Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis.

Autor: Luukkonen PK; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT.; Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki 00290, Finland.; Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland., Sakuma I; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT., Gaspar RC; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT., Mooring M; Department of Pediatrics, The Yale Liver Center, Yale School of Medicine, New Haven 06520, CT., Nasiri A; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT., Kahn M; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT., Zhang XM; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT., Zhang D; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT., Sammalkorpi H; Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki 00290, Finland., Penttilä AK; Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki 00290, Finland., Orho-Melander M; Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö 21428, Sweden., Arola J; Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland., Juuti A; Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki 00290, Finland., Zhang X; Department of Pathology, Yale School of Medicine, New Haven 06520, CT., Yimlamai D; Department of Pediatrics, The Yale Liver Center, Yale School of Medicine, New Haven 06520, CT., Yki-Järvinen H; Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland.; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland., Petersen KF; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT., Shulman GI; Department of Internal Medicine, Yale School of Medicine, New Haven 06520, CT.; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven 06520, CT.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jan 24; Vol. 120 (4), pp. e2217543120. Date of Electronic Publication: 2023 Jan 20.
DOI: 10.1073/pnas.2217543120
Abstrakt: 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 ( HSD17B13 , 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 Hsd17b13 knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the HSD17B13 rs72613567-A variant in humans and by the Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the HSD17B13 -induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.
Databáze: MEDLINE
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