The endothelial function biomarker soluble E-selectin is associated with nonalcoholic fatty liver disease

Nynke Simons; Mitchell Bijnen; Kristiaan A M Wouters; Sander S Rensen; Joline W J Beulens; Marleen M J van Greevenbroek; Leen M 't Hart; Jan Willem M Greve; Carla J H van der Kallen; Nicolaas C Schaper; Casper G Schalkwijk; Coen D A Stehouwer; Martijn C G J Brouwers

doi:10.1111/liv.14384

The endothelial function biomarker soluble E-selectin is associated with nonalcoholic fatty liver disease

Liver Int. 2020 May;40(5):1079-1088. doi: 10.1111/liv.14384. Epub 2020 Jan 29.

Authors

Nynke Simons^{1

2

3}, Mitchell Bijnen^{2

3}, Kristiaan A M Wouters^{2

3}, Sander S Rensen^{4

5}, Joline W J Beulens^{6

7}, Marleen M J van Greevenbroek^{2

3}, Leen M 't Hart^{6

8

9}, Jan Willem M Greve^{4

5

10}, Carla J H van der Kallen^{2

3}, Nicolaas C Schaper^{1

3

11}, Casper G Schalkwijk^{2

3}, Coen D A Stehouwer^{2

3

12}, Martijn C G J Brouwers^{1

2

3}

Affiliations

¹ Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.
² Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
³ CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
⁴ Department of General Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.
⁵ NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
⁶ Department of Epidemiology and Biostatistics, Amsterdam University Medical Center - location VUmc, the Amsterdam Public Health Research Institute Amsterdam, Amsterdam, The Netherlands.
⁷ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸ Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
⁹ Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰ Department of General Surgery, Zuyderland Medical Center, Heerlen, The Netherlands.
¹¹ CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands.
¹² Department of Internal Medicine, Division of General Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.

Abstract

Background & aims: Plasma soluble E-selectin (sE-selectin) is a frequently used biomarker of systemic endothelial dysfunction. The present study explored the relationship between nonalcoholic fatty liver disease (NAFLD) and plasma sE-selectin levels.

Methods: Expression of E-selectin in liver, visceral adipose tissue (VAT) and muscle was studied in relation to plasma sE-selectin in severely obese individuals (n = 74). The course of hepatic E-selectin expression in relation to hepatic steatosis and inflammation was examined in C57BL/6J LDLR^-/- mice on a Western-type diet. The relationship between biomarkers of NAFLD, that is, plasma aminotransferase (ALT) and NAFLD susceptibility genes (rs738409 [PNPLA3] and rs1260326 [GCKR]), and plasma sE-selectin was studied in the combined CODAM (n = 571) and Hoorn (n = 694) studies.

Results: E-selectin expression in liver, not VAT or muscle, was associated with plasma sE-selectin in severely obese individuals (β = 0.26; 95% CI: 0.05-0.47). NAFLD severity was associated with hepatic E-selectin expression (P = .02) and plasma sE-selectin (P = .003). LDLR^-/- mice on a Western-type diet displayed increased hepatic E-selectin expression that followed the same course as hepatic inflammation, but not steatosis. In the CODAM study, plasma ALT was associated with plasma sE-selectin, independent of potential confounders (β = 0.25; 95% CI: 0.16-0.34). Both rs738409 and rs1260326 were associated with higher plasma sE-selectin in the combined CODAM and Hoorn studies (P = .01 and P = .004 respectively).

Conclusions: NAFLD and related markers are associated with higher expression of hepatic E-selectin and higher levels of plasma sE-selectin. Further studies are required to investigate the role of E-selectin in the pathogenesis of NAFLD and the applicability of sE-selectin as a plasma biomarker of NAFLD/NASH.

Keywords: E-selectin; endothelium; genetic epidemiology; nonalcoholic fatty liver disease; translational research.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Biomarkers
Cadherins / genetics*
Lipase
Liver
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / genetics
Phospholipases A2, Calcium-Independent

Substances

Adaptor Proteins, Signal Transducing
Biomarkers
Cadherins
Cdh1 protein, mouse
Gckr protein, mouse
Lipase
PNPLA3 protein, mouse
Phospholipases A2, Calcium-Independent