GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice

Li, Shasha; Yuan, Jun-Tao; Yue, Wencong; Bi, Yong‐Mei; Shen, Xiyue; Gao, Junling; Xu, Xin; Lu, Zhigang

doi:10.1016/j.bbadis.2018.07.012

Cited by 30 publications

(28 citation statements)

References 57 publications

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“…Hens FLHS commonly selected as a study model of NAFLD owning to the pathogenesis of FLHS was similar to NAFLD in humans, such as excessive triglyceride accumulation, severe hepatic steatosis, insulin resistance, oxidation stress, inflammatory reaction, and autophagy [ 16 ]. It has been demonstrated that GCN2 was a key regulator of liver fatty acid metabolism and the development of NAFLD [ 17 , 18 ]. In addition, isobutyric and isovaleric acids, generated by fermentation of BCAAs, have been confirmed that could inhibit both cAMP-mediated lipolysis and insulin-stimulated de novo lipogenesis in primary rats and human adipocytes [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Jian

Miao

Liu

et al. 2021

Oxidative Medicine and Cellular Longevity

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Valine is an important essential amino acid of laying hens. Dietary supplemented with BCAAs ameliorated gut microbiota, whereas elevated blood levels of BCAAs are positively associated with obesity, insulin resistance, and diabetes in both humans and rodents. General controlled nonrepressed (GCN2) kinase plays a crucial role in regulating intestinal inflammation and hepatic fatty acid homeostasis during amino acids deficiency, while GCN2 deficient results in enhanced intestinal inflammation and developed hepatic steatosis. However, how long-term dietary valine impacts gut health and the development of nonalcoholic fatty liver disease (NAFLD) remains unknown. Hence, in the present study, we elucidated the effects of dietary valine on intestinal barrier function, microbial homeostasis, and the development of NAFLD. A total of 960 healthy 33-weeks-old laying hens were randomly divided into five experimental groups and fed with valine at the following different levels in a feeding trial that lasted 8 weeks: 0.59, 0.64, 0.69, 0.74, and 0.79%, respectively. After 8 weeks of treatment, related tissues and cecal contents were obtained for further analysis. The results showed that diet supplemented with valine ameliorated gut health by improving intestinal villus morphology, enhancing intestinal barrier, decreasing cecum pathogenic bacteria abundances such as Fusobacteriota and Deferribacterota, and inhibiting inflammatory response mediated by GCN2. However, long-term intake of high levels of dietary valine (0.74 and 0.79%) accelerated the development of NAFLD of laying hens by promoting lipogenesis and inhibiting fatty acid oxidation mediated by GCN2-eIF2α-ATF4. Furthermore, NAFLD induced by high levels of dietary valine (0.74 and 0.79%) resulted in strengthening oxidative stress, ER stress, and inflammatory response. Our results revealed that high levels of valine are a key regulator of gut health and the adverse metabolic response to NAFLD and suggested reducing dietary valine as a new approach to preventing NAFLD of laying hens.

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Section: Introductionmentioning

confidence: 99%

Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Jian

Miao

Liu

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…30) GCN2 gene deficiency can alleviate heart inflammation caused by a high-fat diet, thereby alleviating cardiac damage. 13) Moreover, GCN2 gene deficiency can alleviate doxorubicin-induced cardiac damage, and eIF2α gene deficiency showed similar results. 31) Therefore, inhibiting the GCN2 activity was an effective strategy for treating cardiac injury and was the mechanism underlying the relief of cardiac injury by exercise.…”

Section: Discussionmentioning

confidence: 90%

“…12) Reduced GCN2 activity may protect against heart inflammation caused by a high-fat diet and cardiac damage induced by doxorubicin through the inhibition of the eIF2α/ATF4 pathway and then inhibit the expression of inflammatory or apoptotic factors. 13) Although GCN2 is involved in inflammation and cardiac injury, its role in the exercise-preconditioning-mediated alleviation Figure 1. Experimental scheme diagram.…”

