Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity

Yosra Alhindi; Lobke M. Vaanholt; Mustafah Al-Tarrah; Stuart R. Gray; John R. Speakman; Catherine Hambly; Bader S. Alanazi; Brendan M. Gabriel; Arimantas Lionikas; Aivaras Ratkevicius

doi:10.1155/2019/8594825

Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity

Yosra Alhindi^* (Corresponding Author), Lobke M. Vaanholt, Mustafah Al-Tarrah, Stuart R. Gray, John R. Speakman, Catherine Hambly, Bader S. Alanazi, Brendan M. Gabriel, Arimantas Lionikas, Aivaras Ratkevicius

^*Corresponding author for this work

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Abstract

Citrate synthase (CS) is a key mitochondrial enzyme. The aim of this study was to test the hypothesis that low CS activity impairs the metabolic health of mice fed a high fat diet (HFD) and promotes palmitate-induced lipotoxicity in muscle cells. C57BL/6J (B6) mice and congenic B6.A-(rs3676616-D10Utsw1)/KjnB6 (B6.A), a strain which carries the A/J allele of CS on the B6 strain background, were fed HFD (45% kcal from fat) for 12 weeks. C2C12 mouse muscle cells were used to investigate effects of CS knockdown on cell viability and signalling after incubation in 0.8 mM palmitate. CS activity, but not that of β-hydroxyacyl-coenzyme-A dehydrogenase was lower in the gastrocnemius muscle and heart of B6.A mice compared to B6 mice (P<0.001). During HFD feeding, glucose tolerance of mice decreased progressively and to a greater extent in B6.A females compared to B6 females, with males showing a similar trend. Body weight and fat gain did not differ between B6.A and B6 mice. After an 18 h incubation in 0.8 mM palmitate C2C12 muscle cells with ∼50% shRNA mediated reduction in CS activity showed lower (P<0.001) viability and increased (P<0.001) levels of cleaved caspase-3 compared to the scramble shRNA treated C2C12 cells. A/J strain variant of CS is associated with low enzyme activity and impaired metabolic health. This could be due to impaired lipid metabolism in muscle cells.

Original language	English
Article number	8594825
Number of pages	14
Journal	Journal of Nutrition and Metabolism
Volume	2019
DOIs	https://doi.org/10.1155/2019/8594825 https://doi.org/10.1155/2019/9153809
Publication status	Published - 3 Mar 2019

Bibliographical note

This work was supported by Saudi Ministry of Higher Education Grant (to Y.A.), NHS Grampian Endowment Grant (no. 12/21) (to A.R. and S.R.G.), Kuwait Ministry of Health grant (to M.A.T.), and European Social Fund under the Global Grant Measure (VP1-3.1-ŠMM-07-K-02-057) (to A.L. and A.R.). The authors thank Shona Fleming of the School of Biological Sciences, University of Aberdeen, for the technical assistance during their study.

The data used to support the findings of this study are available from the corresponding author upon request.

A corrigendum for this article has been published. Volume 2019 | Article ID 9153809 | https://doi.org/10.1155/2019/9153809

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10.1155/2019/9153809

Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity
Copyright © 2019 Yosra Alhindi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Final published version, 1.77 MBLicence: CC BY

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Alhindi, Y., Vaanholt, L. M., Al-Tarrah, M., Gray, S. R., Speakman, J. R., Hambly, C., Alanazi, B. S., Gabriel, B. M., Lionikas, A., & Ratkevicius, A. (2019). Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity. Journal of Nutrition and Metabolism, 2019, Article 8594825. https://doi.org/10.1155/2019/8594825, https://doi.org/10.1155/2019/9153809

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title = "Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity",

abstract = "Citrate synthase (CS) is a key mitochondrial enzyme. The aim of this study was to test the hypothesis that low CS activity impairs the metabolic health of mice fed a high fat diet (HFD) and promotes palmitate-induced lipotoxicity in muscle cells. C57BL/6J (B6) mice and congenic B6.A-(rs3676616-D10Utsw1)/KjnB6 (B6.A), a strain which carries the A/J allele of CS on the B6 strain background, were fed HFD (45% kcal from fat) for 12 weeks. C2C12 mouse muscle cells were used to investigate effects of CS knockdown on cell viability and signalling after incubation in 0.8 mM palmitate. CS activity, but not that of β-hydroxyacyl-coenzyme-A dehydrogenase was lower in the gastrocnemius muscle and heart of B6.A mice compared to B6 mice (P<0.001). During HFD feeding, glucose tolerance of mice decreased progressively and to a greater extent in B6.A females compared to B6 females, with males showing a similar trend. Body weight and fat gain did not differ between B6.A and B6 mice. After an 18 h incubation in 0.8 mM palmitate C2C12 muscle cells with ∼50% shRNA mediated reduction in CS activity showed lower (P<0.001) viability and increased (P<0.001) levels of cleaved caspase-3 compared to the scramble shRNA treated C2C12 cells. A/J strain variant of CS is associated with low enzyme activity and impaired metabolic health. This could be due to impaired lipid metabolism in muscle cells.",

