IL-6 trans-signaling is increased in diabetes, impacted by glucolipotoxicity and associated with liver stiffness and fibrosis in fatty liver disease

Many people living with diabetes also have non-alcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating soluble receptors (trans-signaling). We investigated whether secretion of IL-6 trans-signaling co-receptors are altered in NAFLD by diabetes, and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated using human hepatocyte, stellate and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed NASH and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and 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 co-receptors. 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 the 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.