Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development

Abstract

Sirt3 is a mitochondrial NAD+-dependent deacetylase that governs mitochondrial metabolism and reactive oxygen species homeostasis. Sirt3 deficiency has been reported to accelerate the development of the metabolic syndrome. However, the role of Sirt3 in atherosclerosis remains enigmatic. We aimed to investigate whether Sirt3 deficiency affects atherosclerosis, plaque vulnerability, and metabolic homeostasis. Low-density lipoprotein receptor knockout (LDLR−/−) and LDLR/Sirt3 double-knockout (Sirt3−/−LDLR−/−) mice were fed a high-cholesterol diet (1.25 % w/w) for 12 weeks. Atherosclerosis was assessed en face in thoraco-abdominal aortae and in cross sections of aortic roots. Sirt3 deletion led to hepatic mitochondrial protein hyperacetylation. Unexpectedly, though plasma malondialdehyde levels were elevated in Sirt3-deficient mice, Sirt3 deletion affected neither plaque burden nor features of plaque vulnerability (i.e., fibrous cap thickness and necrotic core diameter). Likewise, plaque macrophage and T cell infiltration as well as endothelial activation remained unaltered. Electron microscopy of aortic walls revealed no difference in mitochondrial microarchitecture between both groups. Interestingly, loss of Sirt3 was associated with accelerated weight gain and an impaired capacity to cope with rapid changes in nutrient supply as assessed by indirect calorimetry. Serum lipid levels and glucose tolerance were unaffected by Sirt3 deletion in LDLR−/− mice. Sirt3 deficiency does not affect atherosclerosis in LDLR−/− mice. However, Sirt3 controls systemic levels of oxidative stress, limits expedited weight gain, and allows rapid metabolic adaptation. Thus, Sirt3 may contribute to postponing cardiovascular risk factor development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-013-0399-0) contains supplementary material, which is available to authorized users.

Sirt3 is dispensable for oocyte quality and female fertility in lean and obese mice

“…Sirt3 appears dispensable in a number of other in vivo processes 25‐26,47 . One study showed that loss of Sirt3 had no identifiable effect on innate immune responses and host defense against bacterial and fungal infections 25 .…”

Histone Deacetylases and Cardiometabolic Diseases

“…Likewise, loss of SIRT3 promoted hyperacetylation of mitochondrial proteins, resulting in metabolic perturbations and increased susceptibility to metabolic disease 31 . Additionally, SIRT3 was demonstrated to regulate systemic oxidative stress, limit expedited weight gain, and promote metabolic adaptation 32 . Thus, animal studies suggest that SIRTs may protect against the development of metabolic disease.…”

Mechanistic perspectives of calorie restriction on vascular homeostasis

“…) mice results in increases in body weight, plasma glucose level and systemic oxidative stress, but does not accelerate the vascular oxidative stress or the development of atherosclerosis [115]. These findings suggest a potential role of SIRT3 in the development of cardiovascular risk factors and a function of postponing the onset of distinct metabolic risk factors.…”

“…Therefore, it is possible that the activation of SOD in aorta under CR is also obtained through the activation of SIRT3. Although deletion of SIRT3 in LDLR  mice does not result in any exacerbation of vascular oxidative stress [115], we should not rule out the possibility that SIRT3 could regulate vascular oxidative stress under other circumstances. Compared with SIRT1 and SIRT3, other sirtuins, which also sense NAD + /NADH levels, are involved in the regulation of metabolism as well [123,124].…”