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

Aysim Gunes, Clémence 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

Journal: Diabetes 2023;72(12):1820-1834

PMID: 37757741

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Abstract

UNLABELLED

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 line with 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.

ARTICLE HIGHLIGHTS

IL-6 and its circulating coreceptor sgp130 are increased in people with fatty liver disease and steatohepatitis. High glucose and lipids stimulated IL-6 and sgp130 secretion from hepatic stellate cells. sgp130 levels correlated with HbA1c, and diabetes concurrent with steatohepatitis further increased circulating levels of all IL-6 trans-signaling mediators. Circulating sgp130 positively correlated with liver stiffness and hepatic fibrosis. Metabolic stress to liver associated with fatty liver disease might shift the balance of IL-6 classical versus trans-signaling, promoting liver fibrosis that is accelerated by diabetes.

Address: Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada.; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.; Montreal Diabetes Research Centre, Montreal, Quebec, Canada.; Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada.; Programmes de biologie moléculaire, Faculté de médecine, Université de Montréal, Montreal, Quebec, Canada.; Département de radiologie, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada.; Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada.; Liver Unit, Centre hospitalier de l'Université de Montréal (CHUM), Département de médecine, Université de Montréal, Montreal, Quebec, Canada.; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.; Département de chirurgie, Faculté de médecine, Université Laval, Quebec City, Quebec, Canada.; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.; Département de biologie moléculaire, biochimie médicale et pathologie, Université Laval, Quebec City, Quebec, Canada.; Gastroenterology and Hepatology, Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.; Département de pathologie et biologie cellulaire, Université de Montréal, Montreal, Quebec, Canada.; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.; Département de nutrition, Université de Montréal, Montreal, Quebec, Canada.; Labo HépatoNeuro, Centre de recherche du CHUM, Montreal, Quebec, Canada.; Montreal Diabetes Research Centre, Montreal, Quebec, Canada.; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.; Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada.; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.; Montreal Diabetes Research Centre, Montreal, Quebec, Canada.; Département de nutrition, Université de Montréal, Montreal, Quebec, Canada.; Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada.; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.; Montreal Diabetes Research Centre, Montreal, Quebec, Canada.; Programmes de biologie moléculaire, Faculté de médecine, Université de Montréal, Montreal, Quebec, Canada.

DOI: 10.2337/db23-0171

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MeSH Terms: Humans, Cytokine Receptor gp130, Receptors, Interleukin-6, Interleukin-6, Non-alcoholic Fatty Liver Disease, Glycated Hemoglobin, Diabetes Mellitus, Fibrosis, Glucose