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confidence: 99%

Exercise Preconditioning Protects against Acute Cardiac Injury Induced by Lipopolysaccharide Through General Control Nonderepressible 2 Kinase

et al. 2020

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Exercise preconditioning may protect against cardiac injury induced by lipopolysaccharide (LPS), but the mechanism is unresolved. The aim of this study is to explore whether the general control nonderepressible 2 (GCN2) kinase gene is associated with the protective effect of exercise preconditioning. Eight-week-old male C57BL/6J (n = 40) and GCN2 knockout (KO) (n = 40) mice were divided into four groups: control, LPS (L), exercise preconditioning (E), and exercise preconditioning LPS (EL). Mice in the exercise groups performed exercise for eight weeks. After exercise, all mice were given an equal volume of LPS or saline (10 μg/g). We measured the cardiac function using echocardiography and then collected heart tissue. Exercise preconditioning improved cardiac inflammation (interleukin-6, tumor necrosis factor α) and cardiac dysfunction (ejection fraction, fraction shortening) in C57 mice induced by LPS and also decreased the expression levels of GCN2, phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), and activating transcription factor 4 (ATF4). Moreover, GCN2 KO decreased inflammation and cardiac dysfunction induced by LPS in sedentary mice. The inflammation and cardiac dysfunction in the GCN2 KO EL group were lower than in the C57 EL group, and the expression of GCN2, p-eIF2α, and ATF4 in the GCN2 KO EL group was lower than in the C57 EL group. Exercise preconditioning alleviated cardiac injury induced by LPS. GCN2 KO also improved cardiac injury. Exercise preconditioning promoted the effect of GCN2 KO in alleviating cardiac injury, and the GCN2 and eIF2α/ ATF4 pathways play an important role in the process.

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“…Lipid accumulation and the expression of SREBP-1c were both reduced in the liver of ATF4 knockout mice [115]. Additionally, ATF4 knockout mice showed reduced lipid accumulation in the liver after HFD [116]. Exercise reduced ATF4 protein and TG content in the liver of NAFLD mice [54], indicating that exercise reduced the lipid accumulation by controlling ATF4 expression.…”

Section: Ers-related Molecular Mechanism By Whichmentioning

confidence: 96%

Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

Zou

2020

Mediators of Inflammation

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Nonalcoholic fatty liver disease (NAFLD) is globally prevalent and characterized by abnormal lipid accumulation in the liver, frequently accompanied by insulin resistance (IR), enhanced hepatic inflammation, and apoptosis. Recent studies showed that endoplasmic reticulum stress (ERS) at the subcellular level underlies these featured pathologies in the development of NAFLD. As an effective treatment, exercise significantly reduces hepatic lipid accumulation and thus alleviates NAFLD. Confusingly, these benefits of exercise are associated with increased or decreased ERS in the liver. Further, the interaction between diet, medication, exercise types, and intensity in ERS regulation is more confusing, though most studies have confirmed the benefits of exercise. In this review, we focus on understanding the role of exercise-modulated ERS in NAFLD and ERS-linked molecular pathways. Moderate ERS is an essential signaling for hepatic lipid homeostasis. Higher ERS may lead to increased inflammation and apoptosis in the liver, while lower ERS may lead to the accumulation of misfolded proteins. Therefore, exercise acts like an igniter or extinguisher to keep ERS at an appropriate level by turning it up or down, which depends on diet, medications, exercise intensity, etc. Exercise not only enhances hepatic tolerance to ERS but also prevents the malignant development of steatosis due to excessive ERS.

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GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice

Cited by 30 publications

References 57 publications

Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Dietary Valine Ameliorated Gut Health and Accelerated the Development of Nonalcoholic Fatty Liver Disease of Laying Hens

Exercise Preconditioning Protects against Acute Cardiac Injury Induced by Lipopolysaccharide Through General Control Nonderepressible 2 Kinase

Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

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