A recent study published in GUT, co-directed by Ki-Up Lee of the University of Ulsan, South Korea and José C. Fernandez-Checa, leader of the group "Mitochondrial regulation of cell death" at the IIBB, describes a new role for the Sphingomyelinase synthase 1 (SMS1) in hepatocellular death associated with the inflammation characteristic of nonalcoholic steatohepatitis, called pyroptosis.
Nonalcoholic steatohepatitis (NASH) is an advanced stage of fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma, and one of the most prevalent chronic liver diseases due to its association with obesity and type 2 diabetes. Although the mechanisms responsible for NASH are not fully known, hepatocellular death represents the first step that stimulates processes that lead to the development of NASH.
Using experimental models and samples from patients with NASH, the researchers describe in the present study the induction of SMS1, an enzyme that catalyzes the synthesis of sphingomyelin and the generation of diacylglycerol, a lipid that acts as a second messenger. In vitro and in vivo molecular studies using genetically modified mouse models allow the identification of a new signaling pathway initiated by SMS1 that leads to the activation of PKCd and the NLRC4 inflammasome that ultimately leads to the pyroptotic death of hepatocytes and development of EHNA.
These results represent a significant advance for a better understanding of the mechanisms involved in the development of NASH, and identify SMS1 as a possible new therapeutic target.
Reference of the paper
Eun Hee Koh, Ji Eun Yoon, Myoung Seok Ko, Jaechan Leem, Ji-Young Yun, Chung Hwan Hong, Yun Kyung Cho, Seung Eun Lee, Jung Eun Jang, Ji Yeon Baek, Hyun Ju Yoo, Su Jung Kim, Chang Ohk Sung, Joon Seo Lim, Won-Il Jeong, Sung Hoon Back, In-Jeoung Baek, Sandra Torres, Estel Solsona-Vilarrasa, Laura Conde de la Rosa, Carmen Garcia-Ruiz, Ariel E Feldstein, Jose C Fernandez-Checa, Ki-Up Lee. GUT doi: 10.1136/gutjnl-2020-322509