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Photo: KG Pressfoto

Marju Orho-Melander

Professor

Photo: KG Pressfoto

Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease

Author

  • Panu K. Luukkonen
  • Taru Tukiainen
  • Anne Juuti
  • Henna Sammalkorpi
  • P. A. Nidhina Haridas
  • Onni Niemelä
  • Johanna Arola
  • Marju Orho-Melander
  • Antti Hakkarainen
  • Petri T. Kovanen
  • Om Dwivedi
  • Leif Groop
  • Leanne Hodson
  • Amalia Gastaldelli
  • Tuulia Hyötyläinen
  • Matej Orešič
  • Hannele Yki-Järvinen

Summary, in English

Carriers of the hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using 2H2O and 2H-glycerol) and insulin sensitivity using 3H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.

Department/s

  • Diabetes - Cardiovascular Disease
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health
  • Genomics, Diabetes and Endocrinology

Publishing year

2020-03-12

Language

English

Publication/Series

JCI Insight

Volume

5

Issue

5

Document type

Journal article

Publisher

The American Society for Clinical Investigation

Topic

  • Endocrinology and Diabetes
  • Medical Genetics

Status

Published

Research group

  • Diabetes - Cardiovascular Disease
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 2379-3708