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1.
Medicine (Baltimore) ; 102(23): e33912, 2023 Jun 09.
Article in English | MEDLINE | ID: covidwho-20234985

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for severe COVID-19, but the mechanism remains unknown. This study used bioinformatics to help define the relationship between these diseases. The GSE147507 (COVID-19), GSE126848 (NAFLD), and GSE63067 (NAFLD-2) datasets were screened using the Gene Expression Omnibus. Common differentially expressed genes were then identified using a Venn diagram. Gene ontology analysis and KEGG pathway enrichment were performed on the differentially expressed genes. A protein-protein interaction network was also constructed using the STRING platform, and key genes were identified using the Cytoscape plugin. GES63067 was selected for validation of the results. Analysis of ferroptosis gene expression during the development of the 2 diseases and prediction of their upstream miRNAs and lncRNAs. In addition, transcription factors (TFs) and miRNAs related to key genes were identified. Effective drugs that act on target genes were found in the DSigDB. The GSE147507 and GSE126848 datasets were crossed to obtain 28 co-regulated genes, 22 gene ontology terms, 3 KEGG pathways, and 10 key genes. NAFLD may affect COVID-19 progression through immune function and inflammatory signaling pathways. CYBB was predicted to be a differential ferroptosis gene associated with 2 diseases, and the CYBB-hsa-miR-196a/b-5p-TUG1 regulatory axis was identified. TF-gene interactions and TF-miRNA coregulatory network were constructed successfully. A total of 10 drugs, (such as Eckol, sulfinpyrazone, and phenylbutazone) were considered as target drugs for Patients with COVID-19 and NAFLD. This study identified key gene and defined molecular mechanisms associated with the progression of COVID-19 and NAFLD. COVID-19 and NAFLD progression may regulate ferroptosis through the CYBB-hsa-miR-196a/b-5p-TUG1 axis. This study provides additional drug options for the treatment of COVID-19 combined with NAFLD disease.


Subject(s)
COVID-19 , MicroRNAs , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Systems Biology , Gene Expression Profiling/methods , COVID-19/genetics , MicroRNAs/genetics , Computational Biology/methods , Gene Regulatory Networks
2.
Int J Mol Sci ; 24(2)2023 Jan 10.
Article in English | MEDLINE | ID: covidwho-2216329

ABSTRACT

The autophagy gene ATG7 has been shown to be essential for the induction of autophagy, a process that used to be suppressed in nonalcoholic fatty liver disease (NAFLD). However, the specific role of ATG7 in NAFLD remains unclear. The aim of this study was to analyze hepatic ATG7 mRNA and ATG7 protein expression regarding obesity-associated NAFLD. Patients included women classified into normal weight (NW, n = 6) and morbid obesity (MO, n = 72). The second group was subclassified into normal liver (NL, n = 11), simple steatosis (SS, n= 29), and nonalcoholic steatohepatitis (NASH, n = 32). mRNA expression was analyzed by RT-qPCR and protein expression was evaluated by Western blotting. Our results showed that NASH patients presented higher ATG7 mRNA and ATG7 protein levels. ATG7 mRNA expression was increased in NASH compared with SS, while ATG7 protein abundance was enhanced in NASH compared with NL. ATG7 mRNA correlated negatively with the expression of some hepatic lipid metabolism-related genes and positively with endocannabinoid receptors, adiponectin hepatic expression, and omentin levels. These results suggest that ATG7-mediated autophagy may play an important role in the pathogenesis of NAFLD, especially in NASH, perhaps playing a possible protective role. However, this is a preliminary study that needs to be further studied.


Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Female , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Autophagy-Related Protein 7/genetics , Autophagy-Related Protein 7/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Liver/metabolism , Obesity/complications , Obesity/genetics , Obesity/metabolism
3.
Eur J Med Res ; 27(1): 251, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2115714

ABSTRACT

BACKGROUND: Patients with non-alcoholic fatty liver disease (NAFLD) may be more susceptible to coronavirus disease 2019 (COVID-19) and even more likely to suffer from severe COVID-19. Whether there is a common molecular pathological basis for COVID-19 and NAFLD remains to be identified. The present study aimed to elucidate the transcriptional alterations shared by COVID-19 and NAFLD and to identify potential compounds targeting both diseases. METHODS: Differentially expressed genes (DEGs) for COVID-19 and NAFLD were extracted from the GSE147507 and GSE89632 datasets, and common DEGs were identified using the Venn diagram. Subsequently, we constructed a protein-protein interaction (PPI) network based on the common DEGs and extracted hub genes. Then, we performed gene ontology (GO) and pathway analysis of common DEGs. In addition, transcription factors (TFs) and miRNAs regulatory networks were constructed, and drug candidates were identified. RESULTS: We identified a total of 62 common DEGs for COVID-19 and NAFLD. The 10 hub genes extracted based on the PPI network were IL6, IL1B, PTGS2, JUN, FOS, ATF3, SOCS3, CSF3, NFKB2, and HBEGF. In addition, we also constructed TFs-DEGs, miRNAs-DEGs, and protein-drug interaction networks, demonstrating the complex regulatory relationships of common DEGs. CONCLUSION: We successfully extracted 10 hub genes that could be used as novel therapeutic targets for COVID-19 and NAFLD. In addition, based on common DEGs, we propose some potential drugs that may benefit patients with COVID-19 and NAFLD.


Subject(s)
COVID-19 , MicroRNAs , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Gene Regulatory Networks , Systems Biology , Gene Expression Profiling , Computational Biology , COVID-19/genetics , MicroRNAs/genetics
4.
Gene ; 820: 146235, 2022 Apr 30.
Article in English | MEDLINE | ID: covidwho-1778131

ABSTRACT

The relationship of single nucleotide polymorphisms (SNPs) in patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 with outcomes in patients with hepatitis C infection (HCV) is unclear. This study aimed to evaluate the association of PNPLA3, TM6SF2, and MBOAT7 with the baseline fibrosis stage and progression of liver fibrosis after HCV eradication with direct antiviral agents (DAAs). A total of 171 patients who received the DAAs at the Peking University First Hospital between June 2015 and June 2020 were included in the retrospective cohort. Transient elastography was used to determine liver stiffness measurements (LSMs) at the baseline, the end of treatment (EOT), 24 weeks after treatment (W24), and the last follow-up (LFU) visit. We used the QIAamp Blood Mini Kit (Qiagen) for whole blood genomic DNA extraction and polymerase chain reaction for PNPLA3, TM6SF2, and MBOAT7 amplification of the target gene. The PNPLA3 rs738409 SNP was associated with the baseline fibrosis stage in multivariate logistic regression analysis adjusted for other factors, and the adjusted odds ratio (OR) for advanced fibrosis (≥F3) at baseline was 2.52 (95% confidence interval[CI] = 1.096-5.794, p = 0.03). The G and GG alleles were predictive of advanced fibrosis (OR = 1.98, 95% CI = 1.021-4.196, p = 0.015; OR = 3.12, 95% CI = 1.572-6.536, p = 0.005). Similarly, the OR of TM6SF2 rs58542926 at baseline was 2.608 (95% CI = 1.081-6.29, p = 0.033). T and TT alleles were predictive of advanced fibrosis (OR = 2.3, 95% CI = 1.005-5.98, p = 0.007; OR = 3.05, 95% CI = 1.32-6.87, p = 0.001). After adjustment, the MBOAT7 rs641738 T plus TT alleles were not independently associated with the baseline fibrosis stage (95% CI = 0.707-2.959, p = 0.312). At the EOT, there were 35 patients and 136 patients in the fibrosis improvement and fibrosis non-improvement group, respectively. Logistic regression analysis showed that the G allele in PNPLA3 rs738409 was associated with fibrosis progression (OR = 2.47, 95% CI = 1.125-5.89, p = 0.003). The GG alleles were predictive of fibrosis progression (OR = 2.95, 95% CI = 1.35-6.35, p = 0.005). Similarly, the ORs of the T and TT alleles in TM6SF2 rs58542926 for fibrosis progression were 1.82 and 2.21, respectively (95% CI = 1.006-5.373, p = 0.045; 95% CI = 1.18-5.75, p = 0.01). At the W24 visit, we found that there was an association between the G allele in PNPLA3 rs738409 and fibrosis progression (OR = 2.218, 95% CI = 1.095-5.631, p = 0.015). Moreover, GG alleles were also predictive for fibrosis progression (OR = 2.558, 95% CI = 1.252-5.15, p = 0.008). Similarly, the OR of T allele and TT alleles in TM6SF2 rs58542926 for fibrosis progression was 2.056 and 2.652 (95% CI = 1.013-5.592, p = 0.038; 95% CI = 1.25-5.956, p = 0.015). For additional affirmation, we surveyed fibrosis progression utilizing the Cox proportional hazards model. G and GG alleles in PNPLA3 rs738409 were associated with an increased risk of progression to advanced fibrosis in multivariate model (hazard ratio [HR]1.566, 95% CI = 1.02-2.575, p = 0.017; and HR2.109, 95% CI = 1.36-3.271, p = 0.001, respectively). Besides, T and TT alleles in TM6SF2 rs58542926 were associated with an increased risk of progression to advanced fibrosis in multivariate model (HR = 1.322, 95% CI = 1.003-1.857, p = 0.045; and HR = 1.855, 95% CI = 1.35-2.765, p = 0.006, respectively). In contrast, rs641738 in MBOAT7 did not show a significant trend in the univariate and multivariate models. The PNPLA3 CG/GG SNP at rs738409 and TM6SF2 CT/TT SNP at rs58542926 were associated with the baseline fibrosis stage and fibrosis progression after HCV eradication with DAAs.


