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

Luukkonen, Panu K. ; Sakuma, Ikki ; Gaspar, Rafael C. ; Mooring, Meghan ; Nasiri, Ali ; Kahn, Mario ; Zhang, Xian Man ; Zhang, Dongyan ; Sammalkorpi, Henna and Penttilä, Anne K. , et al. (2023) In Proceedings of the National Academy of Sciences of the United States of America 120(4).
Abstract

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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
hydroxysteroid 17-beta dehydrogenase 13, liver fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, pyrimidines
in
Proceedings of the National Academy of Sciences of the United States of America
volume
120
issue
4
article number
e2217543120
publisher
National Academy of Sciences
external identifiers
  • pmid:36669104
  • scopus:85146858013
ISSN
0027-8424
DOI
10.1073/pnas.2217543120
language
English
LU publication?
yes
id
9b87d22f-9e1c-4cf8-8fe2-9fea2c950248
date added to LUP
2023-02-13 08:30:13
date last changed
2024-06-13 23:00:39
@article{9b87d22f-9e1c-4cf8-8fe2-9fea2c950248,
  abstract     = {{<p>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.</p>}},
  author       = {{Luukkonen, Panu K. and Sakuma, Ikki and Gaspar, Rafael C. and Mooring, Meghan and Nasiri, Ali and Kahn, Mario and Zhang, Xian Man and Zhang, Dongyan and Sammalkorpi, Henna and Penttilä, Anne K. and Orho-Melander, Marju and Arola, Johanna and Juuti, Anne and Zhang, Xuchen and Yimlamai, Dean and Yki-Järvinen, Hannele and Petersen, Kitt Falk and Shulman, Gerald I.}},
  issn         = {{0027-8424}},
  keywords     = {{hydroxysteroid 17-beta dehydrogenase 13; liver fibrosis; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; pyrimidines}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis}},
  url          = {{http://dx.doi.org/10.1073/pnas.2217543120}},
  doi          = {{10.1073/pnas.2217543120}},
  volume       = {{120}},
  year         = {{2023}},
}