biostudies-literatureLuukkonen PKNCATS NIH HHSNIBIB NIH HHSHHS | NIH | National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSNCI NIH HHSNovo Nordisk FondenMercke2217543120https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942818biostudies-literatureUnknown120(4)Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (<i>HSD17B13</i>, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in <i>Hsd17b13</i> knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the <i>HSD17B13</i> rs72613567-A variant in humans and by the <i>Hsd17b13</i> knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are Proceedings of the National Academy of Sciences of the United States of AmericaInhibition of <i>HSD17B13</i> protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis.PMC9942818R03 DK124743MISP 59622R01 DK119968P30 DK045735R01 DK113984UL1 TR001863NNF19OC0057503R01 DK129552R01 CA124414NNF18OC0054504R01 DK135645P30 DK036836P30 DK034989T32 EB001026Yki-Jarvinen HZhang DPetersen KFShulman GIMooring MOrho-Melander MYimlamai DGaspar RCKahn MSammalkorpi HSakuma ILuukkonen PKArola JNasiri AZhang XPenttila AKJuuti AZhang XMfalseInhibition of <i>HSD17B13</i> protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis.Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (<i>HSD17B13</i>, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in <i>Hsd17b13</i> knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the <i>HSD17B13</i> rs72613567-A variant in humans and by the <i>Hsd17b13</i> knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are 2023-01-01T00:00:00Z2023 Jan2026-05-29T07:44:04.542Z2025-02-19T01:18:18.184ZS-EPMC99428183666910410.1073/pnas.2217543120