Hydroxysteroid (17β) dehydrogenase 12 is essential for metabolic homeostasis in adult mice.
| Title: | Hydroxysteroid (17β) dehydrogenase 12 is essential for metabolic homeostasis in adult mice. |
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| Authors: | Heikelä H; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Ruohonen ST; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Adam M; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Viitanen R; Turku PET Centre, University of Turku, Turku, Finland.; Liljenbäck H; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku PET Centre, University of Turku, Turku, Finland.; Eskola O; Turku PET Centre, University of Turku, Turku, Finland.; Gabriel M; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Mairinoja L; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Pessia A; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.; Velagapudi V; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.; Roivainen A; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku PET Centre, University of Turku, Turku, Finland.; Turku PET Centre, Turku University Hospital, Turku, Finland.; Zhang FP; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Strauss L; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Poutanen M; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Department of Internal Medicine, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. |
| Source: | American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2020 Sep 01; Vol. 319 (3), pp. E494-E508. Date of Electronic Publication: 2020 Jul 21. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1555 (Electronic) Linking ISSN: 01931849 NLM ISO Abbreviation: Am J Physiol Endocrinol Metab Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Bethesda, MD. : American Physiological Society |
| MeSH Terms: | 17-Hydroxysteroid Dehydrogenases/*physiology ; Homeostasis/*physiology; 17-Hydroxysteroid Dehydrogenases/genetics ; Adipose Tissue, Brown/drug effects ; Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/drug effects ; Adipose Tissue, White/metabolism ; Body Weight/genetics ; Cytokines/metabolism ; Fatty Acids/metabolism ; Homeostasis/genetics ; Lipid Metabolism/genetics ; Lipid Metabolism/physiology ; Liver Diseases/genetics ; Tamoxifen/pharmacology ; Animals ; Behavior, Animal ; Feeding Behavior ; Female ; Lipidomics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Sex Characteristics |
| Abstract: | Hydroxysteroid 17β 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 6 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. Proinflammatory cytokines, such as interleukin-6 (IL-6), IL-17, and granulocyte colony-stimulating factor, were increased in the HSD17B12cKO mice indicating an 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 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. |
| Contributed Indexing: | Keywords: dihydroceramide; lipid; liver; toxicity; weight loss |
| Substance Nomenclature: | 0 (Cytokines); 0 (Fatty Acids); 094ZI81Y45 (Tamoxifen); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.- (HSD17B12 protein, mouse) |
| Entry Date(s): | Date Created: 20200722 Date Completed: 20201230 Latest Revision: 20201230 |
| Update Code: | 20260130 |
| DOI: | 10.1152/ajpendo.00042.2020 |
| PMID: | 32691632 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't