FoxO3 Transcription Factor and Sirt6 Deacetylase Regulate Low Density Lipoprotein (LDL)-cholesterol Homeostasis via Control of the Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Gene Expression

Tao, Rongya; Xiong, Xin; DePinho, Ronald A.; Deng, Chu Xia; Dong, Xiaochen

doi:10.1074/jbc.m113.481473

Cited by 157 publications

(145 citation statements)

References 59 publications

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“…Accordingly, SIRT6 overexpressing mice are protected from diet-induced obesity, and liver-specific SIRT6-deficient mice develop fatty liver [65, 66, 72, 73]. Mechanistically, histone deacetylation by SIRT6 represses transcription of key lipid metabolism factors such as PCSK9 and the SREBP1 and SREBP2 transcriptional regulators [72-74]. Notably, SIRT6 regulation of SREBP1/2 is complex and occurs at multiple levels, including post-translational modification and chromatin targeting [73, 75].…”

Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

SIRT6: Novel Mechanisms and Links to Aging and Disease

Tasselli

Zheng

Chua

2017

Trends in Endocrinology & Metabolism

221

201

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SIRT6, a member of the Sirtuin family of NAD+-dependent enzymes, has established roles in chromatin signaling and genome maintenance. Through these functions, SIRT6 protects against aging-associated pathologies including metabolic disease and cancer, and can promote longevity in mice. Research from the last few years has revealed that SIRT6 is a complex enzyme with multiple substrates and catalytic activities, and uncovered novel SIRT6 functions in maintenance of organismal health span. Here, we review these new discoveries and models of SIRT6 biology in four areas: heterochromatin stabilization and silencing, stem cell biology, cancer initiation and progression, and regulation of metabolic homeostasis. We discuss possible implications of these findings for therapeutic interventions in aging and aging-related disease processes.

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Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

SIRT6: Novel Mechanisms and Links to Aging and Disease

Tasselli

Zheng

Chua

2017

Trends in Endocrinology & Metabolism

221

201

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“…Additionally, SIRT6 suppresses cardiac hypertrophy and heart failure by controlling insulin-like growth factor (IGF)-Akt signaling at the level of chromatin through c-Jun, a stress-responsive transcription factor, and deacetylation of histone H3 at lysine 9 (H3K9) 74 . By the transcriptional repression of Pcsk9 (proprotein convertase subtilisin/kexin type 9), SIRT6 prevents hepatic LDL receptor degradation and lowers plasma LDL-cholesterol level in mice 75 , which may prevent the atherogenesis. Taken together, SIRT6 possesses the preventive effect on vascular aging (Fig.…”

Section: Roles Of Sirt Proteins In Vascular Agingmentioning

confidence: 99%

Sirtuins, Cell Senescence, and Vascular Aging

Kida

Goligorsky

2016

Canadian Journal of Cardiology

215

161

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The sirtuin (SIRTs) constitute a class of proteins with NAD+-dependent deacetylase or ADP-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized both in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, while SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, contributing to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 demonstrate protective functions against vascular aging, while definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and NAD+ stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation.

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“…Sirtuin 6, an NAD + -dependent histone deacetylase is a transcriptional repressor of the PCSK9 because its absence in mouse liver leads to increased expression of this gene, whereas its overexpression reduces it. 83 The insulin-responsive element-binding factor known as FoxO3 recruits Sirtuin 6 to the PCSK9 promoter, where it deacetylates histone 3 and causes local chromatin changes that negate promoter activation. Interestingly, the recognition element of FoxO3 is embedded within that of HNF1α.…”

Section: Nuclear-binding Factorsmentioning

confidence: 99%

“…Interactions between the 2 oppositely acting factors have been demonstrated in coimmunoprecipitation studies. 83 The outcome of this competitive interaction may depend on the relative amounts of these factors and their required cofactors.…”

Section: Nuclear-binding Factorsmentioning

confidence: 99%