

Peiliang Shi: Shipl@nicemice.cn

Anying Song: Songay@nicemice.cn

Zan Huang: Huangzan@nicemice.cn

Dayuan Zou: Zoudy@nicemice.cn

Qin Chen: Chenqin@nicemice.cn

Jianxin Li: lijxnju@nju.edu.cn

Xiang Gao: gaoxiang@nju.edu.cn

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 26 February 2018

Publication date PMC-release: 26 February 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 47

Affiliations

[1 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Collaborative Innovation Center of Genetics and Development, Model Animal Research Center, Nanjing Biomedical Research Institute, , Nanjing University, ; 12 Xuefu Road, Pukou District, Nanjing, Jiangsu 210061 China

[2 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, , Nanjing University, ; 22 Hankou Road, Nanjing, Jiangsu 210093 China

[3 ]ISNI 0000 0000 9750 7019, GRID grid.27871.3b, Jiangsu Province Key Laboratory of Gastrointestinal Nutrition and Animal Health, , Nanjing Agriculture University, ; 1 Weigang Road, Nanjing, Jiangsu 210095 China

Author information

Zhaoyu Lin http://orcid.org/0000-0003-2095-7814

Article

Publisher ID: 792

DOI: 10.1186/s13287-018-0792-6

PMC ID: 5937047

PubMed ID: 29482657

SO-VID: 3fa8de7d-2fd7-46d1-8059-4bc9e610892c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 November 2017

Date revision received : 25 January 2018

Date accepted : 29 January 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 31301217

Award Recipient : Zhaoyu Lin

Funded by: FundRef http://dx.doi.org/10.13039/501100002855, Ministry of Science and Technology of the People's Republic of China;

Award ID: 2014BAI02B01

Award ID: 2015BAI08B02

Award Recipient : Xiang Gao

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: cpt1,palmitoylcarnitine,oxidative phosphorylation,acyl-coa,reprogramming,fatty acid oxidation,protein kinase c,induced pluripotent stem cells

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: cpt1, palmitoylcarnitine, oxidative phosphorylation, acyl-coa, reprogramming, fatty acid oxidation, protein kinase c, induced pluripotent stem cells

Fatty acid oxidation promotes reprogramming by enhancing oxidative phosphorylation and inhibiting protein kinase C

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

Related collections

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Most cited references 24

The Lin28/let-7 axis regulates glucose metabolism.

Direct cell reprogramming is a stochastic process amenable to acceleration

Metabolic plasticity in stem cell homeostasis and differentiation.

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Affiliations

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