SIRT4 Is a Regulator of Insulin Secretion Elma Zaganjor, Sejal Vyas, Marcia C. Haigis  Cell Chemical Biology  Volume 24, Issue 6, Pages 656-658 (June 2017) DOI: 10.1016/j.chembiol.2017.06.002 Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 1 Overview of Leucine Catabolism Intermediates of leucine catabolism 3-methylglutaconyl-CoA, 3-methylglutaryl-CoA, and 3-hydroxy-3-methylglutaryl-CoA can function as reactive acyl species to covalently modify and inhibit methylcrotonyl-CoA carboxylase (MCCC) in a negative feedback loop. SIRT4 removes this modification to upregulate leucine catabolism. Additionally, leucine can allosterically activate glutamate dehydrogenase (GDH), an enzyme that is inhibited by SIRT4. Cell Chemical Biology 2017 24, 656-658DOI: (10.1016/j.chembiol.2017.06.002) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 2 SIRT4-Dependent Regulation of Insulin Secretion Active SIRT4 decreases mitochondrial fuel oxidation into the TCA cycle, ultimately resulting in a decreased ATP/ADP ratio to inhibit insulin secretion. SIRT4 promotes leucine catabolism through upregulation of MCCC and inhibits glutaminolysis via regulation of GDH. Loss of SIRT4 function or physiological repression of SIRT4 activity increases TCA cycle anaplerosis, in part via GDH activation, promoting an increased ATP/ADP ratio and stimulating insulin secretion. Additionally, the repression of leucine catabolism due to accumulation of modified MCCC with SIRT4 loss can allow for leucine to function as allosteric activator of GDH. Cell Chemical Biology 2017 24, 656-658DOI: (10.1016/j.chembiol.2017.06.002) Copyright © 2017 Elsevier Ltd Terms and Conditions