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

Abstract

ABSTRACTHydroxysteroid 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 includingHsd17b13. 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 ofHsd17b13(shHsd17b13) in high-fat diet (HFD)-obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia.shHsd17b13decreased elevated serum ALT, serum FGF21 levels and markers of liver fibrosis e.g.Timp2.shHsd17b13knockdown 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) withshHsd17b13and 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,Hsd17b13knockdown 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 POINTSHSD17B13loss-of-function gene variants are associated with decreased risk of metabolic dysfunction-associated (MA) steatotic liver disease and steatohepatitis (MASLD and MASH).RNA-seq analysis of steatotic liver identified beneficial effects of Fenretinide on hepatic gene expression including downregulation ofHsd17b13.Liver-specific shRNA knockdown ofHsd17b13in obese mice markedly improved hepatic steatosis and markers of liver health e.g. serum ALT, serum Fgf21 levels.Hsd17b13 influenced expression of lipid/phospholipid metabolism genes e.g. Cd36 and Cept1 and phosphatidylcholines PC 34:3 and PC 42:10.Our study suggests a mechanism of HSD17B13’s biological function and the strong rationale behind targeting HSD17B13 for MASLD/MASH.