Production of omega-3 eicosapentaenoic acid by metabolic engineering of Yarrowia lipolytica

ABSTRACTIn the oleaginous yeastYarrowia lipolytica,de novolipid synthesis and accumulation are induced under conditions of nitrogen limitation (or a high carbon-to-nitrogen ratio). The regulatory pathway responsible for this induction has not been identified. Here we report that the SNF1 pathway plays a key role in the transition from the growth phase to the oleaginous phase inY. lipolytica. Strains with aY. lipolyticasnf1(Ylsnf1) deletion accumulated fatty acids constitutively at levels up to 2.6-fold higher than those of the wild type. When introduced into aY. lipolyticastrain engineered to produce omega-3 eicosapentaenoic acid (EPA),Ylsnf1deletion led to a 52% increase in EPA titers (7.6% of dry cell weight) over the control. Other components of theY. lipolyticaSNF1 pathway were also identified, and their function in limiting fatty acid accumulation is suggested by gene deletion analyses. Deletion of the gene encoding YlSnf4, YlGal83, or YlSak1 significantly increased lipid accumulation in both growth and oleaginous phases compared to the wild type. Furthermore, microarray and quantitative reverse transcription-PCR (qRT-PCR) analyses of theYlsnf1mutant identified significantly differentially expressed genes duringde novolipid synthesis and accumulation inY. lipolytica. Gene ontology analysis found that these genes were highly enriched with genes involved in lipid metabolism. This work presents a new role for Snf1/AMP-activated protein kinase (AMPK) pathways in lipid accumulation in this oleaginous yeast.

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Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer’s Dementia in the Oldest Old

Nutrients ◽

10.3390/nu13020461 ◽

2021 ◽

Vol 13 (2) ◽

pp. 461

Author(s):

Debora Melo van Lent ◽

Sarah Egert ◽

Steffen Wolfsgruber ◽

Luca Kleineidam ◽

Leonie Weinhold ◽

...

Keyword(s):

Fatty Acids ◽

Eicosapentaenoic Acid ◽

Linolenic Acid ◽

Oldest Old ◽

Omega 3 ◽

Alpha Linolenic Acid ◽

Multicenter Cohort Study ◽

Cognitive Health ◽

Apoe Ε4 ◽

Serum Phospholipids

Background. Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties. Methods. We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer’s disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD. Results. During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia. Conclusions. Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age.

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Increased Lipid Production in Yarrowia lipolytica from Acetate through Metabolic Engineering and Cosubstrate Fermentation

ACS Synthetic Biology ◽

10.1021/acssynbio.1c00405 ◽

2021 ◽

Author(s):

Lin Chen ◽

Wei Yan ◽

Xiujuan Qian ◽

Minjiao Chen ◽

Xiaoyu Zhang ◽

...

Keyword(s):

Metabolic Engineering ◽

Yarrowia Lipolytica ◽

Lipid Production

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Dietary omega 3 fatty acids and endothelium-dependent relaxations in porcine coronary arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.256.4.h968 ◽

1989 ◽

Vol 256 (4) ◽

pp. H968-H973 ◽

Cited By ~ 13

Author(s):

H. Shimokawa ◽

P. M. Vanhoutte

Keyword(s):

Fatty Acids ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Polyunsaturated Fatty Acids ◽

