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Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease
Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
Institute for Molecular Medicine Finland, Helsinki, Finland.
Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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2020 (English)In: JCI Insight, ISSN 2379-3708, Vol. 5, no 5, article id 132158Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Clinical Investigation , 2020. Vol. 5, no 5, article id 132158
Keywords [en]
Fibrosis, Genetic variation, Hepatitis, Hepatology, Metabolism
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:oru:diva-80607DOI: 10.1172/jci.insight.132158ISI: 000519997400006PubMedID: 32161197Scopus ID: 2-s2.0-85082739096OAI: oai:DiVA.org:oru-80607DiVA, id: diva2:1414537
Funder
Novo Nordisk
Note

Funding Agencies:

Elucidating Pathways of Steatohepatitis consortium - Horizon 2020 Framework Program of the European Union 634413

Innovative Medicines Initiative 2 Joint Undertaking 777377

European Union (EU)

European Federation of Pharmaceutical Industries and Associations  

Academy of Finland

EVO  

Sigrid Juselius Foundation

Ministry of Education, Universities and Research  

Italian National Research Council

British Heart Foundation Senior Fellowship in Basic Science  FS/15/56/31645

Jalmari and Rauha Ahokas Foundation  

Paulo Foundation 

Available from: 2020-03-13 Created: 2020-03-13 Last updated: 2020-05-12Bibliographically approved

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Hyötyläinen, TuuliaOresic, Matej

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