Ectodysplasin A Is Increased in Non-Alcoholic Fatty Liver Disease, But Is Not Associated With Type 2 Diabetes

Abstract

Ectodysplasin A (EDA) was recently identified as a liver-secreted protein that is increased in the liver and plasma of obese mice and causes skeletal muscle insulin resistance. We assessed if liver and plasma EDA is associated with worsening non-alcoholic fatty liver disease (NAFLD) in obese patients and evaluated plasma EDA as a biomarker for NAFLD. Using a cross-sectional study in a public hospital, patients with a body mass index >30 kg/m2 (n=152) underwent liver biopsy for histopathology assessment and fasting liver EDA mRNA. Fasting plasma EDA levels were also assessed. Non-alcoholic fatty liver (NAFL) was defined as >5% hepatic steatosis and nonalcoholic steatohepatitis (NASH) as NAFLD activity score ≥3. Patients were divided into three groups: No NAFLD (n=45); NAFL (n=65); and NASH (n=42). Liver EDA mRNA was increased in patients with NASH compared with No NAFLD (P=0.05), but not NAFL. Plasma EDA levels were increased in NAFL and NASH compared with No NAFLD (P=0.03). Plasma EDA was related to worsening steatosis (P=0.02) and fibrosis (P=0.04), but not inflammation or hepatocellular ballooning. ROC analysis indicates that plasma EDA is not a reliable biomarker for NAFL or NASH. Plasma EDA was not increased in patients with type 2 diabetes and did not correlate with insulin resistance. Together, we show that plasma EDA is increased in NAFL and NASH, is related to worsening steatosis and fibrosis but is not a reliable biomarker for NASH. Circulating EDA is not associated with insulin resistance in human obesity.Clinical Trial Registrationhttps://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000875505, identifier ACTRN12615000875505.

Increased Circulating Levels of Ectodysplasin A in Newly Diagnosed Type 2 Diabetic Patients

“…Nevertheless, our findings did not accord with the recent study performed by Bayliss et al. ( 21 ) in which serum EDA was not elevated in patients with T2DM and had nothing to do with FPG, HbA1c, and HOMA-IR in obese individuals. The differences may be caused by different sample sizes, populations, reagents, and disease duration of T2DM.…”

Ectodysplasin A/Ectodysplasin A Receptor System and Their Roles in Multiple Diseases

“…Significant and positive associations were found between EDA-A2 levels and BMI, waist-to-hip ratio (WHR), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR), a series of anthropometric parameters and some parameters of glucose metabolism and insulin function. In addition, Bayliss et al (2021) found that liver EDA mRNA levels were higher in NASH group than in those without NAFLD; however, no difference was detected between NAFL and non-NAFLD patients. Compared with patients without NAFLD, plasma EDA concentrations were increased in both the NAFL and NASH groups and were positively correlated with the degree of steatosis.…”

“…Several studies have shown that EDA, a recently identified hepatokine, is mainly expressed in the liver and can be secreted into the circulatory system to participate in energy and glycolipid metabolism ( Awazawa et al, 2017 ; Yang et al, 2019 ; Bayliss et al, 2021 ). Awazawa et al (2017) found that the expression levels of EDA, corresponding to miR-676, were higher in the livers of db/db mice than in those of control mice.…”

“…Additionally, the serum EDA-A2 level is dependent on T2DM, body mass index (BMI), and obesity ( Yang et al, 2019 ). In patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), the plasma EDA content is high and is associated with deteriorating steatosis and fibrosis ( Bayliss et al, 2021 ). In addition to the effects on HED and metabolic disorders, several studies have reported that EDA and its receptors are involved in cancer pathogenesis by regulating the apoptosis, proliferation, differentiation, and migration of cancer cells ( Soraas and Stebbing, 2018 ; Vial et al, 2019 ; Li et al, 2020 ; Wang et al, 2020 ); however, this possibility remains controversial.…”

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

“…Pathways include hemostasis [57], neutrophil degranulation [58], immune system [59] and cytokine signaling in immune system [60] are responsible for progression of GDM. LGR5 [61], GREM1 [62], GLRA3 [63], NEUROD4 [64], CYP2J2 [65], KCNH6 [66], LBP (lipopolysaccharide binding protein) [67], CXCL14 [68], RGN (regucalcin) [69], NPY2R [70], SERPINB13 [71], WNT5A [72], EDA (ectodysplasin A) [73], HSD11B2 [74], ACVR1C [75], NEUROD1 [76], SLIT2 [77], PPARGC1A [78], IGF1 [79], OSR1 [80], CYP46A1 [81], TLR3 [82], BMP7 [83], SELP (selectin P) [84], HLA-A [85], NOTCH2 [86], LRP1 [87], CLU (clusterin) [88], FCN1 [89], CDKN1A [90], SMAD3 [91], HLA-E [92], PTPRC (protein tyrosine phosphatase receptor type C) [93], MYH9 [94], JAK3 [95], IL6R [96], TIMP1 [97], DOCK8 [98], TNFRSF1B [99], ITGAL (integrin subunit alpha L) [100], CD47 [101], RARA (retinoic acid receptor alpha) [102], DGKD (diacylglycerol kinase delta) [103], PLEK (pleckstrin) [104], PREX1 [105], BSCL2 [106], PANX1 [107], IRF7 [108], NOTCH1 [109], STIM1 [110], TRIM13 [111], LRBA (LPS responsive beige-like anchor protein) [112], CXCR4 [113], MDM4 [114], MYO9B [115] and PDE5A [116] were revealed to be expressed in diabetes mellitus, but these genes might be novel targets for GDM. SIX1 [117], GREM1 [118], GHRHR (growth hormone releasing hormone receptor) [119], GPR37L1 [120], CYP2J2 [121], AQP4 [122], ROS1 [123], LBP (lipopolysaccharide binding protein) [124], SGCD (sarcoglycan delta) [125], CXCL14 [126], RGN...…”