1570-P: Myeloid-Specific Inactivation of Basp1 Protects Mice from Diet-Induced NASH through Attenuating NLRP3 Inflammasome Activation

Abstract

Nonalcoholic steatohepatitis (NASH) is characterized by persistent liver injury, inflammation, and fibrosis. Myeloid cells, including macrophages and dendritic cells, play an integral role in host defense, tissue homeostasis, and disease progression. Despite this, how myeloid cells contribute to NASH pathogenesis remains obscure. We previously identified NASH-associated macrophages (NAMs) as a unique population of monocyte-derived macrophages in NASH liver. We observed that hepatic NAMs exhibited abundant expression of Brain acid-soluble protein 1 (Basp1), which was markedly induced in the liver upon diet-induced NASH in mice. We generated myeloid-specific Basp1 knockout (Mye-Basp1 KO) mice to determine its role in NASH pathogenesis. Compared to control, Mye-Basp1 KO mice displayed significantly improved liver injury and fibrosis following NASH diet feeding, as shown by lower plasma ALT/AST levels and reduced Sirius Red staining on liver sections, respectively. Hepatocytes from Mye-Basp1 KO mice contained smaller lipid droplets without altering the total liver triglyceride content. Mechanistically, bone marrow-derived macrophages (BMDMs) lacking Basp1 exhibited diminished response to pro-inflammatory stimuli. Importantly, Basp1-deficient BMDMs displayed impaired activation of the NLRP3 inflammasome and secretion of interleukin-1 beta. Together, we propose that Basp1 is a novel regulator of inflammatory signaling in myeloid cells that plays a critical role in NASH pathogenesis. Disclosure Z.Meng: None. L.Zhou: None. S.Hong: None. T.Liu: None. X.Qiu: None. Z.Chen: None. S.Li: None. K.Inoki: None. J.Lin: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK102456)