Hydroxysteroid (17 beta) dehydrogenase 12 is essential for metabolic homeostasis in adult mice

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Heikelä , H , Ruohonen , S T , Adam , M , Viitanen , R , Liljenback , H , Eskola , O , Gabriel , M , Mairinoja , L , Pessia , A , Velagapudi , V , Roivainen , A , Zhang , F-P , Strauss , L & Poutanen , M 2020 , ' Hydroxysteroid (17 beta) dehydrogenase 12 is essential for metabolic homeostasis in adult mice ' , American Journal of Physiology: Endocrinology and Metabolism , vol. 319 , no. 3 , pp. E494-E508 . https://doi.org/10.1152/ajpendo.00042.2020

Title: Hydroxysteroid (17 beta) dehydrogenase 12 is essential for metabolic homeostasis in adult mice
Author: Heikelä, Hanna; Ruohonen, Suvi T.; Adam, Marion; Viitanen, Riikka; Liljenback, Heidi; Eskola, Olli; Gabriel, Michael; Mairinoja, Laura; Pessia, Alberto; Velagapudi, Vidya; Roivainen, Anne; Zhang, Fu-Ping; Strauss, Leena; Poutanen, Matti
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2020-09
Language: eng
Number of pages: 15
Belongs to series: American Journal of Physiology: Endocrinology and Metabolism
ISSN: 0193-1849
URI: http://hdl.handle.net/10138/324877
Abstract: Hydroxysteroid 17-beta dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within six days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Pro-inflammatory cytokines, such as interleukin 6 (IL-6), IL-17 and granulocyte-colony stimulating factor were increased in the HSD17B12cKO mice indicating inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in the fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis, and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.
Subject: dihydroceramide
lipid
liver
toxicity
weight loss
FOOD-INTAKE
HEPATIC STEATOSIS
LIVER-INJURY
17-BETA-HYDROXYSTEROID-DEHYDROGENASE
EXPRESSION
CYTOKINE
HSD17B12
PROTEIN
CELLS
DIHYDROCERAMIDE
3121 General medicine, internal medicine and other clinical medicine
1184 Genetics, developmental biology, physiology
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