Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice

Abstract

BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis (NASH) is the second leading indication for liver transplantation. To date, only moderately effective pharmacotherapies exist to treat NASH. Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies. The inflammatory cytokine tumor necrosis factor alpha (TNF-α) is important for the progression of liver disease. TNF signaling via TNF receptor 1 (TNFR1) has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models. AIM To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH. METHODS NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes (TNFR1 ΔHEP ) and their wild-type littermates (TNFR1 fl/fl ). Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding. After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight, liver steatosis, liver fibrosis and markers of liver inflammation. RESULTS Obesity, liver injury, inflammation, steatosis and fibrosis was not different between TNFR1 ΔHEP and TNFR1 fl/fl mice. However, Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance. CONCLUSION Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH. However, improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis.

The TNFR1 Antagonist Atrosimab Is Therapeutic in Mouse Models of Acute and Chronic Inflammation

“…Our observation that Atrosimab reduces liver injury, steatosis and fibrosis is of clinical relevance since NASH is histologically characterized by the presence of liver steatosis and evidence of liver injury which can result in the development of liver fibrosis/cirrhosis ( 39 ). Our results together with evidence from the literature that TNFR1 contributes to fibrotic liver injury ( 18 ), insulin resistance ( 40 ) and hepatocellular carcinoma formation in NAFLD ( 41 , 42 ) indicate that TNFR1 is a promising novel drug target for NAFLD and highlight the potential of Atrosimab as a novel therapeutic to treat NAFLD. Notably, we determined a shorter half-life of Atrosimab compared to the full IgG Atrosab.…”

Overview of Cellular and Soluble Mediators in Systemic Inflammation Associated with Non-Alcoholic Fatty Liver Disease

“…Hence, it could be tempting to suggest that the TNFα/TNFR1 axis plays a role in the progression of NAFL toward NASH. However, though some beneficial effects on glucose homeostasis were detected in a TNFR1-deficient murine model of diet-induced NASH, no hepatic improvement was observed by Bluemel et al [119]. It is worthy of mention that TNFR1 had only been knocked-out in hepatocytes, which could have been a limitation of this research.…”

Apoptotic cell death in disease—Current understanding of the NCCD 2023

“…Moreover, Tnf deletion [ 785 , 786 ], whole-body deletion of Tnfrsf1a (encoding TNF-R1) alone or in combination with the gene encoding TNF-R2 [ 787 , 788 ] as well as inhibition of TNF [ 789 – 791 ] or TNF-R1 [ 792 ] significantly reduced hepatic steatosis, fibrosis, damage, and metabolic alterations in several diet-induced or genetic models of non-alcoholic fatty liver disease (NAFLD). In apparent contrast with these findings, the hepatocyte-specific deletion of Tnfrsf1a failed to protect mice from diet-driven NASH [ 793 ]. Moreover, Tnfrsf1a deletion accelerated the progression of steatosis to steatohepatitis in mice on a HFD [ 794 ].…”