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Altérations métaboliques cellulaires : la voie de biosynthèse des acides gras monoinsaturés comme cible thérapeutique

Abstract : Stearoyl Co-A desaturase (SCD) is the key enzyme of the metabolism of mono-unsaturated fatty acids (MUFA). Its activity  9 desaturase introduces a double bond cis in position 9 of saturated fatty acids (SFA), induced formation of MUFA. Impaired biosynthesis of MUFA is involved in many diseases such as cancer and cardiovascular disease. Cancer cells have a de novo synthesis of fatty acids increased with an accumulation MUFA. This change in the metabolism of fatty acids is associated with overexpression SCD1 which catalyzes the conversion of saturated fatty acids, monounsaturated fat. Several reports have shown that inhibition of SCD1 leads to blockage of proliferation and induction of apoptosis in cancer cells. However, the mechanism of cell death activation remains to be understood. In this study, we demonstrated that the extinction of SCD1 by siRNA, synthetic or natural inhibitor induces the abolition of de novo MUFA synthesis in cancer cells or not. SCD1 inhibition activates cell death by apoptosis only in cancer cells. In addition, depletion of SCD1 induced endoplasmic reticulum stress, these features being XBP1 mRNA splicing, phosphorylation of eIF2α and increased expression of CHOP. However, activation of ER stress in the abolition of SCD1 is special because we do not show changes in expression of the chaperone protein GRP78, another characteristic of ER stress. Finally, we showed that induction of CHOP is involved in activation of cell death during shutdown of SCD1. Indeed, overexpression of dominant negative constructs and anti-CHOP partially restores the viability of cancer cells depleted of SCD1. In conclusion, these results suggest that inhibition of de novo synthesis of MUFA through the extinction of SCD1 could be a promising therapeutic target against cancer by inducing cell death through the activation of the stress and endoplasmic reticulum transcription factor CHOP. We are also interested in the regulation of SCD by different MUFA in a cellular model linked with atherosclerotic disease. Many risk factors contribute to the development of this disease, including trans fatty acid (TFA). Indeed, epidemiological studies have correlated the consumption of TFA from industrial sources and the risk of cardiovascular disease. TFA could play their atherogenic effects by altering the lipid metabolism of vascular cells. The accumulation of lipids in vascular smooth muscle cells (SMC) is a feature of atherosclerosis and a consequence of increased lipogenesis. The expression of SCD is associated with the induction of lipogenesis and development of atherosclerosis. We are interested in the regulation of SCD1 activity in SMCs exposed to isomers of MUFA C18 [cis-9 oleic (OL), trans-11 vaccenic acid (TVA) and acid trans -9 elaidic (ELA)]. We showed that SCD which is present in SMC was regulated differently depending on the isomer C18: 1. Indeed, we observed an increase in the expression and activity of SCD1 as a result of treatment with ELA and a significant decrease for treatment with OL. The effect of the TVA on the expression and activity in SMCs remains modest decrease is nevertheless found. We correlated the activity of SCD with its level of protein expression. Indeed, it is increased by the ELA and decreased by OL. This regulation is posttranslational and expression of SCD1 during treatment with the OL and the ELA is modulated at the transcriptional level. To conclude, we demonstrated a modulation of SCD activity by MUFA (C18: 1) cis and trans-mediated regulation of SCD1 gene transcription.
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Submitted on : Monday, March 26, 2012 - 2:07:19 PM
Last modification on : Thursday, September 1, 2022 - 11:14:04 AM
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  • HAL Id : tel-00682619, version 1

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Mélaine Minville. Altérations métaboliques cellulaires : la voie de biosynthèse des acides gras monoinsaturés comme cible thérapeutique. Sciences agricoles. Université de Bourgogne, 2010. Français. ⟨NNT : 2010DIJOS079⟩. ⟨tel-00682619⟩

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