Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6

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

doi:10.1194/jlr.m039339

Cited by 151 publications

(128 citation statements)

References 70 publications

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“…The Ericson group suggested that SREBP2 is targeted for ubiquitination and proteasome degradation by GSK3β and the E3 ligase FBW7 (36,45). Other studies suggest that the NAD-dependent deacetylases SIRT1 and SIRT6 could potentially promote SREBP2 protein turnover (46,47). In our studies, we unexpectedly found that ChREBP could be a potent factor promoting ubiquitination and destabilization of the mature SREBP2 protein.…”

Section: Methodsmentioning

confidence: 41%

Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity

Zhang

Tong

VanDommelen

et al. 2017

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 41%

Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity

Zhang

Tong

VanDommelen

et al. 2017

Journal of Clinical Investigation

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“…5). Specifically, SIRT6 and FOXO3 can coordinate to regulate cholesterol homeostasis via FOXO3-mediated recruitment of SIRT6 by the SREBP1/2 gene promoter, wherein it deacetylates H3 at Lys-9 (H3K9) and Lys-56 (H3K56) and promotes a repressive chromatin state (170). Moreover, cholesterol metabolism is regulated by SIRT6 via repression of lipogenic transcription factors SREBP1 and SREBP2 and their target genes, the inhibition of SREBP1/SREBP2 cleavage into their active forms, and the activation of AMPK that phosphorylates and inhibits SREBP1 (53).…”

Section: Sirt1 and Sirt6 In Cardiovascular Diseasementioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

299

238

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Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD + )-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple ''omic'' technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.

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“…Additionally, we observed 80% reductions in the transcript levels of SREBP-2 target genes, Hmgcs1 and Ldlr, in Plin2-null mice (p Ͻ 0.001) (Fig. 3B) (23). Because FXR and LXR are involved in Srebp gene transcription, we determined their gene expression responses as well.…”

Section: Plin2-null Mice On Long-term Western Diet Are Protected Frommentioning

confidence: 99%

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Libby¹,

Bales²,

Orlicky

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanPerilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in -3 and -6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease.

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Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6

Cited by 151 publications

References 70 publications

Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity

Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

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