SIRT6 regulates metabolic homeostasis in skeletal muscle through activation of AMPK

Cui, Xiaona; Lü, Yan; Yang, Xiaoying; Gao, Yong; Fang, Fude; Zhang, Jun; Wang, Qinghua; Chang, Yongsheng

doi:10.1152/ajpendo.00122.2017

Cited by 76 publications

(70 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expression of PGC-1α is regulated by a series of proteins (NOS, P38, ERK1/2, Akt, CaN, CaMK, CDK, AMPK) [41,42], among which nitric oxide synthase (NOS) [43], adenylate-activated protein kinase (AMPK) [44], Akt [45] and ERK1/2 [46] are regulated by Sirt6. Our results showed that the NOS inhibitor L-NAME did not affect the expression of PGC-1α induced by Sirt6, but the AMPK inhibitor Comp C not only blocked the effect of Sirt6 on PGC-1α but also promoted the mtDNA damage, ROS accumulation, and MDA upregulation induced by GCDC.…”

Section: Discussionmentioning

confidence: 99%

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Chen

et al. 2020

Cell Biosci

View full text Add to dashboard Cite

Background: Induction of biliary epithelial cell apoptosis by toxic bile acids is involved in the development of cholestatic disease, but the underlying molecular mechanism is not clear. The purpose of this study was to investigate the molecular mechanisms involved in Sirt6 protection against the apoptosis of human intrahepatic biliary epithelial cells (HiBEC) induced by the bile acid glycochenodeoxycholate (GCDC). Results: Sirt6 was either overexpressed or knocked down in HiBEC, with or without GCDC pretreatment. The CCK-8 assay was used to assess cell viability and, Hoechst 33258 staining was used to determine apoptotic rate. Mitochondrial DNA (mtDNA) copy number, malondialdehyde (MDA) and reactive oxygen species (ROS) production were detected to evaluate the severity of the mitochondrial dysfunction and oxidative stress. The mRNA and protein levels of PGC-1α, Nrf1, and Nrf2 were analyzed using RT-qPCR and western blot assay. The results showed that Sirt6 opposed GCDC-induced apoptosis in HiBEC via up-regulating PGC-1α expression and stabilizing mtDNA. We used agonists and inhibitors of AMPK to demonstrate that Sirt6 increased PGC-1α expression through the AMPK pathway whereas GCDC had the opposite effect. Finally, western blot, luciferase assay, and co-immunoprecipitation were used to describe a direct interaction and acetylation modification of PGC-1α by Sirt6. Conclusion: Our data illuminated that Sirt6 ameliorated GCDC-induced HiBEC apoptosis by upregulating PGC-1α expression through the AMPK pathway and its deacetylation effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Chen

et al. 2020

Cell Biosci

View full text Add to dashboard Cite

show abstract

“…SIRT1 was found necessary for induction of SIRT6 in mouse liver during the unfed period (23), and deletion of SIRT6 in mouse muscle reduced whole‐body insulin sensitivity (27). In the present study, SIRT1 protein content and activity was increased with the hypercaloric saturated HFD without concomitant change in SIRT6 protein content, suggesting that SIRT1 activation is not sufficient to induce SIRT6 protein content in human skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid type–specific regulation of SIRT1 does not affect insulin sensitivity in human skeletal muscle

et al. 2019

View full text Add to dashboard Cite

The nicotinamide adenine dinucleotide–dependent deacetylase, sirtuin (SIRT)1, in skeletal muscle is reduced in insulin‐resistant states. However, whether this is an initial mechanism responsible for mediating insulin resistance in human skeletal muscle remains to be investigated. Also, SIRT1 acts as a mitochondrial gene transcriptional regulator and is induced by a short‐term, high‐fat diet (HFD) in human skeletal muscle. Whether saturated or unsaturated fatty acids (FAs) in the diet are important for this is unknown. We subjected 17 healthy, young men to a eucaloric control (Con) diet and 1 of 2 hypercaloric [+75% energy (E%)] HFDs for 3 d enriched in either saturated (Sat) FA (79 E% fat; Sat) or unsaturated FA (78 E% fat; Unsat). After Sat, SIRT1 protein content and activity in skeletal muscle increased (P < 0.05; ∼40%) while remaining unchanged after Unsat. Whole‐body insulin sensitivity and insulin‐stimulated leg glucose uptake were reduced (P < 0.01; ∼20%) to a similar extent compared to Con after both HFDs. We demonstrate a novel FA type‐dependent regulation of SIRT1 protein in human skeletal muscle. Moreover, regulation of SIRT1 does not seem to be an initiating factor responsible for mediating insulin resistance in human skeletal muscle.—Fritzen, A. M., Lundsgaard, A.‐M., Jeppesen, J. F., Sjøberg, K. A., Høeg, L. D., Deleuran, H. H., Wojtaszewski, J. F. P., Richter, E. A., Kiens, B. Fatty acid type–specific regulation of SIRT1 does not affect insulin sensitivity in human skeletal muscle. FASEB J. 33, 5510–5519 (2019). http://www.fasebj.org

show abstract

“…Whole body deletion of SIRT6 causes 60% mice death around 4 weeks owning to hypoglycemia (Xiao et al, 2010). Nevertheless, the skeletal muscle-specific knockout of SIRT6 causes insulin resistance and impairs glucose homeostasis of mKO mice (Cui et al, 2017). Because the activity of AMPK is reduced in SIRT6-mKO mice, the glycolipids absorption and utilization of skeletal muscles are impaired, and the exercise capacity of the mice was also attenuated (Cui et al, 2017).…”

Section: Sirt6 Improves Muscle Fitness and Exercise Capacitymentioning

confidence: 99%

Role of Histone Deacetylases in Skeletal Muscle Physiology and Systemic Energy Homeostasis: Implications for Metabolic Diseases and Therapy

et al. 2020

View full text Add to dashboard Cite

Skeletal muscle is the largest metabolic organ in the human body and is able to rapidly adapt to drastic changes during exercise. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), which target histone and non-histone proteins, are two major enzyme families that control the biological process of histone acetylation and deacetylation. Balance between these two enzymes serves as an essential element for gene expression and metabolic and physiological function. Genetic KO/TG murine models reveal that HDACs possess pivotal roles in maintaining skeletal muscles' metabolic homeostasis, regulating skeletal muscles motor adaptation and exercise capacity. HDACs may be involved in mitochondrial remodeling, insulin sensitivity regulation, turn on/off of metabolic fuel switching and orchestrating physiological homeostasis of skeletal muscles from the process of myogenesis. Moreover, many myogenic factors and metabolic factors are modulated by HDACs. HDACs are considered as therapeutic targets in clinical research for treatment of cancer, inflammation, and neurological and metabolic-related diseases. This review will focus on physiological function of HDACs in skeletal muscles and provide new ideas for the treatment of metabolic diseases.

show abstract

SIRT6 regulates metabolic homeostasis in skeletal muscle through activation of AMPK

Cited by 76 publications

References 43 publications

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Fatty acid type–specific regulation of SIRT1 does not affect insulin sensitivity in human skeletal muscle

Role of Histone Deacetylases in Skeletal Muscle Physiology and Systemic Energy Homeostasis: Implications for Metabolic Diseases and Therapy

Contact Info

Product

Resources

About