Abstract
ABSTRACTThe 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.
Highlights
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
Given that lipid metabolism is involved in many diseases but is 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
The yeast Yarrowia lipolytica has been identified as a promising microbial cell factory for the production of biofuels and oleochemicals [1], and while metabolic engineering approaches have been employed to increase its lipid production [2,3,4], how its lipid metabolism is regulated remains largely unknown
Summary
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. 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. 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. Data are means (SD) of results from three independent chemostats. rGluc (mmol gDWϪ1 hϪ1), glucose uptake rate in millimoles per gram dry weight per hour; rO2, oxygen uptake rate; rCO2, CO2 excretion rate; RQ, respiratory quotient; Ysx, biomass yield
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