PhD ceremony Ms. M. Aparicio Vergara: TNF signaling in nonalcoholic fatty liver disease

PhD ceremony: Ms. M. Aparicio Vergara, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: TNF signaling in nonalcoholic fatty liver disease

Promotor(s): prof. M.H. Hofker

Faculty: Medical Sciences

The dramatic increase in obesity has been paralleled to a rise in its adverse health outcomes, including type 2 diabetes, insulin resistance, heart disease, cancer and fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver-related disorders, ranging from a benign and reversible state of fat accumulation in the hepatocytes (hepatic steatosis) to hepatic inflammation (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although the mechanisms underlying the pathogenesis of NAFLD are not fully understood, a central role for pro-inflammatory cytokines and their receptors in its development has been elucidated. Indeed, it is generally accepted that Tumor Necrosis Factor alpha (TNFα) and its receptor TNFR1 are involved in the development of NAFLD and insulin resistance. In this thesis, we aimed to establish the exact role of TNFR1 signaling in the pathophysiologies of NAFLD and insulin resistance. We used young and aged knock-in mice expressing a mutated TNFR1 ectodomain ( p55^Δns ), incapable of shedding and dampen the inflammatory response. The studies described in this thesis show that TNF-signaling via TNFR1 plays a pivotal role in the pathogenesis of NASH. Moreover, in contrast to the alleged association between inflammation and insulin resistance, we report dissociation between the development of macrophage-associated inflammation and the onset of insulin resistance in a mouse model with persistent TNFα signaling, thereby breaking an important dogma.