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  • In the present study we sought

    2024-02-09

    In the present study we sought to decipher the role of ATP-citrate lyase and of the mitochondrial NADH-dependent Mae in the oleaginous yeast Y. lipolytica. Indeed, although this yeast is one of the major models for lipid metabolism, the function of these enzymes is still not clear. As the study of these genes has revealed the existence of a link between mannitol and FA, the interconnection between both metabolisms was analyzed.
    Material and methods
    Results and discussion
    Conclusions and perspectives The aim of this work was to understand the role of the Acl and the mitochondrial NAD(H)-dependent Mae in Y. lipolytica. The results obtained in this study clearly demonstrate that Acl is essential for FA synthesis in Y. lipolytica. Inactivation of ACL1 dramatically reduces FA synthesis while promoting citrate and mannitol synthesis. On the other hand, results obtained with strains inactivated for MAE1 definitively demonstrate that Mae is not involved in FA synthesis in Y. lipolytica but plays, in one way or another, a role in the management of storage carbon. The most striking result was to discover the balance between mannitol and FA in strains inactivated for ACL1 and MAE1 mutants. The relationship between FA and mannitol was also observed when YlSDR was inactivated. On fructose, ΔYlsdr was strongly impaired for mannitol production and carbon flux was partially redirected to the FA synthesis pathway. The origin of the balance between mannitol and FA could be attributed to a BLZ945 for carbon flux. Additionally, the phenotype of the ΔYlsdr confirms that YlSDR encodes a mannitol dehydrogenase and represents the first example of this type of enzyme in Ascomycetes yeasts. Moreover, the ΔYlsdr mutant is still able to produce mannitol from fructose, probably due to the activity of enzymes encoded by YALI0D18964g and YALI0E12463g. The deletion of these genes, could help us to better understand mannitol metabolism in Ascomycetes yeasts. The following are the supplementary data related to this article.
    Competing interests
    Acknowledgements This work was funded by the Institut National de la Recherche Agronomique. T. Dulermo and Z. Lazar were funded by the Agence Nationale de la Recherche (Investissements d'avenir program; reference ANR-11-BTBR-0003). Z. Lazar received financial support from the European Union in the form of an AgreenSkills Fellowship (Grant agreement no. 267196; Marie-Curie FP7 COFUND People Program). We would like to thank Dr. Jonathan Verbeke for providing us the JME1619 and JMY1855 vectors and Dr. Pamela J. Trotter (Augustana College, USA), for reading the draft of the manuscript and for critical comments.
    Bempedoic acid is a novel oral agent that reduces hepatic cholesterol synthesis by inhibiting ATP-citrate lyase (ACL) leading to upregulation of the LDL receptor and a reduction in plasma low-density lipoprotein cholesterol (LDL-C). Although this mechanism of action is similar to that of statins, the effect of lowering LDL-C by inhibiting ACL on the risk of cardiovascular events is unknown. We constructed a genetic score consisting of independently inherited variants in the ACL gene that are associated with lower LDL-C to mimic the effect of ACL inhibition. We used this score as an instrument to naturally randomize participants to higher or lower LDL-C and evaluated the effect of lower LDL-C mediated by ACL variants on the risk of cardiovascular events in a Mendelian randomization study. The primary outcome was major cardiovascular events (MVE) defined as a composite of coronary death, MI, stroke or coronary revascularization. A total of 101,236 participants (13,964 MVE) from 14 prospective cohort or case-control studies were included in the analysis. Participants with an ACL score below the median had 2.0 mg/dL lower LDL-C, 1.8 mg/dL lower APOB, and a corresponding 3.5% lower risk of MVE (OR: 0.965, 95%CI: 0.942-0.988, p=0.003). This effect was similar in all subgroups studied. In analyses standardized for a common decrement of 10 mg/dL lower LDL-C, variants that mimic the effect of an ACL inhibitor had a very similar effect on the risk of cardiovascular events (OR: 0.832, 95%CI: 0.736-0.940) as compared to variants that mimic the effect of statins (OR: 0.844, 95%CI: 0.806-0.885), ezetimibe (OR: 0.833, 95%CI: 0.755-0.920) and PCSK9 inhibitors (OR: 0.843, 95%CI: 0.805-0.882), all of which lower LDL-C through the LDL receptor pathway.