<i>FNDC5</i> polymorphism influences the association between sarcopenia and liver fibrosis in adults with biopsy-proven non-alcoholic fatty liver disease

Gao, Feng; Zheng, Kenneth I.; Zhu, Pei-Wu; Li, Yangyang; Ma, Hong-Lei; Li, Gang; Tang, Liang‐Jie; Liu, Wen‐Yue; Pan, Xiaoyan; Targher, Giovanni; Byrne, Christopher D.; Chen, Yongping; Zheng, Ming‐Hua

doi:10.1017/s0007114520004559

Cited by 12 publications

(11 citation statements)

References 37 publications

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“…We found upregulation of genes involved in bile acid synthesis and carnitine synthesis including cholesterol 7 alpha hydroxylase (CYP7A1) and gamma-butyrobetaine hydroxylase 1 (BBOX1), respectively[ 26 - 28 ]. Notably, we saw upregulation of the novel myokine fibronectin type 3 (FNDC5), which correlated with NAFLD severity and extracellular matrix deposition[ 29 ]. Interestingly, we found upregulation of the lamin-associated gene muscular LMNA interacting protein.…”

Section: Resultsmentioning

confidence: 99%

Transcriptome changes in stages of non-alcoholic fatty liver disease

Aljabban¹,

Rohr²,

Syed³

et al. 2022

WJH

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BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a ‘multiple hit’ hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury. AIM To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis. METHODS We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies. RESULTS Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset. CONCLUSION In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.

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Section: Resultsmentioning

confidence: 99%

Transcriptome changes in stages of non-alcoholic fatty liver disease

Aljabban¹,

Rohr²,

Syed³

et al. 2022

WJH

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“…Low levels of circulating irisin have been reported in individuals with loss of muscle strength and atrophy (Chang et al, 2017). It is important to highlight that recent findings have shown that there is a significant interaction between the FNDC5 genotype and the state of sarcopenia in patients with non-alcoholic liver disease (Gao et al, 2020). Thus, irisin is a potential biomarker for muscle dysfunction and can help in the early diagnosis of sarcopenia and muscle changes associated with age (Chang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Dietary Intervention, When Not Associated With Exercise, Upregulates Irisin/FNDC5 While Reducing Visceral Adiposity Markers in Obese Rats

et al. 2021

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Obesity is an epidemic disease and the expansion of adipose tissue, especially visceral fat, promotes the secretion of factors that lead to comorbidities such as diabetes and cardiovascular diseases. Thus, diet and exercise have been proposed as an intervention to reverse these complications. An adipocytokine, known as irisin, mediates the beneficial effects of exercise. It has been proposed as a therapeutic potential in controlling obesity. In view of the above, this paper attempts to determine the modulation of irisin, visceral adiposity and biochemical markers in response to dietary intervention and aerobic exercise. To do this, 52 diet-induced obese male Wistar rats were divided into the following four groups: high-fat diet and exercise (HFD-Ex); HFD-Sedentary (HFD-Sed); chow-diet and exercise (CD-Exercise); and CD-Sed. The exercise-trained group performed a treadmill protocol for 60 min/day, 3 days/week for 8 weeks. Body mass (BM), body fat (BF), fat mass (FM), and fat-free mass (FFM) were analyzed. Mesenteric (MES), epididymal (EPI), and retroperitoneal (RET) adipose tissue was collected and histological analysis was performed. Biochemical irisin, triglycerides, glucose, insulin and inflammatory markers were determined and, FNDC5 protein expression was analyzed. In this study, the diet was the most important factor in reducing visceral adiposity in the short and long term. Exercise was an important factor in preserving muscle mass and reducing visceral depots after a long term. Moreover, the combination of diet and exercise can enhance these effects. Diet and exercise exclusively were the factors capable of increasing the values of irisin/FNDC5, however it did not bring cumulative effects of both interventions. Prescriptions to enhance the obesity treatments should involve reducing visceral adiposity by reducing the fat content in the diet associated with aerobic exercise.

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“…Subsequently, GO annotation and REACTOME pathway enrichment analysis were performed to elucidate the significance of these identified altered expressed genes. Pathways and GO annotation include signal transduction [ [108], SOCS1 [109], GPR183 [110], AKR1B10 [111], TREM2 [112], SCD (stearoyl-CoA desaturase) [113], GCK (glucokinase) [114], LPL (lipoprotein lipase) [115], ANGPTL8 [116], UGT1A1 [117], IL2RA [118], CDKN1A [119], GAS6 [120], ACE2 [121], NLRP6 [122], S1PR4 [123], FADS2 [124], FASN (fatty acid synthase) [125], TIMP3 [126], CHI3L1 [127], ADAMTSL2 [128], FNDC5 [129], MMP9 [130] and TMC4 [131] were involved in progression of NAFLD. EGR1 [132], NR4A2 [133], DUSP1 [134], DLK1 [135], SIK1 [136], CCN1 [137], CEBPD (CCAAT enhancer binding protein delta) [138], SOCS2 [139], IRS2 [91], GADD45B [140], CXCL2 [141], ZFAND5 [142], EGR3 [143], PTGS2 [144], KL (klotho) [145], SOCS3 [146], MMP1 [147], CXCR4 [148], THBS1 [149], SLC7A11 [150], FAM83A [151], EGR2 [152], ZFP36…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

Vastrad¹

2021

Preprint

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Non alcoholic fatty liver disease (NAFLD) is the most common metabolic disease in humans, affecting the majority of individuals. In the current investigation, we aim to identify potential key genes linked with NAFLD through bioinformatics analyses of next generation sequencing (NGS) dataset. NGS dataset of GSE135251 from the Gene Expression Omnibus (GEO) database were retrieved. Differentially expressed genes (DEGs) were obtained by DESeq2 package. g:Profiler database was further used to identify the potential gene ontology (GO) and REACTOME pathways. Protein-protein interaction (PPI) network was constructed using the Hippie interactome database. miRNet and NetworkAnalyst databases were used to establish a miRNA-hub gene regulatory network and TF-hub gene regulatory network for the hub genes. Hub genes were verified based on receiver operating characteristic curve (ROC) analysis. Totally, 951 DEGs were identified including 476 up regulated genes and 475 down regulated genes screened in NAFLD and normal control. GO showed that DEGs were significantly enhanced for signaling and regulation of biological quality. REACTOME pathway analysis revealed that DEGs were enriched in signaling by interleukins and extracellular matrix organization. ESR2, JUN, PTN, PTGER3, CEBPB, IKBKG, HSPA8, SFN, CDKN1A and E2F1 were indicated as hub genes from PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Furthermore, ROC analysis revealed that ESR2, JUN, PTN, PTGER3, CEBPB, IKBKG, HSPA8, SFN, CDKN1A and E2F1 might serve as diagnostic biomarkers in NAFLD. The current investigation provided insights into the molecular mechanism of NAFLD that might be useful in further investigations.

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FNDC5 polymorphism influences the association between sarcopenia and liver fibrosis in adults with biopsy-proven non-alcoholic fatty liver disease

Cited by 12 publications

References 37 publications

Transcriptome changes in stages of non-alcoholic fatty liver disease

Transcriptome changes in stages of non-alcoholic fatty liver disease

Dietary Intervention, When Not Associated With Exercise, Upregulates Irisin/FNDC5 While Reducing Visceral Adiposity Markers in Obese Rats

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

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