Subject(s)
Acyltransferases/economics , Acyltransferases/genetics , Liver Cirrhosis/genetics , Membrane Proteins/economics , Membrane Proteins/genetics , Phospholipases A2, Calcium-Independent/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Alleles , Disease Progression , Female , Genetic Predisposition to Disease , Hepacivirus , Hepatitis C/complications , Hepatitis C/virology , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/genetics , Prognosis , Retrospective Studies
5.
Clin Gastroenterol Hepatol ; 20(7): 1553-1560.e78, 2022 07.
Article in English | MEDLINE | ID: covidwho-1729615

ABSTRACT

BACKGROUND & AIMS: The coronavirus disease 2019 (COVID-19) pandemic has witnessed more than 4.5 million deaths as of the time of writing. Whether nonalcoholic fatty liver disease (NAFLD) increases the risk for severe COVID-19 remains unclear. We sought to address this question using 2-sample Mendelian randomization (TSMR) analysis approaches in large cohorts. METHODS: We performed large-scale TSMR analyses to examine whether there is a causal relationship between NAFLD, serum alanine aminotransferase, grade of steatosis, NAFLD Activity Score, or fibrosis stage and severe COVID-19. To maximize the power of this analysis, we performed a genome-wide meta-analysis to identify single nucleotide polymorphisms associated with NAFLD. We also examined the impact of 20 major comorbid factors of NAFLD on severe COVID-19. RESULTS: Univariate analysis of the UK Biobank data demonstrated a significant association between NAFLD and severe COVID-19 (odds ratio [OR], 3.06; P = 1.07 × 10-6). However, this association disappeared after demographic and comorbid factors were adjusted (OR, 1.57; P = .09). TSMR study indicated that NAFLD (OR, 0.97; P = .61), alanine aminotransferase level (OR, 1.03; P = .47), grade of steatosis (OR, 1.08; P = .41), NAFLD Activity Score (OR, 1.02; P = .39), and fibrosis stage (OR, 1.01; P = .87) were not associated with severe COVID-19. Among all NAFLD-related comorbid factors, body mass index (OR, 1.73; P = 7.65 × 10-9), waist circumference (OR, 1.76; P = 2.58 × 10-5), and hip circumference (OR, 1.33; P = 7.26 × 10-3) were the only ones demonstrated a causal impact on severe COVID-19. CONCLUSIONS: There is no evidence supporting that NAFLD is a causal risk factor for severe COVID-19. Previous observational associations between NAFLD and COVID-19 are likely attributed to the correlation between NAFLD and obesity.


