Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease

Abstract

Sirtuins, NAD + dependent proteins belonging to class III histone deacetylases, are involved in regulating numerous cellular processes including cellular stress, insulin resistance, inflammation, mitochondrial biogenesis, chromatin silencing, cell cycle regulation, transcription, and apoptosis. Of the seven mammalian sirtuins present in humans, Sirt6 is an essential nuclear sirtuin. Until recently, Sirt6 was thought to regulate chromatin silencing, but new research indicates its role in aging, diabetes, cardiovascular disease, lipid metabolism, neurodegenerative diseases, and cancer. Various murine models demonstrate that Sirt6 activation is beneficial in alleviating many disease conditions and increasing lifespan, showing that Sirt6 is a critical therapeutic target in the treatment of various disease conditions in humans. Sirt6 also regulates the pathogenesis of multiple diseases by acting on histone proteins and non-histone proteins. Endogenous and non-endogenous modulators regulate both activation and inhibition of Sirt6. Few Sirt6 specific non-endogenous modulators have been identified. Hence the identification of Sirt6 specific modulators may have potential therapeutic roles in the diseases described above. In this review, we describe the development of Sirt6, the role it plays in the human condition, the functional role and therapeutic importance in disease processes, and specific modulators and molecular mechanism of Sirt6 in the regulation of metabolic homeostasis, cardiovascular disease, aging, and neurodegenerative disease.

Aberrant Expression of SIRT6 and VNN1 in Peripheral Blood Monocytes of Children with Primary Nephrotic Syndrome and Its Diagnostic and Prognostic Values

“…Relevant studies testify that SIRT6 is nearly correlated to the mitochondrial function of body cells [ 18 , 19 ]. SIRT6 exerts a critical role in antioxidant stress, mitochondrial substrate metabolism, and cell survival, and is able to mitigate the severity of renal tubular injury via protecting mitochondrial integrity [ 20 , 21 ]. The study manifested that the AUC of SIRT6 and VNN1 jointly examining and evaluating the degree of renal function impairment in NS child patients outweighed SIRT6 alone, illustrating that the combined detection of SIRT6 and VNN1 provides an assessed value in the severity of the disease in NS child patients.…”

“…The combined detection Refline correlated to the mitochondrial function of body cells [18,19]. SIRT6 exerts a critical role in antioxidant stress, mitochondrial substrate metabolism, and cell survival, and is able to mitigate the severity of renal tubular injury via protecting mitochondrial integrity [20,21].…”

Metabolic memory: mechanisms and diseases

“… 362 , 363 The interaction between diabetes and cognition is complicated by the influence of epigenetic factors. 364 , 365 On the one hand, persistent insulin resistance in peripheral tissues of metabolic syndrome leads to dysregulation of insulin receptor pathway activity in the brain, which ultimately results in brain insulin resistance. 366 Brain insulin resistance increases the accumulation of Aβ and tau hyperphosphorylation, causing intense inflammation and neurodegeneration of nerve cells, which is considered to be an important pathogenetic component of AD.…”

Multiple Roles of Sirtuin 6 in Adipose Tissue Inflammation

“…Second, although it is evident that Sirt6 is present in both adipocytes and SVCs, transcriptional regulatory networks and intracellular signaling pathways that lead to functional interplay among the cells which compose adipose tissue have not been identified. Third, the therapeutic role of Sirt6 specific modulators (activators and inhibitors) in metabolic diseases including obesity and diabetes need to be understood to a better extent, despite the fact that several compounds have already been identified [ 80 , 81 ]. However, Sirt6 is known to promote the development of certain types of cancer [ 82 ].…”