author = "Yosra Alhindi and Vaanholt, {Lobke M.} and Mustafah Al-Tarrah and Gray, {Stuart R.} and Speakman, {John R.} and Catherine Hambly and Alanazi, {Bader S.} and Gabriel, {Brendan M.} and Arimantas Lionikas and Aivaras Ratkevicius",

note = "This work was supported by Saudi Ministry of Higher Education Grant (to Y.A.), NHS Grampian Endowment Grant (no. 12/21) (to A.R. and S.R.G.), Kuwait Ministry of Health grant (to M.A.T.), and European Social Fund under the Global Grant Measure (VP1-3.1-{\v S}MM-07-K-02-057) (to A.L. and A.R.). The authors thank Shona Fleming of the School of Biological Sciences, University of Aberdeen, for the technical assistance during their study. The data used to support the findings of this study are available from the corresponding author upon request. A corrigendum for this article has been published. Volume 2019 | Article ID 9153809 | https://doi.org/10.1155/2019/9153809 ",

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AU - Alhindi, Yosra

AU - Vaanholt, Lobke M.

AU - Al-Tarrah, Mustafah

AU - Gray, Stuart R.

AU - Speakman, John R.

AU - Hambly, Catherine

AU - Alanazi, Bader S.

AU - Gabriel, Brendan M.

AU - Lionikas, Arimantas

AU - Ratkevicius, Aivaras

N1 - This work was supported by Saudi Ministry of Higher Education Grant (to Y.A.), NHS Grampian Endowment Grant (no. 12/21) (to A.R. and S.R.G.), Kuwait Ministry of Health grant (to M.A.T.), and European Social Fund under the Global Grant Measure (VP1-3.1-ŠMM-07-K-02-057) (to A.L. and A.R.). The authors thank Shona Fleming of the School of Biological Sciences, University of Aberdeen, for the technical assistance during their study. The data used to support the findings of this study are available from the corresponding author upon request. A corrigendum for this article has been published. Volume 2019 | Article ID 9153809 | https://doi.org/10.1155/2019/9153809

PY - 2019/3/3

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N2 - Citrate synthase (CS) is a key mitochondrial enzyme. The aim of this study was to test the hypothesis that low CS activity impairs the metabolic health of mice fed a high fat diet (HFD) and promotes palmitate-induced lipotoxicity in muscle cells. C57BL/6J (B6) mice and congenic B6.A-(rs3676616-D10Utsw1)/KjnB6 (B6.A), a strain which carries the A/J allele of CS on the B6 strain background, were fed HFD (45% kcal from fat) for 12 weeks. C2C12 mouse muscle cells were used to investigate effects of CS knockdown on cell viability and signalling after incubation in 0.8 mM palmitate. CS activity, but not that of β-hydroxyacyl-coenzyme-A dehydrogenase was lower in the gastrocnemius muscle and heart of B6.A mice compared to B6 mice (P<0.001). During HFD feeding, glucose tolerance of mice decreased progressively and to a greater extent in B6.A females compared to B6 females, with males showing a similar trend. Body weight and fat gain did not differ between B6.A and B6 mice. After an 18 h incubation in 0.8 mM palmitate C2C12 muscle cells with ∼50% shRNA mediated reduction in CS activity showed lower (P<0.001) viability and increased (P<0.001) levels of cleaved caspase-3 compared to the scramble shRNA treated C2C12 cells. A/J strain variant of CS is associated with low enzyme activity and impaired metabolic health. This could be due to impaired lipid metabolism in muscle cells.

AB - Citrate synthase (CS) is a key mitochondrial enzyme. The aim of this study was to test the hypothesis that low CS activity impairs the metabolic health of mice fed a high fat diet (HFD) and promotes palmitate-induced lipotoxicity in muscle cells. C57BL/6J (B6) mice and congenic B6.A-(rs3676616-D10Utsw1)/KjnB6 (B6.A), a strain which carries the A/J allele of CS on the B6 strain background, were fed HFD (45% kcal from fat) for 12 weeks. C2C12 mouse muscle cells were used to investigate effects of CS knockdown on cell viability and signalling after incubation in 0.8 mM palmitate. CS activity, but not that of β-hydroxyacyl-coenzyme-A dehydrogenase was lower in the gastrocnemius muscle and heart of B6.A mice compared to B6 mice (P<0.001). During HFD feeding, glucose tolerance of mice decreased progressively and to a greater extent in B6.A females compared to B6 females, with males showing a similar trend. Body weight and fat gain did not differ between B6.A and B6 mice. After an 18 h incubation in 0.8 mM palmitate C2C12 muscle cells with ∼50% shRNA mediated reduction in CS activity showed lower (P<0.001) viability and increased (P<0.001) levels of cleaved caspase-3 compared to the scramble shRNA treated C2C12 cells. A/J strain variant of CS is associated with low enzyme activity and impaired metabolic health. This could be due to impaired lipid metabolism in muscle cells.

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Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity

Abstract

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