Phosphorylation of 17 beta-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice

17 beta-hydroxysteroid dehydrogenase-13 is a hepatocyte-specific, lipid droplet-associated protein. A common loss-of-function variant of HSD17B13 (rs72613567: TA) protects patients against non-alcoholic fatty liver disease with underlying mechanism incompletely understood. In the present study, we identify the serine 33 of 17 beta-HSD13 as an evolutionally conserved PKA target site and its phosphorylation facilitates lipolysis by promoting its interaction with ATGL on lipid droplets. Targeted mutation of Ser33 to Ala (S33A) decreases ATGL-dependent lipolysis in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Importantly, a transgenic knock-in mouse strain carrying the HSD17B13 S33A mutation (HSD17B13(33A/A)) spontaneously develops hepatic steatosis with reduced lipolysis and increased inflammation. Moreover, Hsd17B13(33A/A) mice are more susceptible to high-fat diet-induced nonalcoholic steatohepatitis. Finally, we find reproterol, a potential 17 beta-HSD13 modulator and FDA-approved drug, confers a protection against nonalcoholic steatohepatitis via PKA-mediated Ser33 phosphorylation of 17 beta-HSD13. Therefore, targeting the Ser33 phosphorylation site could represent a potential approach to treat NASH. A truncating variant of 17 beta-hydroxysteroid dehydrogenase-13 (17 beta-HSD13), a lipid droplet -associated protein, associates with lower risk of chronic liver disease. Here the authors identify a phosphorylation site in 17 beta-HSD13 which promotes lipolysis, and report that a knock-in mouse with a 17 beta-HSD13 mutant defective for phosphorylation is more susceptible to nonalcoholic steatohepatitis.