Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

Ghorpade, Devram Sampat; Zheng, Ze; Souza, J. C.; Chen, Ke; Bessler, Marc; Bagloo, Melissa; Schrope, Beth; Pestell, Richard G.; Tabas, Ira

doi:10.1016/j.celrep.2022.111015

Cited by 5 publications

(2 citation statements)

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“…However, whether TXA 2 ‐triggered Ca 2+ signalling induces ER stress in hepatocytes and the key proteins that mediate it are unknown. In agreement with our findings, CaMKIIγ is a key signalling molecule involved in the ER stress pathway that causes defective insulin signalling (Ozcan et al, 2022). Therefore, our results innovatively identified that TXA 2 enhanced Ca 2+ /CaMKIIγ to promote ER stress, up‐regulated PERK–Chop pathway and subsequently induced activation of TRB3 to inhibit insulin signalling.…”

Section: Discussionsupporting

confidence: 93%

Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non‐alcoholic fatty liver disease

Dai,

Xu,

Chen

et al. 2023

British J Pharmacology

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Background and PurposeDefective insulin signalling and dysfunction of the endoplasmic reticulum (ER), driven by excessive lipid accumulation in the liver, is a characteristic feature in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). Thromboxane A2 (TXA2), an arachidonic acid metabolite, is significantly elevated in obesity and plays a crucial role in hepatic gluconeogenesis and adipose tissue macrophage polarization. However, the role of liver TXA2/TP receptors in insulin resistance and lipid metabolism is largely unknown.Experimental ApproachTP receptor knockout (TP−/−) mice were generated and fed a high‐fat diet for 16 weeks. Insulin sensitivity, ER stress responses and hepatic lipid accumulation were assessed. Furthermore, we used primary hepatocytes to dissect the mechanisms by which the TXA2/TP receptor axis regulates insulin signalling and hepatocyte lipogenesis.Key ResultsTXA2 was increased in diet‐induced obese mice, and depletion of TP receptors in adult mice improved systemic insulin resistance and hepatic steatosis. Mechanistically, we found that the TXA2/TP receptor axis disrupts insulin signalling by activating the Ca2+/calcium calmodulin‐dependent kinase II γ (CaMKIIγ)–protein kinase RNA‐like endoplasmic reticulum kinase (PERK)–C/EBP homologous protein (Chop)–tribbles‐like protein 3 (TRB3) axis in hepatocytes. In addition, our results revealed that the TXA2/TP receptor axis directly promoted lipogenesis in primary hepatocytes and contributed to Kupffer cell inflammation.Conclusions and ImplicationsThe TXA2/TP receptor axis facilitates insulin resistance through Ca2+/CaMKIIγ to activate PERK–Chop–TRB3 signalling. Inhibition of hepatocyte TP receptors improved hepatic steatosis and inflammation. The TP receptor is a new therapeutic target for NAFLD and metabolic syndrome.

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Section: Discussionsupporting

confidence: 93%

Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non‐alcoholic fatty liver disease

Dai,

Xu,

Chen

et al. 2023

British J Pharmacology

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“…Signaling pathways include GPCR ligand binding [89], neutrophil degranulation [90], immune system [91], metabolism of lipids [92] and signal transduction [93] made great contribution to the development of IPF. MAP3K15 [94], PRTN3 [95], CX3CR1 [96], AGRP (agouti related neuropeptide) [97], MPO (myeloperoxidase) [98], CD5L [99], S100A8 [100], NPR3 [101], VEGFD (vascular endothelial growth factor D) [102], CXCL11 [103], IL1A [104], CBS (cystathionine beta-synthase) [105], WNT7A [106], SCD (stearoyl-CoA desaturase) [107], LRP2 [108], SLC6A4 [109], BDNF (brain derived neurotrophic factor) [110], CXCL10 [111], ANGPTL7 [112], S100A9 [113], NPY1R [114], IL1B [115], GPIHBP1 [116], CYP1B1 [117], CD36 [118], MACROD2 [119], TRIB3 [120], SPX (spexin hormone) [121], PCSK9 [122], GPD1 [123], CDH13 [124], FFAR4 [125], FGF2 [126], FASN (fatty acid synthase) [127], DGAT2 [128], DACH1 [129], PNPLA3 [130], FGF9 [131], SLC7A11 [132], CLIC5 [133], VIP (vasoactive intestinal peptide) [134], SMAD6 [135], BMPR2 [136], APOA1 [137], INSIG1 [138], TLR3 [139], NLRP12 [140], ADRB1 [141], TLR8 [142], GATA3 [143], CCR2 [144], TLR7 [145], CCRL2 [146], BMPER (BMP binding endothelial regulator) [147], CAV1 [148], TFPI (tissue factor pathway inhibitor) [149], FADS1 [150], SUCNR1 [151], CADM2 [152], SLC19A3 [153], SGCG (sarcoglycan gamma) [154], ADH1B [155], NEGR1 [156], HSD17B12 [157], OXTR (oxytocin receptor) [158] and ANKK1 […”

Section: Discussionmentioning

confidence: 99%

Study on potential differentially expressed genes in idiopathic pulmonary fibrosis by bioinformatics and next generation sequencing data analysis

Vastrad,

Vastrad

2023

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with reduced quality of life and earlier mortality, but its pathogenesis and key genes are still unclear. In this investigation, bioinformatics was used to deeply analyze the pathogenesis of IPF and related key genes, so as to investigate the potential molecular pathogenesis of IPF and provide guidance for clinical treatment. Next generation sequencing dataset GSE213001 was obtained from Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) were identified between IPF and normal control group. The DEGs between IPF and normal control group were screened with the DESeq2 package of R language. The Gene Ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed. Using the g:Profiler, the function and pathway enrichment analysis of DEGs were performed. Then, a protein protein interaction (PPI) network was constructed via the Integrated Interactions Database (IID) database. Cytoscape with Network Analyzer was used to identify the hub genes. miRNet and NetworkAnalyst database was used to construct the targeted microRNAs (miRNAs) and transcription factors (TFs) of the hub genes. Finally receiver operating characteristic (ROC) curve analysis was used to validates the hub genes. A total of 958 DEGs were screened out in this study, including 479 up regulated genes and 479 down regulated genes. Most of the DEGs were significantly enriched in response to stimulus, GPCR ligand binding, microtubule-based process and defective GALNT3 causes HFTC. In combination with the results of the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, hub genes including LRRK2, BMI1, EBP, MNDA, KBTBD7, KRT15, OTX1, TEKT4, SPAG8 and EFHC2 were selected. Our findings will contribute to identification of potential biomarkers and novel strategies for the treatment of IPF, and provide a novel strategy for clinical therapy.

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Piperlongumine, a natural alkaloid from Piper longum L. ameliorates metabolic-associated fatty liver disease by antagonizing the thromboxane A2 receptor

Dai,

Chen,

Fang

et al. 2024

Biochemical Pharmacology

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Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

Cited by 5 publications

References 0 publications

Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non‐alcoholic fatty liver disease

Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non‐alcoholic fatty liver disease

Study on potential differentially expressed genes in idiopathic pulmonary fibrosis by bioinformatics and next generation sequencing data analysis

Piperlongumine, a natural alkaloid from Piper longum L. ameliorates metabolic-associated fatty liver disease by antagonizing the thromboxane A2 receptor

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