Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica

Vasdekis, Andreas E.; Silverman, Andrew M.; Stephanopoulos, Gregory; Chardot, ed., Thierry

doi:10.1371/journal.pone.0168889

Title: Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica

Abstract

Despite substantial achievements in elucidating the metabolic pathways of lipogenesis, a mechanistic representation of lipid accumulation and degradation has not been fully attained to-date. Recent evidence suggests that lipid accumulation can occur through increases of either the cytosolic copy-number of lipid droplets (LDs), or the LDs size. However, the prevailing phenotype, or how such mechanisms pertain to lipid degradation remain poorly understood. To address this shortcoming, we employed the–recently discovered–innate bioprocessing fluctuations in Yarrowia lipolytica, and performed single-cell fluctuation analysis using optical microscopy and microfluidics that generate a quasi-time invariant microenvironment. We report that lipid accumulation at early stationary phase in rich medium is substantially more likely to occur through variations in the LDs copy-number, rather than the LDs size. Critically, these mechanistics are also preserved during lipid degradation, as well as upon exposure to a protein translation inhibitor. The latter condition additionally induced a lipid accumulation phase, accompanied by the downregulation of lipid catabolism. Our results enable an in-depth mechanistic understanding of lipid biogenesis, and expand longitudinal single-cell fluctuation analyses from gene regulation to metabolism.

Authors:

; Silverman, Andrew M.; Stephanopoulos, Gregory; Chardot, ed., Thierry

Publication Date:: Wed Jan 04 00:00:00 EST 2017

Research Org.:: Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

Sponsoring Org.:: USDOE Office of Science (SC)

OSTI Identifier:: 1338431

Alternate Identifier(s):: OSTI ID: 1627811

Grant/Contract Number:: SC 0008744; SC0008744

Resource Type:: Published Article

Journal Name:: PLoS ONE

Additional Journal Information:: Journal Name: PLoS ONE Journal Volume: 12 Journal Issue: 1; Journal ID: ISSN 1932-6203

Publisher:: Public Library of Science (PLoS)

Country of Publication:: United States

Language:: English

Subject:: Science & Technology - Other Topics

Citation Formats


                    Vasdekis, Andreas E., Silverman, Andrew M., Stephanopoulos, Gregory, and Chardot, ed., Thierry. Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica.  United States: N. p., 2017. 
Web.  doi:10.1371/journal.pone.0168889.

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                    Vasdekis, Andreas E., Silverman, Andrew M., Stephanopoulos, Gregory, & Chardot, ed., Thierry. Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica.  United States.  https://doi.org/10.1371/journal.pone.0168889

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                    Vasdekis, Andreas E., Silverman, Andrew M., Stephanopoulos, Gregory, and Chardot, ed., Thierry. Wed .  
"Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica".  United States.  https://doi.org/10.1371/journal.pone.0168889.

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@article{osti_1338431,

  title        = {Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica},

  author       = {Vasdekis, Andreas E. and Silverman, Andrew M. and Stephanopoulos, Gregory and Chardot, ed., Thierry},

  abstractNote = {Despite substantial achievements in elucidating the metabolic pathways of lipogenesis, a mechanistic representation of lipid accumulation and degradation has not been fully attained to-date. Recent evidence suggests that lipid accumulation can occur through increases of either the cytosolic copy-number of lipid droplets (LDs), or the LDs size. However, the prevailing phenotype, or how such mechanisms pertain to lipid degradation remain poorly understood. To address this shortcoming, we employed the–recently discovered–innate bioprocessing fluctuations in Yarrowia lipolytica, and performed single-cell fluctuation analysis using optical microscopy and microfluidics that generate a quasi-time invariant microenvironment. We report that lipid accumulation at early stationary phase in rich medium is substantially more likely to occur through variations in the LDs copy-number, rather than the LDs size. Critically, these mechanistics are also preserved during lipid degradation, as well as upon exposure to a protein translation inhibitor. The latter condition additionally induced a lipid accumulation phase, accompanied by the downregulation of lipid catabolism. Our results enable an in-depth mechanistic understanding of lipid biogenesis, and expand longitudinal single-cell fluctuation analyses from gene regulation to metabolism.},

  doi          = {10.1371/journal.pone.0168889},

  journal      = {PLoS ONE},

  number       = 1,

  volume       = 12,

  place        = {United States},

  year         = {Wed Jan 04 00:00:00 EST 2017},

  month        = {Wed Jan 04 00:00:00 EST 2017}

}

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Title: Exploiting Bioprocessing Fluctuations to Elicit the Mechanistics of De Novo Lipogenesis in Yarrowia lipolytica

