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

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Luukkonen , P K , Tukiainen , T , Juuti , A , Sammalkorpi , H , Haridas , P A N , Niemelä , O , Arola , J , Orho-Melander , M , Hakkarainen , A , Kovanen , P T , Dwivedi , O , Groop , L , Hodson , L , Gastaldelli , A , Hyötyläinen , T , Oresic , M & Yki-Järvinen , H 2020 , ' Hydroxysteroid 17-beta dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease ' , JCI INSIGHT , vol. 5 , no. 5 , 132158 . https://doi.org/10.1172/jci.insight.132158

Title: Hydroxysteroid 17-beta dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease
Author: Luukkonen, Panu K.; Tukiainen, Taru; Juuti, Anne; Sammalkorpi, Henna; Haridas, P. A. Nidhina; Niemelä, Onni; Arola, Johanna; Orho-Melander, Marju; Hakkarainen, Antti; Kovanen, Petri T.; Dwivedi, Om; Groop, Leif; Hodson, Leanne; Gastaldelli, Amalia; Hyötyläinen, Tuulia; Oresic, Matej; Yki-Järvinen, Hannele
Contributor: University of Helsinki, HUS Internal Medicine and Rehabilitation
University of Helsinki, Genomics of Sex Differences
University of Helsinki, HUS Abdominal Center
University of Helsinki, HUS Abdominal Center
University of Helsinki, HUSLAB
University of Helsinki, HUS Medical Imaging Center
University of Helsinki, Wihuri Research Institute
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Department of Medicine
Date: 2020-03-12
Language: eng
Number of pages: 12
Belongs to series: JCI INSIGHT
ISSN: 2379-3708
URI: http://hdl.handle.net/10138/325971
Abstract: Carriers of the hydroxysteroid 17-beta 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 [ONLI and adipose tissue lipolysis [ATL] using (H2O)-H-2 and H-2-glycerol) and insulin sensitivity using H-3-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, ONL, 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.
Subject: DE-NOVO LIPOGENESIS
INSULIN-RESISTANCE
PHOSPHATIDYLCHOLINE
CHOLINE
GLUCOSE
STEATOHEPATITIS
INDIVIDUALS
HOMEOSTASIS
NUTRIENT
PACKAGE
3121 Internal medicine
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