Title: Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in Yarrowia lipolytica

Abstract

ABSTRACT The yeast Yarrowia lipolytica is a potent accumulator of lipids, and lipogenesis in this organism can be influenced by a variety of factors, such as genetics and environmental conditions. Using a multifactorial study, we elucidated the effects of both genetic and environmental factors on regulation of lipogenesis in Y. lipolytica and identified how two opposite regulatory states both result in lipid accumulation. This study involved comparison of a strain overexpressing diacylglycerol acyltransferase ( DGA1 ) with a control strain grown under either nitrogen or carbon limitation conditions. A strong correlation was observed between the responses on the transcript and protein levels. Combination of DGA1 overexpression with nitrogen limitation resulted in a high level of lipid accumulation accompanied by downregulation of several amino acid biosynthetic pathways, including that of leucine in particular, and these changes were further correlated with a decrease in metabolic fluxes. This downregulation was supported by the measured decrease in the level of 2-isopropylmalate, an intermediate of leucine biosynthesis. Combining the multi-omics data with putative transcription factor binding motifs uncovered a contradictory role for TORC1 in controlling lipid accumulation, likely mediated through 2-isopropylmalate and a Leu3-like transcription factor. IMPORTANCE The ubiquitous metabolism of lipids involves refined regulation, andmore » an enriched understanding of this regulation would have wide implications. Various factors can influence lipid metabolism, including the environment and genetics. We demonstrated, using a multi-omics and multifactorial experimental setup, that multiple factors affect lipid accumulation in the yeast Yarrowia lipolytica . Using integrative analysis, we identified novel interactions between nutrient restriction and genetic factors involving regulators that are highly conserved among eukaryotes. Given that lipid metabolism is involved in many diseases but is also vital to the development of microbial cell factories that can provide us with sustainable fuels and oleochemicals, we envision that our report introduces foundational work to further unravel the regulation of lipid accumulation in eukaryal cells.« less

Authors:

Kerkhoven, Eduard J.  ^[1];

• Search DOE PAGES for author "Kerkhoven, Eduard J."
• Search DOE PAGES for ORCID "0000-0002-3593-5792"

Kim, Young-Mo ^[2]; Wei, Siwei ^[2]; Nicora, Carrie D. ^[2]; Fillmore, Thomas L. ^[2]; Purvine, Samuel O. ^[2]; Webb-Robertson, Bobbie-Jo ^[3]; Smith, Richard D. ^[2]; Baker, Scott E.  ^[2];

• Search DOE PAGES for author "Baker, Scott E."
• Search DOE PAGES for ORCID "0000-0001-5085-3106"

Metz, Thomas O. ^[2]; Nielsen, Jens  ^[4];

• Search DOE PAGES for author "Nielsen, Jens"
• Search DOE PAGES for ORCID "0000-0002-9955-6003"

Lee, ed., Sang Yup; Alper, Hal; Nicaud, Jean-Marc

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+ Show Author Affiliations

1. Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden, Novo Nordisk Foundation Center for Biosustainability, Chalmers University of Technology, Göteborg, Sweden
2. Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USA
3. National Security Directorate, Pacific Northwest National Laboratory, Richland, Washington, USA
4. Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden, Novo Nordisk Foundation Center for Biosustainability, Chalmers University of Technology, Göteborg, Sweden, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark

Publication Date:

Wed Jul 05 00:00:00 EDT 2017

Research Org.:

Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)

Sponsoring Org.:

USDOE

OSTI Identifier:

1786912

Alternate Identifier(s):

OSTI ID: 1367382

Report Number(s):

PNNL-SA-122829
Journal ID: ISSN 2161-2129; e00857-17

Grant/Contract Number:  

SC0008744; AC05-76RLO 1830; AC05-76RL01830

Resource Type:

Published Article

Journal Name:

mBio

Additional Journal Information:

Journal Name: mBio Journal Volume: 8 Journal Issue: 3; Journal ID: ISSN 2161-2129

Publisher:

American Society for Microbiology

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; Environmental Molecular Sciences Laboratory; biofuels; biotechnology; metabolic engineering; systems biology; yeast