Abstract

Citation Formats

Microchemostat—microbial continuous culture in a polymer-based, instrumented microbioreactor journal, January 2006

Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin journal, January 2010

Using Fluctuation Analysis to Establish Causal Relations between Cellular Events without Experimental Perturbation journal, December 2014

Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica journal, March 2016

Stochastic Gene Expression in a Single Cell journal, August 2002

Using Gene Expression Noise to Understand Gene Regulation journal, April 2012

The Innate Growth Bistability and Fitness Landscapes of Antibiotic-Resistant Bacteria journal, November 2013

Single microbe trap and release in sub-microfluidics journal, January 2013

Lipophagy: Connecting Autophagy and Lipid Metabolism journal, January 2012

Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae journal, June 2011

Review of methods to probe single cell metabolism and bioenergetics journal, January 2015

Yeast lipid metabolism at a glance journal, March 2014

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets journal, February 2013

Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise journal, May 2006

Heterogeneity in protein expression induces metabolic variability in a modeled Escherichia coli population journal, August 2013

Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control journal, December 2011

Stochasticity in gene expression: from theories to phenotypes journal, May 2005

Open Questions in Lipid Droplet Biology journal, January 2014

Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions journal, November 2012

Enzyme Induction as an All-Or-None Phenomenon journal, July 1957

Engineering the push and pull of lipid biosynthesis in oleaginous yeast Yarrowia lipolytica for biofuel production journal, January 2013

An evolutionary metabolic engineering approach for enhancing lipogenesis in Yarrowia lipolytica journal, May 2015

The oxidative pentose phosphate pathway is the primary source of NADPH for lipid overproduction from glucose in Yarrowia lipolytica journal, July 2015

Stochasticity of metabolism and growth at the single-cell level journal, September 2014

Lipid droplets: a unified view of a dynamic organelle journal, March 2006

Cell-to-Cell Heterogeneity in Lipid Droplets Suggests a Mechanism to Reduce Lipotoxicity journal, August 2013

Identification and characterization of DGA2, an acyltransferase of the DGAT1 acyl-CoA:diacylglycerol acyltransferase family in the oleaginous yeast Yarrowia lipolytica. New insights into the storage lipid metabolism of oleaginous yeasts journal, August 2011

The biophysics and cell biology of lipid droplets journal, November 2013

Single-Cell Metabolomics: Analytical and Biological Perspectives journal, December 2013

Lost in Transition: Start-Up of Glycolysis Yields Subpopulations of Nongrowing Cells journal, January 2014

Summing up the noise in gene networks journal, January 2004

Central dogma at the single-molecule level in living cells journal, July 2011

Transcriptomic Analyses during the Transition from Biomass Production to Lipid Accumulation in the Oleaginous Yeast Yarrowia lipolytica journal, November 2011

Factors underlying the variability of lipid droplet fluorescence in MA-10 leydig tumor cells journal, October 1994

The life cycle of lipid droplets journal, April 2015

Challenges in Engineering Microbes for Biofuels Production journal, February 2007

It Is All about Metabolic Fluxes journal, December 2003

Visualization of yeast cells by electron microscopy journal, January 2012

Accumulation of High-Value Lipids in Single-Cell Microorganisms: A Mechanistic Approach and Future Perspectives journal, March 2014

Stochastic effects are important in intrahost HIV evolution even when viral loads are high journal, October 2012

Origins of Cell-to-Cell Bioprocessing Diversity and Implications of the Extracellular Environment Revealed at the Single-Cell Level journal, December 2015

Lipid Droplets and Cellular Lipid Metabolism journal, July 2012

Metabolic Fluxes and Metabolic Engineering journal, January 1999

Vesicle Photonics journal, July 2013

A trap-and-release integrated microfluidic system for dynamic microarray applications journal, January 2007

Enzyme kinetics for a two-step enzymic reaction with comparable initial enzyme-substrate ratios journal, December 1988

Control of Lipid Accumulation in the Yeast Yarrowia lipolytica journal, October 2008

Functional overexpression and characterization of lipogenesis-related genes in the oleaginous yeast Yarrowia lipolytica journal, February 2016

