Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity
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-D10Ut...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of Nutrition and Metabolism |
| Online Access: | http://dx.doi.org/10.1155/2019/8594825 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yosra Alhindi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b4875ebd3ac24aa68c191b315c0619be |
| institution | Kabale University |
| issn | 2090-0724 2090-0732 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Nutrition and Metabolism |
| spelling | doaj-art-b4875ebd3ac24aa68c191b315c0619be2025-02-03T05:57:37ZengWileyJournal of Nutrition and Metabolism2090-07242090-07322019-01-01201910.1155/2019/85948258594825Low Citrate Synthase Activity Is Associated with Glucose Intolerance and LipotoxicityYosra Alhindi0Lobke M. Vaanholt1Mustafah Al-Tarrah2Stuart R. Gray3John R. Speakman4Catherine Hambly5Bader S. Alanazi6Brendan M. Gabriel7Arimantas Lionikas8Aivaras Ratkevicius9Clinical Pharmacy Department, Pharmacy Collage, Umm Al-Qura University, Makkah, Saudi ArabiaInstitute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UKSchool of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UKInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UKInstitute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UKInstitute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UKSchool of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UKKarolinska Institute, Department of Physiology and Pharmacology, Integrative Physiology, Stockholm, SwedenSchool of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UKDepartment of Applied Biology and Rehabilitation, Lithuanian Sports University, Sporto 6, Kaunas LT 44221, LithuaniaCitrate 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.http://dx.doi.org/10.1155/2019/8594825 |
| spellingShingle | 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 Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity Journal of Nutrition and Metabolism |
| title | Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity |
| title_full | Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity |
| title_fullStr | Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity |
| title_full_unstemmed | Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity |
| title_short | Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity |
| title_sort | low citrate synthase activity is associated with glucose intolerance and lipotoxicity |
| url | http://dx.doi.org/10.1155/2019/8594825 |
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