Hydroxysteroid 17-beta dehydrogenase 13 (Hsd17b13) knockdown attenuates liver steatosis in high-fat diet obese mice

Abstract

Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) loss-of-function gene variants are associated with decreased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Our RNA-seq analysis of steatotic liver from obese mice -/+ Fenretinide treatment identified major beneficial effects of Fenretinide on hepatic gene expression including Hsd17b13. We sought to determine the relationship between Hsd17b13 expression and MASLD and to validate it as a therapeutic target by liver-specific knockdown. Hsd17b13 expression, which is unique to hepatocytes and associated with the lipid-droplet, was elevated in multiple models of MASLD and normalised with prevention of obesity and steatotic liver. Direct, liver- specific, shRNA-mediated knockdown of Hsd17b13 (shHsd17b13) in high-fat diet (HFD)-obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia. shHsd17b13 decreased elevated serum ALT, serum FGF21 levels and markers of liver fibrosis e.g. Timp2. shHsd17b13 knockdown in HFD-obese mice and Hsd17b13 overexpression in cells reciprocally regulated expression of lipid metabolism genes e.g. Cd36. Global lipidomic analysis of liver tissue revealed a major decrease in diacylglycerols (e.g. DAG 34:3) with shHsd17b13 and an increase in phosphatidylcholines containing polyunsaturated fatty acids (PUFA) e.g. PC 34:3 and PC 42:10. Expression of key genes involved in phospholipid and PUFA metabolism e.g. Cept1, were also reciprocally regulated suggesting a potential mechanism of Hsd17b13 biological function and role in MASLD. In conclusion, Hsd17b13 knockdown in HFD-obese adult mice was able to alleviate MASLD via regulation of fatty acid and phospholipid metabolism, thereby confirming HSD17B13 as a genuine therapeutic target for MASLD and development of liver fibrosis. KEY POINTSO_LIHSD17B13 loss-of-function gene variants are associated with decreased risk of metabolic dysfunction-associated (MA) steatotic liver disease and steatohepatitis (MASLD and MASH). C_LIO_LIRNA-seq analysis of steatotic liver identified beneficial effects of Fenretinide on hepatic gene expression including downregulation of Hsd17b13. C_LIO_LILiver-specific shRNA knockdown of Hsd17b13 in obese mice markedly improved hepatic steatosis and markers of liver health e.g. serum ALT, serum Fgf21 levels. C_LIO_LIHsd17b13 influenced expression of lipid/phospholipid metabolism genes e.g. Cd36 and Cept1 and phosphatidylcholines PC 34:3 and PC 42:10. C_LIO_LIOur study suggests a mechanism of HSD17B13s biological function and the strong rationale behind targeting HSD17B13 for MASLD/MASH. C_LI