SirT1 catalytic activity is required for male fertility and metabolic homeostasis in mice

Abstract

The protein encoded by the sirt1 gene is an enzyme, SirT1, that couples the hydrolysis of NAD(+) to the deacetylation of acetyl-lysine residues in substrate proteins. Mutations of the sirt1 gene that fail to encode protein have been introduced into the mouse germ line, and the animals homozygous for these null mutations have various physiological abnormalities. To determine which of the characteristics of these sirt1(-/-) mice are a consequence of the absence of the catalytic activity of the SirT1 protein, we created a mouse strain carrying a point mutation (H355Y) that ablates the catalytic activity but does not affect the amount of the SirT1 protein. Mice carrying point mutations in both sirt1 genes, sirt1(Y/Y), have a phenotype that is overlapping but not identical to that of the sirt1-null animals. The sirt1(Y/Y) phenotype is significantly milder than that seen in the sirt1(-/-) animals. For example, female sirt1(Y/Y) animals are fertile, while sirt1(-/-) females are sterile. On the other hand, both sirt1(-/-) and sirt1(Y/Y) male mice are sterile and hypermetabolic. We report that sirt1(Y/Y) mice respond aberrantly to caloric restriction, although the effects are more subtle than seen in sirt1(-/-) mice. Thus, the SirT1 protein has functions that can be attributed to the catalytic activity of the protein, as well as other functions that are conferred by the protein itself.

Di-(2-ethylhexyl) phthalate inhibits DNA replication leading to hyperPARylation, SIRT1 attenuation and mitochondrial dysfunction in the testis

“…4c, e). NAD + is a key factor for the deacetylation activity of the mitochondrial regulator SIRT1 and this protein may play a crucial role in male fertility3334. Since NAD + consumption by hyperPARylation may impair SIRT1 activity33, we further asked whether DEHP treatment could also reduce SIRT1 activity and cause mitochondrial malfunction.…”

An exploratory double‐blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease

“…There is increasing evidence that SirT1 may have other activities aside from HDAC activity. As an example, Pfister et al [36] have shown that overexpression of different SirT1 mutants with catalytic-site mutations may still be neuroprotective while Seifert et al [37] showed that SirT1 may have both HDAC-dependent and -independent roles. Finally, HDAC4, highly relevant for HD, is known to have at least two enzymatic activities (HDAC and SUMO ligase activities).…”

The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance

“…First, to determine whether the effect of Sirt1 on Aire-driven gene expression was dependent on its catalytic activity, we used a well-established transgenic mouse model in which the wild-type Sirt1 allele is replaced with a mutated Sirt1 allele that encodes a catalytically inactive Sirt1 protein (Sirt1 H355Y ) 29 . Indeed, quantitative PCR analysis showed significantly lower expression of Aire-dependent genes in mTECs sorted from Sirt1 H355Y mice than in those from Sirt1 +/+ mice (Fig.…”

“…B6.Sirt1 fl/fl mice (Jackson Laboratories) were crossed with B6.Foxn1-Cre mice (obtained from D. Graf with the consent of N. Manley) for the generation of Sirt1 fl/fl Foxn1-Cre mice. Sirt1 −/− and Sirt1 H355Y mice 28,29,34 were maintained on a mixed 129sv/ICR genetic background. B6.Aire-GFP reporter (Adig) mice and the NOD.Aire −/− mice were provided by M. Anderson and by D. Mathis and C. Benoist, respectively.…”