Eicosapentaenoic Acid ◽

Coronary Arteries ◽

Treated Group ◽

Omega 3 ◽

Relaxing Factor ◽

Endothelium Derived Relaxing Factor

Dietary supplementation with cod-liver oil significantly augments endothelium-dependent relaxations in porcine coronary arteries. The present study was designed to examine the effect of dietary administration of omega 3 polyunsaturated fatty acids (mainly eicosapentaenoic acid, the major component of fish oil) on endothelium-dependent relaxations in porcine coronary arteries. Male Yorkshire pigs were maintained 4 wk on a regular diet with or without supplementation with purified eicosapentaenoic acid (3.5 g/day) and docosahexaenoic acid (1.5 g/day). Endothelium-dependent relaxations were examined in vitro. In rings from the treated group, endothelium-dependent relaxations were augmented in response to bradykinin, serotonin, and ADP, but not to the calcium ionophore A23187. These augmentations were not altered by indomethacin but were significantly inhibited by methylene blue, an inhibitor of guanylate cyclase. In the treated group, endothelium-dependent relaxations to aggregating platelets also were significantly augmented; platelet-induced contractions of quiescent rings were inhibited more by the presence of the endothelium than in arteries from the control group. Bioassay experiments demonstrated that the release of endothelium-derived relaxing factor(s) by bradykinin and relaxations of the vascular smooth muscle to the factor(s) were greater in arteries from the treated group. These observations indicate that dietary omega 3 polyunsaturated fatty acids augment receptor-operated endothelium-dependent relaxations, partly due to the augmented release of endothelium-derived relaxing factor(s) and partly due to the augmented relaxation of the vascular smooth muscle to the factor(s).

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P3712The omega-3 fatty acid eicosapentaenoic acid (EPA) is inversely associated with ischemic brain infarcts in elderly patients with atrial fibrillation

European Heart Journal ◽

10.1093/eurheartj/ehz745.0566 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M F Reiner ◽

P Baumgartner ◽

A Wiencierz ◽

S Aeschbacher ◽

N Rodondi ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Elderly Patients ◽

Eicosapentaenoic Acid ◽

Brain Mri ◽

Omega 3 ◽

Total N ◽

Stroke Incidence ◽

Ischemic Brain ◽

Brain Infarcts

Abstract Background The association of individual omega-3 fatty acids (n-3 FAs) with ischemic stroke remains unclear. Experimental data strongly suggest that n-3 FAs reduce ischemic stroke due to their anti-thrombotic and anti-inflammatory properties. Yet, recent clinical trials yielded mixed results. While marine n-3 FA supplementation (1g/day) did not reduce stroke, icosapent ethyl, a purified eicosapentaenoic acid (EPA) ethyl ester (4g/day), significantly reduced stroke incidence in patients at high cardiovascular risk. In the current study, we examined the association of fish-derived EPA, docosapentaenoic acid (DPA), docosahexaenoic acid (DHA) and the plant-derived alpha-linolenic acid (ALA) with the prevalence of ischemic brain infarcts in elderly patients with atrial fibrillation. Methods In this cross-sectional analysis of the Swiss atrial fibrillation (swissAF) cohort study, we determined baseline whole blood n-3 FAs by gas chromatography according to the HS-Omega-3 Index methodology in 1665 patients aged ≥65 years with atrial fibrillation. Large non-cortical and cortical infarcts (LNCCI) were assessed by brain MRI. Total and individual n-3 FAs were correlated with the prevalence of LNCCI in a logit model with continuous factors. Analyses were adjusted for sex, age, body mass index, smoking, alcohol intake, family history of cardiovascular disease and atrial fibrillation, physical activity, hypertension, diabetes, chronic kidney disease, prior stroke, prior transient ischemic attack, aspirin, anticoagulation and type of atrial fibrillation. Results A total of 373 patients with LNCCI (22.4%) were identified. After adjustment, lower risk of LNCCI was associated with higher EPA (odds ratio [OR] 0.50 per increase of one percentage point EPA, 95% confidence interval [CI] 0.28–0.88) and a higher risk was detected with DPA (OR 2.39, 95% CI 1.43–4.01). No statistically significant association was detected with DHA (OR 1.13, 95% CI 0.94–1.35), ALA (OR 0.83, 95% CI 0.23–2.95) or total n-3 FAs (OR 1.03, 95% CI 0.92–1.16). Conclusions Higher levels of EPA are associated with a lower prevalence of ischemic infarcts in aged patients with atrial fibrillation. Unexpectedly, DPA shows a direct correlation with ischemic infarcts. This study demonstrates that individual n-3 FAs may differentially affect stroke risk and that supplementation of EPA may be an interesting strategy to prevent ischemic stroke in atrial fibrillation patients. Acknowledgement/Funding Swiss National Science Foundation

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