Sirtuin 6 deficiency transcriptionally up-regulates TGF-β signaling and induces fibrosis in mice

Abstract

Caloric restriction has been associated with increased life span and reduced aging-related disorders and reduces fibrosis in several diseases. Fibrosis is characterized by deposition of excess fibrous material in tissues and organs and is caused by aging, chronic stress, injury, or disease. Myofibroblasts are fibroblast-like cells that secrete high levels of extracellular matrix proteins, resulting in fibrosis. Histological studies have identified many-fold increases of myofibroblasts in aged organs where myofibroblasts are constantly generated from resident tissue fibroblasts and other cell types. However, it remains unclear how aging increases the generation of myofibroblasts. Here, using mouse models and biochemical assays, we show that sirtuin 6 (SIRT6) deficiency plays a major role in aging-associated transformation of fibroblasts to myofibroblasts, resulting in tissue fibrosis. Our findings suggest that SIRT6-deficient fibroblasts transform spontaneously to myofibroblasts through hyperactivation of transforming growth factor β (TGF-β) signaling in a cell-autonomous manner. Importantly, we noted that SIRT6 haploinsufficiency is sufficient for enhancing myofibroblast generation, leading to multiorgan fibrosis and cardiac dysfunction in mice during aging. Mechanistically, SIRT6 bound to and repressed the expression of key TGF-β signaling genes by deacetylating SMAD family member 3 (SMAD3) and Lys-9 and Lys-56 in histone 3. SIRT6 binding to the promoters of genes in the TGF-β signaling pathway decreased significantly with age and was accompanied by increased binding of SMAD3 to these promoters. Our findings reveal that SIRT6 may be a potential candidate for modulating TGF-β signaling to reduce multiorgan fibrosis during aging and fibrosis-associated diseases.

Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats

“…First, in the present study, we have observed significant reduction in protein expressions of Sirt1, Sirt3, and Sirt6 in the DM+PBS group, except Sirt2, compared with the control rats. This observation might support the hypothesis that Sirt1, Sirt3, and Sirt6 could play an important role in the development of tissue fibrosis induced by diabetes, which is consistent with previous research results [24,41,42] and Sirt2 might not participate in this process. Administration of MSCs results in a significant increase in Sirt3 protein expressions but fails to upregulate the protein expressions of Sirt1 and Sirt6, suggesting that the protective effect of MSCs against diabetic lung fibrosis may be sirt3-dependent, which may be related to the paracrine effects of MSCs [84], but the specific mechanism is not clear.…”

“…MSCs Activate the Sirt3/SOD2 Signaling Pathway. It is well known that the sirtuin family is composed of seven members (Sirt1 to Sirt7), out of which Sirt1, Sirt2, Sirt3, and Sirt6 exert positive effects on tissue fibrosis, especially Sirt3 [41,42]. To investigate the mechanisms of MSCs against diabetes-induced lung fibrosis, we hypothesized that the capability of MSCs might mainly result from upregulating the Sirt3/SOD2 signaling pathway.…”

Protective Effects of SIRT6 Overexpression against DSS-Induced Colitis in Mice

“…TGF-β signaling has been reported to be dysregulated in IBD patients, and its impairment results in spontaneous colitis in mouse model [ 31 ]. SIRT6 could bind to and repress the expression of key TGF-β genes to decrease the activation of TGF-β signaling [ 32 ]. We speculate that TAK1, as an important component of TGF-β signaling, whose activation is to be suppressed by inhibited TGF-β signaling regulated by SIRT6 [ 31 , 32 ].…”

“…SIRT6 could bind to and repress the expression of key TGF-β genes to decrease the activation of TGF-β signaling [ 32 ]. We speculate that TAK1, as an important component of TGF-β signaling, whose activation is to be suppressed by inhibited TGF-β signaling regulated by SIRT6 [ 31 , 32 ]. This still requires further research to prove.…”

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators

“…Research progress over the past few years has described critical roles for SIRT6 in DNA repair, metabolic regulation, tumor suppression, and longevity (179,180). Given these biological roles, SIRT6 has emerged as a candidate for small molecule activation to extend lifespan through the treatment or prevention of age-associated disease, including nonalcoholic fatty liver disease, cancer, fibrosis, and cardiac hypertrophy (52,(181)(182)(183). Early work demonstrated the ability of SIRT6 to be activated in vitro by various small molecules, including free fatty acids and natural products (25,115,147,152).…”