Subject(s)
COVID-19 , Non-alcoholic Fatty Liver Disease , Alanine Transaminase , Body Mass Index , COVID-19/complications , Fibrosis , Humans , Mendelian Randomization Analysis , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/genetics
6.
Nutrients ; 14(3)2022 Jan 27.
Article in English | MEDLINE | ID: covidwho-1667256

ABSTRACT

The coronavirus disease 2019 (COVID-19) lockdown dramatically changed people's lifestyles. Diet, physical activity, and the PNPLA3 gene are known risk factors for non-alcoholic fatty liver disease (NAFLD). Aim: To evaluate changes in metabolic and hepatic disease in NAFLD patients after the COVID-19 lockdown. Three hundred and fifty seven NAFLD patients were enrolled, all previously instructed to follow a Mediterranean diet (MD). Anthropometric, metabolic, and laboratory data were collected before the COVID-19 lockdown in Italy and 6 months apart, along with ultrasound (US) steatosis grading and information about adherence to MD and physical activity (PA). In 188 patients, PNPLA3 genotyping was performed. After the lockdown, 48% of patients gained weight, while 16% had a worsened steatosis grade. Weight gain was associated with poor adherence to MD (p = 0.005), reduced PA (p = 0.03), and increased prevalence of PNPLA3 GG (p = 0.04). At multivariate analysis (corrected for age, sex, MD, PA, and PNPLA3 GG), only PNPLA3 remained independently associated with weight gain (p = 0.04), which was also associated with worsened glycemia (p = 0.002) and transaminases (p = 0.02). During lockdown, due to a dramatic change in lifestyles, half of our cohort of NAFLD patients gained weight, with a worsening of metabolic and hepatologic features. Interestingly, the PNPLA3 GG genotype nullified the effect of lifestyle and emerged as an independent risk factor for weight gain, opening new perspectives in NAFLD patient care.


Subject(s)
COVID-19 , Non-alcoholic Fatty Liver Disease , Communicable Disease Control , Genotype , Humans , Life Style , Lipase/genetics , Membrane Proteins/genetics , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/genetics , SARS-CoV-2/genetics
7.
J Clin Invest ; 131(6)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1172783

ABSTRACT

Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSECs) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that VCAM-1 mediates monocyte adhesion to LSECs. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein, we report that VCAM-1 was a top upregulated adhesion molecule in the NASH mouse liver transcriptome. Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of LSEC VCAM-1 in murine NASH. Moreover, LSEC VCAM-1 expression was significantly increased in human NASH. LSEC VCAM-1 expression was upregulated by palmitate treatment in vitro and reduced with inhibition of the mitogen-activated protein 3 kinase (MAP3K) mixed lineage kinase 3 (MLK3). Likewise, LSEC VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing Ab or pharmacological inhibition attenuated diet-induced NASH in mice, mainly via reducing the proinflammatory monocyte hepatic population as examined by mass cytometry by time of flight (CyTOF). Moreover, endothelium-specific Vcam1 knockout mice were also protected against NASH. In summary, lipotoxic stress enhances the expression of LSEC VCAM-1, in part, through MLK3 signaling. Inhibition of VCAM-1 was salutary in murine NASH and might serve as a potential therapeutic strategy for human NASH.


Subject(s)
Non-alcoholic Fatty Liver Disease/etiology , Vascular Cell Adhesion Molecule-1/metabolism , Animals , Antibodies, Neutralizing/administration & dosage , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Gene Expression Profiling , Humans , Liver/drug effects , Liver/metabolism , Liver/pathology , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Palmitates/toxicity , RNA, Messenger/genetics , Up-Regulation/drug effects , Vascular Cell Adhesion Molecule-1/antagonists & inhibitors , Vascular Cell Adhesion Molecule-1/genetics
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