ATM Regulates Adipocyte Differentiation and Contributes to Glucose Homeostasis

Takagi, Motoki; Uno, Hatsume; Nishi, Rina; Sugimoto, Masataka; Hasegawa, Setsuko; Piao, Jinhua; Ihara, Norimasa; Kanai, Setsuko; Kakei, Saori; Tamura, Yasuaki; Suganami, Takayoshi; Kamei, Yasutomi; Shimizu, Toshiaki; Yasuda, Akio; Ogawa, Yoshihiro; Mizutani, Shuki

doi:10.1016/j.celrep.2015.01.027

Cited by 37 publications

(32 citation statements)

References 60 publications

(60 reference statements)

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“…This was attributed to impaired adipocyte differentiation under ATM deficiency due to defective induction of transcriptional factors such as CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPAR-γ). (34) Likewise, Schneider et.al. observed glucose dyshomeostasis and acceleration of atherosclerosis in ATM+/-mice compared with ATM+/+ mice, both on an ApoE-/-background, accompanied by deteriorated hepatic insulin signaling.…”

Section: Evidence From Animal Studiesmentioning

confidence: 99%

“…In contrast to the aforementioned improved liver phenotype observed during ATM deficiency, in another study, HFD‐fed ATM‐deficient mice were more insulin resistant and were presented with lipodystrophy, predominantly in the subcutaneous AT. This was attributed to impaired adipocyte differentiation under ATM deficiency due to defective induction of transcriptional factors such as CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator‐activated receptor gamma (PPAR‐γ) . Likewise, Schneider et.al.…”

Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 99%

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The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

et al. 2019

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In recent years, cellular senescence has generated a lot of interest among researchers because of its involvement in both the normal aging process and common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, and genomic and mitochondrial DNA damage, leading to irreversible cell cycle arrest, and secretion of proinflammatory cytokines. Evidence suggests that the complex process of senescence is involved in the development of a plethora of chronic diseases including metabolic and inflammatory disorders and tumorigenesis. Recently, several human and animal studies have emphasized the involvement of senescence in the pathogenesis and development of liver steatosis including the progression to nonalcoholic steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning, and liver fibrosis. The development of nonalcoholic fatty liver disease (NAFLD) and its progression to NASH are commonly accompanied by several pathophysiological events including metabolic dysregulation and inflammatory phenomena occurring within the liver that may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. Conclusion: In this review, we summarize the current literature on the impact of cellular senescence in NAFLD/NASH and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. Finally, we identify the open questions and issues to be addressed in the near future.

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Section: Evidence From Animal Studiesmentioning

confidence: 99%

Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 99%

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

et al. 2019

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“…Beyond the well-known role of ataxia-telangiectasia mutated (ATM) in the DNA damage response, the phosphorylation landscape and functions of this versatile protein are also the focus of growing interest [1][2][3][4][5][6]. The lack of kinase activity leads to the impairment of a very large network of signalling pathways, including regulation of the cellular redox homeostasis and metabolic pathways [7][8][9][10][11][12][13][14]. Metabolic defects are considered to play a crucial role in the complex physiopathology [15][16][17][18] and the resulting altered metabolism can be a source of oxidative stress [19].…”

Section: Introductionmentioning

confidence: 99%

“…ATM localizes to the cytosol and, in particular, to organelles such as the mitochondria to manage the antioxidant response, as well as orchestrate mitochondrial metabolism, autophagy and the overall cellular metabolism [13,15,18,19,47,48]. In addition, a growing body of evidence suggests that metabolic defects strongly contribute to the complex A-T phenotype observed in patients [10,14,[23][24][25]28,[49][50][51]. Among the impaired metabolic pathways, glucose, purine metabolism and lipid turnover are the most well known.…”

mentioning

confidence: 99%

Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2‐mediated antioxidant response

et al. 2016

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Ataxia telangiectasia (A-T) is a rare incurable neurodegenerative disease caused by biallelic mutations in the gene for ataxia-telangiectasia mutated (ATM). The lack of a functional ATM kinase leads to a pleiotropic phenotype, and oxidative stress is considered to have a crucial role in the complex physiopathology. Recently, steroids have been shown to reduce the neurological symptoms of the disease, although the molecular mechanism of this effect is largely unknown. In the present study, we have demonstrated that dexamethasone treatment of A-T lymphoblastoid cells increases the content of two of the most abundant antioxidants [glutathione (GSH) and NADPH] by up to 30%. Dexamethasone promoted the nuclear accumulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 to drive expression of antioxidant pathways involved in GSH synthesis and NADPH production. The latter effect was via glucose 6-phosphate dehydrogenase activation, as confirmed by increased enzyme activity and enhancement of the pentose phosphate pathway rate. This evidence indicates that glucocorticoids are able to potentiate antioxidant defenses to counteract oxidative stress in ataxia telangiectasia, and also reveals an unexpected role for dexamethasone in redox homeostasis and cellular antioxidant activity

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“…Nevertheless, for reasons not clear, several observations appear to suggest a substantial role of ATM in glucose homeostasis. For example, ataxia telangiectasia patients can manifest a severe form of diabetes, and Atm (−/−) knockout mice exhibit insulin resistance and abnormal adipose distribution (Takagi et al, 2015). More recently, in a large GWAS consisting of ~13,000 participants, the Metformin Genetics (MetGen) Consortium reported an association between an SLC2A2 (facilitated glucose transporter) variant and metformin treatment response (Zhou et al, 2016).…”

Section: Genetic Studies Of Pgx Traitsmentioning

confidence: 99%

Personalized medicine: Genetic risk prediction of drug response

Zhang

Nebert

2017

Pharmacology & Therapeutics

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Pharmacogenomics (PGx), a substantial component of “personalized medicine”, seeks to understand each individual's genetic composition to optimize drug therapy reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits –– influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance –– thus having limited predictive power and clinical utility.

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ATM Regulates Adipocyte Differentiation and Contributes to Glucose Homeostasis

Cited by 37 publications

References 60 publications

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2‐mediated antioxidant response

Personalized medicine: Genetic risk prediction of drug response

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