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

Luukkonen, Panu K. ; Tukiainen, Taru ; Juuti, Anne ; Sammalkorpi, Henna ; Nidhina Haridas, P. A. ; Niemelä, Onni ; Arola, Johanna ; Orho-Melander, Marju LU ; Hakkarainen, Antti and Kovanen, Petri T. , et al. (2020) In JCI Insight 5(5).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
5
issue
5
article number
e132158
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85082739096
  • pmid:32161197
ISSN
2379-3708
DOI
10.1172/jci.insight.132158
language
English
LU publication?
yes
id
5b947aa8-940e-4d5a-91bc-a17b27693383
date added to LUP
2020-04-21 16:42:35
date last changed
2022-10-02 00:21:16
@article{5b947aa8-940e-4d5a-91bc-a17b27693383,
  abstract     = {{<p>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 <sup>2</sup>H<sub>2</sub>O and <sup>2</sup>H-glycerol) and insulin sensitivity using <sup>3</sup>H-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.</p>}},
  author       = {{Luukkonen, Panu K. and Tukiainen, Taru and Juuti, Anne and Sammalkorpi, Henna and Nidhina Haridas, P. A. and Niemelä, Onni and Arola, Johanna and Orho-Melander, Marju and Hakkarainen, Antti and Kovanen, Petri T. and Dwivedi, Om and Groop, Leif and Hodson, Leanne and Gastaldelli, Amalia and Hyötyläinen, Tuulia and Orešič, Matej and Yki-Järvinen, Hannele}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{5}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.132158}},
  doi          = {{10.1172/jci.insight.132158}},
  volume       = {{5}},
  year         = {{2020}},
}