Activation of the canonical ER stress IRE1–XBP1 pathway by insulin regulates glucose and lipid metabolism

Peng, Jinghua; Qin, Caolitao; Ramatchandirin, Balamurugan; Pearah, Alexia; Guo, Shaodong; Hussain, Mehboob A.; Yu, Liqing; Wondisford, Fredric E.; He, Liang

doi:10.1016/j.jbc.2022.102283

Cited by 14 publications

(8 citation statements)

References 35 publications

(58 reference statements)

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“…ER stress regulates lipid metabolism through multiple pathways. The IRE1a-XBP1 axis regulates gene expression related to lipid biosynthesis and triglyceride contents, including ACC, FAS, and SCD1 31 , 60 , 61 . Furthermore, XBP1 upregulates the transcription of fatty acid synthase genes by binding to the promoter of SREBP1 60 , 62 .…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

Wang,

Tan,

Liu

et al. 2023

Nat Commun

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Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

Wang,

Tan,

Liu

et al. 2023

Nat Commun

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“…Coactivator P300 can be induced by XBP1s, thus increasing glucose production in the liver (see below) [ 67 , 68 ]. Our recent study revealed that the activation of IRE1-XBP1 signaling by insulin-activated AKT increases XBP1s to stimulate liver lipogenesis in the fed state ( Figure 3 ), while in the fasted state augmentation of XBP1u (the unspliced form) upregulates liver gluconeogenesis to maintain the euglycemia [ 69 ]. Thus, XBP1s can affect both glucose and lipid metabolism.…”

Section: Regulation Of Liver Metabolism By Transcription Factorsmentioning

confidence: 99%

“…In the liver, activation of the PI3K-AKT signaling by insulin results in increased expression of SREBP1c through mTOCR1 ( Figure 3 ) [ 157 ]. Activated AKT can directly phosphorylate IRE1 at S724 to mediate the splicing of XBP1 mRNA and the generation of spliced form XBP1s; subsequently, XBP1s stimulates SREBP1c expression ( Figure 3 ) [ 69 ]. Elevated blood insulin levels can increase the glucokinase activity to augment the generation of glucose 6-phosphate, then, xylulose 5-phosphate via the pentose-phosphate pathway.…”

Section: Coordinated Regulation Of Glucose and Lipid Metabolism By Tr...mentioning

confidence: 99%

“…Xylulose 5-phosphate can promote ChREBP1 nuclear entry and lipogenesis ( Figure 3 ) [ 158 ]. Furthermore, activated AKT mediates phosphorylation of FOXO1 and nuclear exclusion leads to the decreased expression of microsomal triglyceride transfer protein (MTP), limiting the export of triglyceride from the liver and favoring triglyceride accumulation in the liver [ 69 ].…”

Section: Coordinated Regulation Of Glucose and Lipid Metabolism By Tr...mentioning

confidence: 99%

“…Plasma FFA can be re-esterified and channeled into VLDL ( Figure 5 ). Moreover, impaired insulin signaling can prevent the degradation of FOXO1 and phosphorylation of this protein by PKA can increase FOXO1 nuclear localization [ 35 ] and upregulate the expression of MTP [ 69 ]. Collectively, these effects will increase lipogenesis and VLDL production in the liver ( Figure 5 ).…”

Section: Abnormal Lipid Metabolism In the Liver Of T2dm And Obesitymentioning

confidence: 99%

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Regulation of Liver Glucose and Lipid Metabolism by Transcriptional Factors and Coactivators

Ramatchandirin

Pearah

2023

Life

Self Cite

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The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide is on the rise and NAFLD is becoming the most common cause of chronic liver disease. In the USA, NAFLD affects over 30% of the population, with similar occurrence rates reported from Europe and Asia. This is due to the global increase in obesity and type 2 diabetes mellitus (T2DM) because patients with obesity and T2DM commonly have NAFLD, and patients with NAFLD are often obese and have T2DM with insulin resistance and dyslipidemia as well as hypertriglyceridemia. Excessive accumulation of triglycerides is a hallmark of NAFLD and NAFLD is now recognized as the liver disease component of metabolic syndrome. Liver glucose and lipid metabolisms are intertwined and carbon flux can be used to generate glucose or lipids; therefore, in this review we discuss the important transcription factors and coactivators that regulate glucose and lipid metabolism.

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Emerging role of IRE1α in vascular diseases

Shi,

He,

2024

Journal of Cell Communication and Signaling

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A mounting body of evidence suggests that the endoplasmic reticulum stress and the unfolded protein response are involved in the underlying mechanisms responsible for vascular diseases. Inositol‐requiring protein 1α (IRE1α), the most ancient branch among the UPR‐related signaling pathways, can possess both serine/threonine kinase and endoribonuclease (RNase) activity and can perform physiological and pathological functions. The IRE1α‐signaling pathway plays a critical role in the pathology of various vascular diseases. In this review, we provide a general overview of the physiological function of IRE1α and its pathophysiological role in vascular diseases.

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Activation of the canonical ER stress IRE1–XBP1 pathway by insulin regulates glucose and lipid metabolism

Cited by 14 publications

References 35 publications

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

Regulation of Liver Glucose and Lipid Metabolism by Transcriptional Factors and Coactivators

Emerging role of IRE1α in vascular diseases

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