The biogenesis and functions of lipid bodies in animals, plants and microorganisms journal, September 2001

Regulation of noise in the expression of a single gene journal, April 2002

Microchemostat—microbial continuous culture in a polymer-based, instrumented microbioreactor
journal, January 2006

Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin
journal, January 2010

Using Fluctuation Analysis to Establish Causal Relations between Cellular Events without Experimental Perturbation
journal, December 2014

Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica
journal, March 2016

Stochastic Gene Expression in a Single Cell
journal, August 2002

Using Gene Expression Noise to Understand Gene Regulation
journal, April 2012

The Innate Growth Bistability and Fitness Landscapes of Antibiotic-Resistant Bacteria
journal, November 2013

Single microbe trap and release in sub-microfluidics
journal, January 2013

Lipophagy: Connecting Autophagy and Lipid Metabolism
journal, January 2012

Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae
journal, June 2011

Review of methods to probe single cell metabolism and bioenergetics
journal, January 2015

Yeast lipid metabolism at a glance
journal, March 2014

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets
journal, February 2013

Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise
journal, May 2006

Heterogeneity in protein expression induces metabolic variability in a modeled Escherichia coli population
journal, August 2013

Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control
journal, December 2011

Stochasticity in gene expression: from theories to phenotypes
journal, May 2005

Open Questions in Lipid Droplet Biology
journal, January 2014

Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions
journal, November 2012

Enzyme Induction as an All-Or-None Phenomenon
journal, July 1957

Engineering the push and pull of lipid biosynthesis in oleaginous yeast Yarrowia lipolytica for biofuel production
journal, January 2013

An evolutionary metabolic engineering approach for enhancing lipogenesis in Yarrowia lipolytica
journal, May 2015

The oxidative pentose phosphate pathway is the primary source of NADPH for lipid overproduction from glucose in Yarrowia lipolytica
journal, July 2015

Stochasticity of metabolism and growth at the single-cell level
journal, September 2014

Lipid droplets: a unified view of a dynamic organelle
journal, March 2006

Cell-to-Cell Heterogeneity in Lipid Droplets Suggests a Mechanism to Reduce Lipotoxicity
journal, August 2013

Identification and characterization of DGA2, an acyltransferase of the DGAT1 acyl-CoA:diacylglycerol acyltransferase family in the oleaginous yeast Yarrowia lipolytica. New insights into the storage lipid metabolism of oleaginous yeasts
journal, August 2011

The biophysics and cell biology of lipid droplets
journal, November 2013

Single-Cell Metabolomics: Analytical and Biological Perspectives
journal, December 2013

Lost in Transition: Start-Up of Glycolysis Yields Subpopulations of Nongrowing Cells
journal, January 2014

Summing up the noise in gene networks
journal, January 2004

Central dogma at the single-molecule level in living cells
journal, July 2011

Transcriptomic Analyses during the Transition from Biomass Production to Lipid Accumulation in the Oleaginous Yeast Yarrowia lipolytica
journal, November 2011

Factors underlying the variability of lipid droplet fluorescence in MA-10 leydig tumor cells
journal, October 1994

The life cycle of lipid droplets
journal, April 2015

Challenges in Engineering Microbes for Biofuels Production
journal, February 2007

It Is All about Metabolic Fluxes
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Visualization of yeast cells by electron microscopy
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Accumulation of High-Value Lipids in Single-Cell Microorganisms: A Mechanistic Approach and Future Perspectives
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Stochastic effects are important in intrahost HIV evolution even when viral loads are high
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Origins of Cell-to-Cell Bioprocessing Diversity and Implications of the Extracellular Environment Revealed at the Single-Cell Level
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Lipid Droplets and Cellular Lipid Metabolism
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Metabolic Fluxes and Metabolic Engineering
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Vesicle Photonics
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A trap-and-release integrated microfluidic system for dynamic microarray applications
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Enzyme kinetics for a two-step enzymic reaction with comparable initial enzyme-substrate ratios
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Control of Lipid Accumulation in the Yeast Yarrowia lipolytica
journal, October 2008

Functional overexpression and characterization of lipogenesis-related genes in the oleaginous yeast Yarrowia lipolytica
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The biogenesis and functions of lipid bodies in animals, plants and microorganisms
journal, September 2001

Regulation of noise in the expression of a single gene
journal, April 2002