IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease

Aysim Gunes, Clemence Schmitt, Laurent Bilodeau, Catherine Huet, Assia Belblidia, Cindy Baldwin, Jeanne Marie Giard, Laurent Biertho, Annie Lafortune, Christian Yves Couture, Angela Cheung, Bich N. Nguyen, Eithan Galun, Chantal Bémeur, Marc Bilodeau, Mathieu Laplante, An Tang, May Faraj, Jennifer L. Estall*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Many people living with diabetes also have nonalcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating (trans-signaling) soluble receptors. We investigated whether secretion of IL-6 trans-signaling coreceptors are altered in NAFLD by diabetes and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated with use of human hepatocyte, stellate, and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed steatohepatitis and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and soluble gp130 (sgp130) secretion. In linewith this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling coreceptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes.

Original languageAmerican English
Pages (from-to)1820-1834
Number of pages15
JournalDiabetes
Volume72
Issue number12
DOIs
StatePublished - 1 Dec 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 by the American Diabetes Association.

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