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

Abstract

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.

Conditional deletion of CEACAM1 causes hepatic stellate cell activation

“…B inflammation and MAPK proliferation pathways downstream of EGFR in HSCs (and in hepatocytes at the basal state) and of VEGFR in endothelial cells. Consistent with elevated serum IL-6 levels in patients with advanced hepatic fibrosis[54], loss of Ceacam1 in HSCs caused an elevation in plasma IL-6 levels concurrently wth hepatic fibrosis in LratCre+Cc1 fl/fl mutants. Together, this proposes that inducing CEACAM1 expression could become an effective therapeutic approach to curb fibrosis, not only in early stages of the disease, but also at a later stage.In summary, the current report provides an in vivo demonstration of a novel mechanistic link between a distinct CEACAM1/EGFR/NF-B signaling module in murine HSCs and hepatic fibrosis, an advanced component of MASH.…”

Interleukins: Pathogenesis in Non-Alcoholic Fatty Liver Disease

“…Reduced production of soluble IL-6 receptor (sIL-6R) was linked to monocyte activation. In people with concurrent diabetes, the existence of hyperglycemia and hyperlipidemia may have a direct effect on IL-6 trans-signaling, which may enhance the severity of NAFLD [ 45 ].…”

“…The presence of hyperglycemia and hyperlipidemia may directly impact IL-6 trans-signaling, potentially contributing to the increased severity of NAFLD in individuals with concurrent diabetes [45].…”