IL-6 trans-signaling promotes steatosis and cardiomegaly in metabolic-associated steatohepatitis with cardiomyopathy

Metabolic-associated steatohepatitis (MASH) is multisystem disease. Genes, drugs, high carbohydrate, fat and/or protein diets are suspected contributors to disease. MASH-associated liver failure is one of the most common causes of liver transplantation in many parts of the world, while most deaths are due to cardiovascular disease (MASH-CM). Despite strong linkages between MASH and increased risk of cardiovascular disease, mechanistic connections between MASH and MASH-CM have not been completely established in key areas such as hepatitis, steatosis and cardiomegaly. IL-6-induced inflammation is a hallmark of MASH and a driver of cardiovascular disease. IL-6 signaling utilizes two mechanisms: IL-6 binds to the signal transducing subunit gp130 either with the soluble IL-6 receptor (sIL-6R, trans) or in complex with the membrane-bound receptor (classical). IL-6 classical signaling is required for hepatic homeostasis. In trans-signaling, sIL-6R is released by ADAM17 from cells expressing membrane-bound IL-6 receptor (IL-6R). We hypothesize that IL-6 trans-signaling regulates hepatitis, steatosis and cardiomegaly in MASH and MASH-CM. We tested our hypothesis utilizing a drug-induced model in IL-33 deficient mice, where male mice reliably develop MASH with MASH-CM when compared to similarly treated female mice 15 weeks following immunization on days 0 and 7 with a cytochrome p450 2E1 epitope emulsified in complete Freund’s adjuvant. Selective IL-6 trans-signaling blockade was accomplished in male mice utilizing sgp130Fc. Hepatic histological steatosis and inflammation, body weight and heart size (heart weight/tibia length ratios) ± sgp130Fc, as well as hepatic and cardiac IL-6, IL-6R and ADAM17 levels by ELISA without sgp130Fc treatment were measured. Data were analyzed by Mann-Whitney U. In male immunized mice, steatosis (2.0±0.9 vs 0.0±0.0 and 0.0±0.0). and heart size (0.011±0.001 vs 0.008±0.001 and 0.009±0.001) were increased when compared to immunized females (p<0.001, p<0.05), and un-immunized males (p<0.001, p<0.05), while inflammation was similar between sexes, but increased from un-immunized males (2.7±1.9 vs 0.0±0.0, p<0.001) and un-immunized females (2.9±0.9 vs 0.8±0.0, p<0.001), as previously described. Hepatic and cardiac IL-6 and IL-6Ra were reduced (p<0.001) while cardiac ADAM17 (p<0.05) was increased in immunized males when compared to females. Hepatic ADAM17 and cardiac IL-6 were not significantly different following immunizations. Sgp130Fc reduced hepatic steatosis (2.0±0.9 vs 0.4±0.5, p<0.01) and heart size (0.011±0.001 vs 0.009±0.001, p<0.05) but not inflammation in males. Heart and body weights were reduced in sgp130Fc-treated males (p=NS). Our results strongly suggest critical, mechanistic roles for IL-6 trans-signaling in MASH and MASH-CM via reduction in steatosis and heart size in males. We are determining the molecular and functional significance of these findings to ascertain translation for disease mitigation. Research start up funding This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.