R+D CSIC

A new therapeutic target for the treatment of nonalcoholic fatty liver disease

Scientists of the IIBB-CSIC discover a new role for sphingomyelin synthase 1 enzyme in nonalcoholic steatohepatitis, an advanced stage of fatty liver disease. The work identifies SMS1 enzyme as a possible new therapeutic target.

A recent study published in GUT magazine, 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 Institut d’Investigacions Biomèdiques de Barcelona (IIBB) of the CSIC, describes a new role for the Sphingomyelinase synthase 1 (SMS1) enzyme 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 carcinoma in the liver, 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 hepatocellular death by piroptosis and development of NASH.

These results represent a significant step forward for a better understanding of the mechanisms involved in the development of NASH, and identify SMS1 enzyme as a possible new therapeutic target.

Reference article:

Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis, Eun Hee Koh et al.. GUT doi: 10.1136/gutjnl-2020-322509

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