The DEAD‐box helicase DDX3x ameliorates non‐alcoholic fatty liver disease via mTORC1 signalling pathway

Abstract

Background & Aims: The DEAD (Asp-Glu-Ala-Asp)-box helicase family member DDX3x has been proven to involve in hepatic lipid disruption during HCV infection.However, the role of DDX3x in non-alcoholic fatty liver disease (NAFLD), in which lipid homeostasis is severely disrupted, remains unclear. Here, we aimed to illustrate the potential role of DDX3x in NAFLD. Methods: DDX3x protein levels were evaluated in NAFLD patients and NAFLD models via immunohistochemistry or western blotting. In vivo ubiquitin assay was performed to identify the ubiquitination levels of DDX3x in the progression of steatosis. DDX3x protein levels in mice livers were manipulated by adeno-associated virus-containing DDX3x short hairpin RNA or DDX3x overexpression plasmid. Hepatic or serum triglyceride and total cholesterol were evaluated and hepatic steatosis was confirmed by haematoxylin and eosin staining and oil red o staining. Western blotting was performed to identify the underlying mechanisms of DDX3x involving in the progression of NAFLD. Results: DDX3x protein levels were significantly decreased in NAFLD patients and NAFLD models. DDX3x protein might be degraded via ubiquitin-proteasome system in the progression of steatosis. Knockdown of hepatic DDX3x exacerbated HFDinduced hepatic steatosis in mice, while overexpression of hepatic DDX3x alleviated HFD-induced hepatic steatosis in mice. Further explorative experiments revealed that knockdown of DDX3x could lead to the overactivation of mTORC1 signalling pathway which exacerbates NAFLD. Conclusions: DDX3x involved in the progression of NAFLD via affecting the mTORC1 signalling pathway. DDX3x might be a potential target for NAFLD treatment.

Protective and Adverse Roles of DDX3X in Different Cell Types in Nonalcoholic Steatohepatitis Progression

“…A previous study demonstrated that the protein level of DDX3X was decreased in NAFLD patients [ 7 ]. We further analyzed the Gene Expression Omnibus (GEO) database with a larger sample size of 151 NAFLD/NASH patients and 28 controls (GSE213621) and reached the same conclusion that DDX3X expression was decreased in NASH patients (Fig.…”

“…Persistent hepatic cellular metabolic stress and liver inflammatory stimuli are key signatures of NASH, suggesting that DDX3X may play a crucial role in NASH progression. Previous investigation has shown that DDX3X reduces steatosis during NAFLD progression [ 7 ]. However, the role of DDX3X in inflammation is not fully explored, and the function of DDX3X in NASH remains unclear.…”

“…DEAD-box helicase 3, X-linked ( Ddx3x ), a member of the DEAD-box family, has been reported to regulate lipid homeostasis during hepatitis C virus (HCV)-induced steatosis [ 6 ]. Recent study reported that hepatic DDX3X relieved high-fat diet (HFD)-induced lipid metabolism disorder and liver steatosis [ 7 ]. However, mice fed an HFD develop NAFLD but rarely NASH.…”

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

“…Altered expression of CEACAM1 [176], ACSL1 [285], STAT1 [286], TLR4 [287], ABCA1 [288], TLR5 [183], F2RL1 [289], CYP2D6 [290], PDK4 [291], RNF213 [186], JAK2 [292], TLR8 [189], NOTCH2 [293], CENPJ (centromere protein J) [294], FNIP1 [295], TLR2 [296], KIDINS220 [297], DUSP6 [298], CYP1B1 [299], S1PR3 [300], NCOA2 [301], HDAC9 [302], PELI1 [303], EGR1 [304], HIF1A [305], CCR2 [306], IRAK3 [307], KLF3 [308], VEGFA (vascular endothelial growth factor A) [309], OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) [310], PHLPP1 [213], FMR1 [311], IGF2R [312], PRKAR1A [313], WDR11 [314], LDLR (low density lipoprotein receptor) [315], TLR6 [316], SIRT1 [317], ALDH1A1 [318], NOD2 [319], ACSL4 [320], ELOVL6 [321], VCAN (versican) [322], CLIC5 [323], CLCN3 [324], OSBPL11 [162], HELZ2 [325], TET2 [326], KDM6A [327], PHF2 [328], PHGDH (phosphoglycerate dehydrogenase) [329], VEGFB (vascular endothelial growth factor B) [330], ZBTB7A [331], PC (pyruvate carboxylase) [332], CCR7 [333], PRDX2 [334], MAF1 [335], HSPB1 [336], ESF1 [281], LGALS3 [337], OLFM2 [338] and HDAC11 [339] had been confirmed in obesity. CEACAM1 [340], ACSL1 [341], TLR4 [342], ABCA1 [343], TLR5 [344], CYP2D6 [345], JAK2 [346], NOTCH2 [347], DDX3X [348], NCOA4 [349], EGR1 [350], IQGAP2 [351], GCLC (glut...…”

“…Based on the miRNA-hub gene regulatory network and TF-hub gene regulatory network constructed by the online database miRNet and NetworkAnalyst, we identified hub genes, miRNAs and TFs. Previous study showed that DDX3X [348], EGR1 [350] and SREBF1 [539] were associated with non-alcoholic fatty liver disease. EGR1 [84], HIF1A [88], STAT1 [60], hsa-mir-16-5p [540], hsa-mir-532-3p [541], hsa-mir-503-5p [542], SREBF1 [543] and FOXP3 [544] plays a pivotal role in the atherosclerosis.…”