Characterization of the metabolic adaptions in the immune infiltrate during the transition from non alcoholic steatohepatitis (NASH) to hepatocellular carcinomas (HCC)
Gastroenterology
Hematology, Oncology
Immunology
Final Report Abstract
Kupffer cells (KC) are a unique subset of immune cells found exclusively in liver tissue. Recently, KC have been shown to be essential for preventing the exaggerated inflammatory responses in the liver that cause several liver diseases. Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory response triggered by malnutrition that leads to liver cancer in the long term. KCs disappear in the NASH liver at a very early stage of disease progression. Using a transgenic mouse model in which KCs are protected from programmed cell death, we found that protecting KCs attenuates the development of NASH. In particular, the number of a specific KC subpopulation, called KC2, was increased in the transgenic KC-protective animal model. The KC2 inherited higher levels of oxidized lipids than other KCs. These oxidized lipids can induce ferroptosis, a specific type of cell death. The protein Gpx4 is known to be an important modulator of ferroptosis. Therefore, we studied NASH in a specific transgenic model where Gpx4 was specifically missing in KC. Interestingly, mice lacking Gpx4 in KC didn't show differences in the number of KC or in the severity of NASH. Another distinctive feature of KC2 was the high expression of the fatty acid transporter CD36, which regulates cellular metabolism through the uptake of fatty acids into the cell. Inhibition of CD36-mediated fatty acid uptake by treatment with a specific antibody protected against NASH-induced liver injury as measured by serum alanine transaminase (ALT). Interestingly, this did not affect the loss of KC or the histologic tissue integrity of the liver. Further studies are needed to elucidate the interplay between the protective role of different KC subpopulations, their fate during NASH development and CD36-mediated fatty acid uptake. This would pave the way for efficient pharmacological interventions at the onset of NASH as well as modulation of the long-term risk of HCC formation.
