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. 2021 Mar 4:12:642432.
doi: 10.3389/fendo.2021.642432. eCollection 2021.

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

Jacqueline Bayliss  1 , Geraldine J Ooi  2 , William De Nardo  1 , Yazmin Johari Halim Shah  2 , Magdalene K Montgomery  1 , Catriona McLean  3 , William Kemp  4 , Stuart K Roberts  4 , Wendy A Brown  2 , Paul R Burton  2 , Matthew J Watt  1
Affiliations

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

Jacqueline Bayliss et al. Front Endocrinol (Lausanne). .

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 registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000875505, identifier ACTRN12615000875505.

Keywords: ectodysplasin A; hepatokine; insulin resistance; non-alcoholic fatty liver disease; type 2 diabetes (T2DM).

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Conflict of interest statement

MW has received consultancy fees from Gilead Science, Inc. WB has received grants from Johnson and Johnson, Medtronic, GORE, Applied Medical, and Novo Nordisk, and personal fees from GORE, Novo Nordisk, and Merck Sharpe and Dohme for lectures and advisory boards. All were outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Liver EDA mRNA and NAFLD progression. Hepatic EDA expression by (A) patient group, (B) steatosis grade, (C) lobular inflammation score, (D) hepatocellular ballooning score and (E) fibrosis score. Shown are median and 95% confidence interval. Data were analyzed by Kruskal-Wallis test and Dunn’s multiple comparisons test. Adjoining lines indicate P<0.05.
Figure 2
Figure 2
Plasma EDA and NAFLD progression. Plasma EDA levels by (A) patient group, (B) steatosis grade, (C) lobular inflammation score, (D) hepatocellular ballooning score and (E) fibrosis score. Shown are median and 95% confidence interval. Data were analyzed by Kruskal-Wallis test and Dunn’s multiple comparisons test. Adjoining lines indicate P<0.05. (F) Relationship between liver EDA mRNA and plasma EDA.
Figure 3
Figure 3
Receiver operating characteristic (ROC) curve for the prediction of NAFL and NASH. The diagnostic accuracy of clinical markers with and without the addition of EDA was calculated for (A) NAFL, (B) NASH, and (C) NAFLD. Thicker lines represent statistically significant models with P<0.05.
Figure 4
Figure 4
Relationship between plasma EDA, type 2 diabetes and insulin resistance. (A) Plasma EDA in patients without NAFLD or type 2 diabetes, with NAFLD and without type 2 diabetes and with both NAFLD and type 2 diabetes. Data were analyzed by Kruskal-Wallis test and Dunn’s multiple comparisons test. Adjoining lines indicate P<0.05. (B–D) Relationship between plasma EDA and (B) HOMA-IR (insulin resistance), (C) fasting blood glucose, and (D) HbA1c.
Figure 5
Figure 5
EDA gene expression in various tissues. EDA tissue gene expression (shown as TPM—transcripts per million) adapted from GTEx (based on ENSG00000158813), showing that the liver is the tissue with the 6th highest EDA expression compared to 54 tissues examined. Box plots are shown as median and 25th/75th percentile. Data Source: GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2).
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References

    1. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc (2011) 9(6):524–30.e1; quiz e60. 10.1016/j.cgh.2011.03.020 - DOI - PubMed
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatol (Baltimore Md) (2016) 64(1):73–84. 10.1002/hep.28431 - DOI - PubMed
    1. Ooi GJ, Burton PR, Bayliss J, Raajendiran A, Earnest A, Laurie C, et al. Effect of Body Mass Index, Metabolic Health and Adipose Tissue Inflammation on the Severity of Non-alcoholic Fatty Liver Disease in Bariatric Surgical Patients: a Prospective Study. Obes Surg (2019) 29(1):99–108. 10.1007/s11695-018-3479-2 - DOI - PubMed
    1. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes (2000) 49(5):749–58. 10.2337/diabetes.49.5.749 - DOI - PubMed
    1. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol (2019) 71(4):793–801. 10.1016/j.jhep.2019.06.021 - DOI - PubMed

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