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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	biofuels biotechnology metabolic engineering systems biology yeast Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/081d30fdf779464a8dd4d253b786341b
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spelling	oai:doaj.org-article:081d30fdf779464a8dd4d253b786341b2021-11-15T15:51:28ZLeucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic>10.1128/mBio.00857-172150-7511https://doaj.org/article/081d30fdf779464a8dd4d253b786341b2017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00857-17https://doaj.org/toc/2150-7511ABSTRACT 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.Eduard J. KerkhovenYoung-Mo KimSiwei WeiCarrie D. NicoraThomas L. FillmoreSamuel O. PurvineBobbie-Jo Webb-RobertsonRichard D. SmithScott E. BakerThomas O. MetzJens NielsenAmerican Society for Microbiologyarticlebiofuelsbiotechnologymetabolic engineeringsystems biologyyeastMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	biofuels biotechnology metabolic engineering systems biology yeast Microbiology QR1-502
spellingShingle	biofuels biotechnology metabolic engineering systems biology yeast Microbiology QR1-502 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>
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.
format	article
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
title	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_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_sort	leucine biosynthesis is involved in regulating high lipid accumulation in <italic toggle="yes">yarrowia lipolytica</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/081d30fdf779464a8dd4d253b786341b
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Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in <italic toggle="yes">Yarrowia lipolytica</italic>

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