TY - JOUR
T1 - SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells
AU - Haigis, Marcia C.
AU - Mostoslavsky, Raul
AU - Haigis, Kevin M.
AU - Fahie, Kamau
AU - Christodoulou, Danos C.
AU - Murphy, Andrew J J.
AU - Valenzuela, David M.
AU - Yancopoulos, George D.
AU - Karow, Margaret
AU - Blander, Gil
AU - Wolberger, Cynthia
AU - Prolla, Tomas A.
AU - Weindruch, Richard
AU - Alt, Frederick W.
AU - Guarente, Leonard
N1 - Funding Information:
We thank P. Bradshaw and J. Huang for help with the CR experiments. We also thank D. Lombard, L. Bordone, R. Olivieira, X. Li, and N. Bishop for comments on the paper and helpful discussion and S. Imai for discussion and cells. We also thank C. Stanley for helpful discussions. This work was supported by grants from the NIH to L.G., R.W., and M.C.H.; a grant from Estee Lauder to G.B.; an Ellison Foundation Senior Scholar Award to F.W.A.; and grants from the Human Frontier Science Program and The Leukemia & Lymphoma Society to R.M. K.M.H. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation. F.W.A. and C.W. are investigators of the Howard Hughes Medical Institute.
PY - 2006/9/8
Y1 - 2006/9/8
N2 - Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic β cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in β cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
AB - Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic β cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in β cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
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U2 - 10.1016/j.cell.2006.06.057
DO - 10.1016/j.cell.2006.06.057
M3 - Article
C2 - 16959573
AN - SCOPUS:33748316536
SN - 0092-8674
VL - 126
SP - 941
EP - 954
JO - Cell
JF - Cell
IS - 5
ER -