Low citrate synthase activity is associated with glucose intolerance and lipotoxicity

Alhindi, Y., Vaanholt, L. M., Al-Tarrah, M., Gray, S. R. , Speakman, J. R., Hambly, C., Alanazi, B. S., Gabriel, B. M., Lionikas, A. and Ratkevicius, A. (2019) Low citrate synthase activity is associated with glucose intolerance and lipotoxicity. Journal of Nutrition and Metabolism, 2019, 8594825. (doi: 10.1155/2019/8594825)

Abstract

Citrate synthase (CS) is a key mitochondrial enzyme. (e 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-hydroxyacylcoenzyme-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. (is could be due to impaired lipid metabolism in muscle cells.

• Item Type: Articles
• Additional Information: (is 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-SMM-07-K-02-057) (to ˇ A.L. and A.R.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gray, Professor Stuart
• Authors: Alhindi, Y., Vaanholt, L. M., Al-Tarrah, M., Gray, S. R., Speakman, J. R., Hambly, C., Alanazi, B. S., Gabriel, B. M., Lionikas, A., and Ratkevicius, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Nutrition and Metabolism
• Publisher: Hindawi
• ISSN: 2090-0724
• ISSN (Online): 2090-0732
• Copyright Holders: Copyright © 2019 Yosra Alhindi et al.
• First Published: First published in Journal of Nutrition and Metabolism 2019: 8594825
• Publisher Policy: Reproduced under a Creative Commons License