SIRT6 Protects Against Liver Fibrosis by Deacetylation and Suppression of SMAD3 in Hepatic Stellate Cells

Zhong, Xiaolin; Huang, Menghao; Kim, Hyeong-Geug; Zhang, Yang; Chowdhury, Kushan; Cai, Wenjie; Saxena, Romil; Schwabe, Robert F.; Liangpunsakul, Suthat; Dong, X. Charlie

doi:10.1016/j.jcmgh.2020.04.005

Cited by 54 publications

(62 citation statements)

References 52 publications

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“…Finally, an early study showed that Sirt6 -KO mice exhibited increased collagen deposition in the liver [ 114 ]. Recently, this appreciation was confirmed by a study that showed exacerbated fibrosis in Sirt6 -KO mice while SIRT6 -overexpressing transgenic mice were protected against fibrosis [ 115 ]. Moreover, SIRT6 levels were considerably reduced in patients as fibrosis progressed to cirrhosis [ 115 ].…”

Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 91%

“…Recently, this appreciation was confirmed by a study that showed exacerbated fibrosis in Sirt6 -KO mice while SIRT6 -overexpressing transgenic mice were protected against fibrosis [ 115 ]. Moreover, SIRT6 levels were considerably reduced in patients as fibrosis progressed to cirrhosis [ 115 ]. In addition, SIRT6 was also downregulated in culture-activated mouse primary HSCs and TGFβ-treated mouse primary HSCs.…”

Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 91%

“…In addition, SIRT6 was also downregulated in culture-activated mouse primary HSCs and TGFβ-treated mouse primary HSCs. In fact, shRNA-mediated SIRT6 silencing enhances the expression of profibrogenic markers such as COL1A1 , ACTA2 , and TIMP1 in TGFβ-stimulated LX2 cells [ 115 ]. Mechanistically, SIRT6 seems to have a dual function, it can deacetylate SMAD3 proteins and inhibit their transcriptional activity on target genes, and it can also deacetylate ac-H3K9 residues in SMAD3 target genes promoters such as COL1A2 and TGFβ1 [ 115 ].…”

Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 99%

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Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Clavería-Cabello

Colyn

Arechederra

et al. 2020

Cells

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Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.

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Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 91%

Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 91%

Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 99%

See 1 more Smart Citation

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Clavería-Cabello

Colyn

Arechederra

et al. 2020

Cells

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“…The study by Zhong et al 12 published in this issue of Cellular and Molecular Gastroenterology and Hepatology identifies a novel key player in the progression of NASH. They discovered that the expression of the NAD-dependent deacetylase/deacylase, 13 , 14 Sirtuin 6 (Sirt-6), is reduced in patients with NASH and murine model of NASH.…”

mentioning

confidence: 99%

“…Although activated hepatic stellate cells are the primary source of myofibroblasts in NASH and thus key drivers of fibrosis, the mechanistic knowledge regarding their activation in the context of NASH is still incomplete. The finding of Zhong et al 12 that Sirt-6 regulates hepatic stellate cell activation via modulation of TGFβ/SMAD3 signaling to regulate fibrosis development in NASH is an important piece to the puzzle that promises to help in the development of novel treatment modalities to block the progression of or even reverse the course of fibrosis.…”

mentioning

confidence: 99%

Sirtuin-6 in Hepatic Fibrosis

Pradhan‐Sundd

2020

Cellular and Molecular Gastroenterology and Hepatology

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Epigenetics and mitochondrial dysfunction insights into the impact of the progression of non‐alcoholic fatty liver disease

Guha

Sesili

Mir

et al. 2022

Cell Biochemistry & Function

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A metabolic problem occurs when regular functions of the body are disrupted due to an undesirable imbalance. Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most common in this category. NAFLD is subclassified and progresses from lipid accumulation to cirrhosis before advancing to hepatocellular cancer. In spite of being a critical concern, the standard treatment is inadequate. Metformin, silymarin, and other nonspecific medications are used in the management of NAFLD.Aside from this available medicine, maintaining a healthy lifestyle has been emphasized as a means of combating this. Epigenetics, which has been attributed to NAFLD, is another essential feature of this disease that has emerged as a result of several sorts of research. The mechanisms by which DNA methylation, noncoding RNA, and histone modification promote NAFLD have been extensively researched.Another organelle, mitochondria, which play a pivotal role in biological processes, contributes to the global threat. Individuals with NAFLD have been documented to have a multitude of alterations and malfunctioning. Mitochondria are mainly concerned with the process of energy production and regulation of the signaling pathway on which the fate of a cell relies. Modulation of mitochondria leads to elevated lipid deposition in the liver. Further, changes in oxidation states result in an impaired balance between the antioxidant system and reactive oxygen species directly linked to mitochondria. Hence mitochondria have a definite role in potentiating NAFLD. In this regard, it is essential to consider the role of epigenetics as well as mitochondrial contribution while developing a medication or therapy with the desired accuracy.

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SIRT6 Protects Against Liver Fibrosis by Deacetylation and Suppression of SMAD3 in Hepatic Stellate Cells

Cited by 54 publications

References 52 publications

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Sirtuin-6 in Hepatic Fibrosis

Epigenetics and mitochondrial dysfunction insights into the impact of the progression of non‐alcoholic fatty liver disease

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