ATF4 Deficiency Promotes Intestinal Inflammation in Mice by Reducing Uptake of Glutamine and Expression of Antimicrobial Peptides

Hu, Xiaoming; Deng, Jiali; Yu, Tianxiang; Chen, Shanghai; Ge, Yadong; Zhou, Ziheng; Guo, Yinlong; Ying, Hao; Zhai, Qiwei; Chen, Yan; Yuan, Feixiang; Niu, Yuguo; Shu, Weigang; Chen, Huimin; Ma, Cong; Liu, Zhanju; Guo, Feifan

doi:10.1053/j.gastro.2018.11.033

Cited by 81 publications

(75 citation statements)

References 59 publications

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“…This is further supported by the PCA and correlation analyses showing negative association of protein intake with a majority of these hepatic and duodenal amino acid sensing and signaling markers. Recent evidence indicates that GCN2 is essential for the protective effects of low protein diets against colitis, and that ATF4 is deficient in intestinal mucosa of patients with inflammatory bowel disease; whether, other amino acid sensing molecules identified here play a role in the protective effects of protein restriction against intestinal inflammation remains to be studied. Although hepatic contributions of FGF21 are well documented, for the first time, we report that FGF21 transcript was dose‐dependently increased with protein restriction specifically in the duodenum.…”

Section: Discussionmentioning

confidence: 94%

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

Zapata

Singh

Pezeshki

et al. 2019

Molecular Nutrition Food Res

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Scope: Dietary protein restriction elicits hyperphagia and increases energy expenditure; however, less is known of whether these responses are a consequence of increasing carbohydrate content. The effects of protein-diluted diets with fixed carbohydrate content on energy balance, hormones, and key markers of protein sensing and thermogenesis in tissues are determined. Methods and results: Obesity-prone rats (n = 13-16 per group) are randomized to diets containing fixed carbohydrate (52% calories) and varying protein concentrations: 15% (control), 10% (mild protein restriction), 5% (moderate protein restriction) or 1% (severe protein restriction) protein calories, or protein-matched to 5% protein, for 21 days. Propranolol and ondansetron are administered to interrogate the roles of sympathetic and serotonergic systems, respectively, in diet-induced changes in energy expenditure. It is found that mild-to-moderate protein restriction promotes transient hyperphagia, whereas severe protein restriction induces hypophagia, with alterations in meal patterns. Protein restriction enhances energy expenditure that is partly attenuated by propranolol, but not ondansetron. Moderate to severe protein restriction decreases gains in body weight, lean and fat mass, decreased postprandial glucose and leptin, but increased fibroblast growth factor-21 concentrations. Protein-matching retains lean mass suggesting that intake of dietary protein, but not calories, is important for preserving lean mass. Notably, protein restriction increases the protein and/or transcript abundance of key amino acid sensing molecules in liver and intestine (PERK, eIF2α, ATF2, CHOP, 4EBP1, FGF21), and upregulated thermogenic markers (β2AR, Klotho, HADH, UCP-1) in brown adipose tissue. Conclusion: Low-protein diets promote hyperphagia and sympathetically mediated increase in energy expenditure, prevent gains in tissue reserves, and concurrently upregulate hepatic and intestinal amino acid sensing intermediaries and thermogenic markers in brown adipose tissue.

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Section: Discussionmentioning

confidence: 94%

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

Zapata

Singh

Pezeshki

et al. 2019

Molecular Nutrition Food Res

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show abstract

“…ATF4 (activating transcription factor 4) is an endoplasmic reticulum stress sensor that defends lungs via induction of heme oxygenase 1 (26). ATF4 were decreased in inflamed intestinal mucosa from patients with active Crohn's disease or active ulcerative colitis, and ATF4 deficiency promotes intestinal inflammation in mice (27). ATF4 was downregulated in the alveolar type II cells of the elderly, compared with the young (28).…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization analysis identified genes pleiotropically associated with the risk and prognosis of COVID-19

Liu

Yang

Feng

et al. 2020

Preprint

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Objectives: COVID-19 has caused a large global pandemic. Patients with COVID-19 exhibited considerable variation in disease behavior. Pervious genome-wide association studies have identified potential genetic variants involved in the risk and prognosis of COVID-19, but the underlying biological interpretation remains largely unclear. Methods: We applied the summary data-based Mendelian randomization (SMR) method to identify genes that were pleiotropically associated with the risk and various outcomes of COVID-19, including severe respiratory confirmed COVID-19 and hospitalized COVID-19. Results: In blood, we identified 2 probes, ILMN_1765146 and ILMN_1791057 tagging IFNAR2, that showed pleiotropic association with hospitalized COVID-19 (Beta; [SE]=0.42 [0.09], P=4.75E-06 and Beta; [SE]=-0.48 [0.11], P=6.76E-06, respectively). Although no other probes were significant after correction for multiple testing in both blood and lung, multiple genes as tagged by the top 5 probes were involved in inflammation or antiviral immunity, and several other tagged genes, such as PON2 and HPS5, were involved in blood coagulation. Conclusions: We identified IFNAR2 and other potential genes that could be involved in the susceptibility or prognosis of COVID-19. These findings provide important leads to a better understanding of the mechanisms of cytokine storm and venous thromboembolism in COVID-19 and potential therapeutic targets for the effective treatment of COVID-19.

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“…Paneth cells are specialised epithelial cells located at the base of small intestinal crypts that act as important effectors of innate immunity through their secretion of antimicrobial peptides (21) . Glutamine has been found to increase antimicrobial peptide expression and reduce gut inflammation in animal models of inflammatory bowel diseases (22) . Thus, we speculated that Gln may affect the expression of antimicrobial peptides through the Paneth cells in the crypt compartment of weaned piglets.…”

Section: Discussionmentioning

confidence: 99%

Effect of glucose, soya oil and glutamine on protein expression and mammalian target of rapamycin complex 1 pathway of jejunal crypt enterocytes in weaned piglets

Xiong

Liu

et al. 2019

Br J Nutr

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ATF4 Deficiency Promotes Intestinal Inflammation in Mice by Reducing Uptake of Glutamine and Expression of Antimicrobial Peptides

Cited by 81 publications

References 59 publications

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

Mendelian randomization analysis identified genes pleiotropically associated with the risk and prognosis of COVID-19

Effect of glucose, soya oil and glutamine on protein expression and mammalian target of rapamycin complex 1 pathway of jejunal crypt enterocytes in weaned piglets

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