Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic>
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 re...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2017-07-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00857-17 |
| _version_ | 1819203060538277888 |
|---|---|
| author | Eduard J. Kerkhoven Young-Mo Kim Siwei Wei Carrie D. Nicora Thomas L. Fillmore Samuel O. Purvine Bobbie-Jo Webb-Robertson Richard D. Smith Scott E. Baker Thomas O. Metz Jens Nielsen |
| author_facet | Eduard J. Kerkhoven Young-Mo Kim Siwei Wei Carrie D. Nicora Thomas L. Fillmore Samuel O. Purvine Bobbie-Jo Webb-Robertson Richard D. Smith Scott E. Baker Thomas O. Metz Jens Nielsen |
| author_sort | Eduard J. Kerkhoven |
| collection | DOAJ |
| description | 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, and 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. |
| first_indexed | 2024-12-23T04:13:55Z |
| format | Article |
| id | doaj.art-081d30fdf779464a8dd4d253b786341b |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-23T04:13:55Z |
| publishDate | 2017-07-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-081d30fdf779464a8dd4d253b786341b2022-12-21T18:00:24ZengAmerican Society for MicrobiologymBio2150-75112017-07-018310.1128/mBio.00857-17Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic>Eduard J. Kerkhoven0Young-Mo Kim1Siwei Wei2Carrie D. Nicora3Thomas L. Fillmore4Samuel O. Purvine5Bobbie-Jo Webb-Robertson6Richard D. Smith7Scott E. Baker8Thomas O. Metz9Jens Nielsen10Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, SwedenEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USAEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USAEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USAEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USAEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USANational Security Directorate, Pacific Northwest National Laboratory, Richland, Washington, USAEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USAEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USAEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USASystems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg, SwedenABSTRACT 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, and 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.https://journals.asm.org/doi/10.1128/mBio.00857-17biofuelsbiotechnologymetabolic engineeringsystems biologyyeast |
| spellingShingle | Eduard J. Kerkhoven Young-Mo Kim Siwei Wei Carrie D. Nicora Thomas L. Fillmore Samuel O. Purvine Bobbie-Jo Webb-Robertson Richard D. Smith Scott E. Baker Thomas O. Metz Jens Nielsen Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic> mBio biofuels biotechnology metabolic engineering systems biology yeast |
| title | Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic> |
| title_full | Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic> |
| title_fullStr | Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic> |
| title_full_unstemmed | Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic> |
| title_short | Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic> |
| title_sort | leucine biosynthesis is involved in regulating high lipid accumulation in italic toggle yes yarrowia lipolytica italic |
| topic | biofuels biotechnology metabolic engineering systems biology yeast |
| url | https://journals.asm.org/doi/10.1128/mBio.00857-17 |
| work_keys_str_mv | AT eduardjkerkhoven leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT youngmokim leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT siweiwei leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT carriednicora leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT thomaslfillmore leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT samuelopurvine leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT bobbiejowebbrobertson leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT richarddsmith leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT scottebaker leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT thomasometz leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic AT jensnielsen leucinebiosynthesisisinvolvedinregulatinghighlipidaccumulationinitalictoggleyesyarrowialipolyticaitalic |