Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway

Jiang, Rui; Zhou, Y.; Wang, Sufan; Pang, Nengzhi; Huang, Yuanling; Ye, Mingtong; Wan, Ting; Qiu, Yun; Pei, Lei; Jiang, Xuye; Huang, Yu‐Feng; Yang, Hainan; Liu, Wenhua; Li, Xufeng; Zhang, Zhenfeng; Yang, Lili

doi:10.1016/j.lfs.2019.03.064

Cited by 43 publications

(37 citation statements)

References 41 publications

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“…Although they are known regulators of caloric restriction beneficial effects, sirtuins have also been linked to cell survival and apoptosis in cancer, DNA repair, development, inflammation and neuroprotection [ 88 ]. Recently, sirtuins have been proposed as new therapeutic targets for the treatment of liver fibrosis ( Table 2 ), being SIRT1 the most well-characterized ( Figure 1 ) [ 89 ]. SIRT1 is downregulated during HSCs activation as demonstrated in in vitro studies, including TGFβ-stimulated LX2 cells [ 90 , 91 ], and activated rat [ 92 ] and mouse [ 90 , 93 ] primary HSCs.…”

Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 99%

“…According to this, PPARγ inhibition blocks the antifibrogenic effects of SIRT1 overexpression in HSCs [ 93 ]. Second, SIRT1-mediated SMAD3 deacetylation blocks TGFβ-induced LX2 and mouse primary HSCs activation [ 89 , 99 ]. Third, SIRT1-mediated deacetylation of EZH2, which is involved in HSCs transdifferentiation to myofibroblasts, decreases its stability, therefore facilitating its degradation in LX2 and rat primary HSCs exposed to TGFβ [ 92 ].…”

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: 99%

Section: Acetylation/deacetylation Of Histones In Liver Fibrosismentioning

confidence: 99%

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

Clavería-Cabello

Colyn

Arechederra

et al. 2020

Cells

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“…Previous study has also demonstrated that genetic blockade of NAD synthesis exerts inflammatory effects on the liver reflecting by activation NLRP-3 inflammasome pathway and production of IL-18 and IL-1β (Jiang and Zhou, 2019). The other independent group shows that pharmacological inhibition of de novo NAD synthesis strengthens transcription genes involved in inflammation, including Desmin and Tgfb (Katsyuba and Mottis, 2018).…”

Section: Discussionmentioning

confidence: 94%

“…Thus, supplementation NAD pool may be an attractive therapy strategy for liver damage related diseases in elderly individual. Notably, NR, this vitamin B3 analog, as a precursor of NAD biosynthesis, is commonly used to boost NAD pool (Jiang and Zhou, 2019).…”

Section: Discussionmentioning

confidence: 99%

Peer Review #2 of "Nicotinamide riboside exerts protective effect against aging-induced NAFLD-like hepatic dysfunction in mice (v0.1)"

2019

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Background & Aims. Aging is one of the risk factors of non-alcoholic fatty liver disease (NAFLD). Yet, the mechanism underlying the aging-associated NAFLD-like syndrome is not fully understood. Nicotinamide adenine dinucleotide (NAD), a ubiquitous coenzyme, has protective effects against aging. Here, we investigated the actions of NAD precursors nicotinamide riboside (NR) on the development of aging-induced NAFLD. Methods. NR supplemented food (2.5g/kg food) was applied to aged mice for three months while normal chow to the other groups. Body weight, food intake, liver weight and fat pat mass were measured. The serum concentrations of lipid content, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and NAD were determined by biochemical assays. Pathological assessment and immunohistochemistry analysis of hepatic tissues were used to evaluate the effect of NR on NAFLD development and inflammatory infiltration. Results. NR repletion significantly reduced fat pat mass in aged mice, while not altered the body weight, food intake, and liver weight. NR repletion significantly rescued the NAD reduction in aged mice. The total cholesterol and triglyceride levels could be lowered by NR repletion in aged mice. The AST level was also significantly reduced by NR repletion in aged group, while the ALT level lowered but without significance. Notably, moderate NAFLD phenotypes, including steatosis and hepatic fibrosis could be markedly corrected by NR repletion. In addition, Kupffer cells accumulated and inflammatory infiltration could also be remarkably reversed by NR repletion in aged mice. Conclusion. Aging was associated with NAFLD-like phenotypes in mice, which could be reversed by oral NR repletion. Therefore, oral NR uptake might be a promising strategy to halt the progression of NAFLD.

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“…Depression of the NAD + metabolome can be counteracted by de novo NAD + synthesis from tryptophan or via salvage pathways from precursor vitamins, nicotinamide (NAM), nicotinic acid (NA) and nicotinamide riboside (NR) (23,24). In rodent models, hepatic carcinogenesis (19), diet-induced steatosis (25), alcohol-induced liver injury (26) and fibrosis (27) can be counteracted by provision of NR, while NA protects against alcoholic fatty liver (11). Moreover, in mice, the condition of postpartum depresses the maternal hepatic NAD metabolome (28) and endogenous metabolism of NR is protective against diet-induced liver damage (29).…”

Section: Introductory Statementmentioning

confidence: 99%

The NAD Metabolome is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-related Liver Disease

Parker

Schmidt

Cain

et al. 2020

Preprint

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Nicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Though hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+ metabolome in alcohol-related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+ metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham NHS Foundation Trust (UHB). The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests (LFT) and histology. NAD-targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography-tandem mass spectrometry (LC-MS). Seventy-two human liver specimens were analyzed including 43 with ArLD. The NAD+ metabolome differed significantly between different types of liver disease (two-way ANOVA p = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+ (432 μM vs. 616 μM in NL) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+ metabolome between ArLD samples with and without steatohepatitis (two-way ANOVA p = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+ (mean 451 μM vs. 381 μM, p = 0.045). NAD+ concentration was inversely related to serum bilirubin concentration (r2 −0.127, p = 0.04) and positively correlated with myeloperoxidase activity (r2 0.31, p = 0.003). The concentration of NAD+ and its precursor molecules are significantly reduced in ArLD and are associated with disease activity. Conclusion: Liver samples from people with ArLD show depressed NAD+ and precursor levels as well as depressed myeloperoxidase activity.

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Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway

Cited by 43 publications

References 41 publications

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

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

Peer Review #2 of "Nicotinamide riboside exerts protective effect against aging-induced NAFLD-like hepatic dysfunction in mice (v0.1)"

The NAD Metabolome is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-related Liver Disease

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