Disruption of HSD17B12 in mouse hepatocytes leads to reduced body weight and defect in the lipid droplet expansion associated with microvesicular steatosis.
| Title: | Disruption of HSD17B12 in mouse hepatocytes leads to reduced body weight and defect in the lipid droplet expansion associated with microvesicular steatosis. |
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| Authors: | Heikelä H; Research Centre for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Mairinoja L; Research Centre for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Ruohonen ST; Research Centre for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Rytkönen KT; Research Centre for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; de Brot S; COMPATH, Institute of Animal Pathology, University of Bern, Bern, Switzerland.; Laiho A; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Koskinen S; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Suomi T; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Elo LL; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Strauss L; Research Centre for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Poutanen M; Research Centre for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.; Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. |
| Source: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Sep 15; Vol. 38 (17), pp. e70034. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Federation of American Societies for Experimental Biology Country of Publication: United States NLM ID: 8804484 Publication Model: Print Cited Medium: Internet ISSN: 1530-6860 (Electronic) Linking ISSN: 08926638 NLM ISO Abbreviation: FASEB J Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2020- : [Bethesda, Md.] : Hoboken, NJ : Federation of American Societies for Experimental Biology ; Wiley; Original Publication: [Bethesda, Md.] : The Federation, [c1987- |
| MeSH Terms: | Lipid Droplets*/metabolism ; Hepatocytes*/metabolism ; Fatty Liver*/metabolism ; Fatty Liver*/pathology ; Fatty Liver*/genetics ; Mice, Knockout*; 17-Hydroxysteroid Dehydrogenases/metabolism ; 17-Hydroxysteroid Dehydrogenases/genetics ; Liver/metabolism ; Liver/pathology ; Fatty Acids/metabolism ; Animals ; Mice ; Lipid Metabolism ; Body Weight ; Male ; Mice, Inbred C57BL |
| Abstract: | The function of hydroxysteroid dehydrogenase 12 (HSD17B12) in lipid metabolism is poorly understood. To study this further, we created mice with hepatocyte-specific knockout of HSD17B12 (LiB12cKO). From 2 months on, these mice showed significant fat accumulation in their liver. As they aged, they also had a reduced whole-body fat percentage. Interestingly, the liver fat accumulation did not result in the typical formation of large lipid droplets (LD); instead, small droplets were more prevalent. Thus, LiB12KO liver did not show increased macrovesicular steatosis with the increasing fat content, while microvesicular steatosis was the predominant feature in the liver. This indicates a failure in the LD expansion. This was associated with liver damage, presumably due to lipotoxicity. Notably, the lipidomics data did not support an essential role of HSD17B12 in fatty acid (FA) elongation. However, we did observe a decrease in the quantity of specific lipid species that contain FAs with carbon chain lengths of 18 and 20 atoms, including oleic acid. Of these, phosphatidylcholine and phosphatidylethanolamine have been shown to play a key role in LD formation, and a limited amount of these lipids could be part of the mechanism leading to the dysfunction in LD expansion. The increase in the Cidec expression further supported the deficiency in LD expansion in the LiB12cKO liver. This protein is crucial for the fusion and growth of LDs, along with the downregulation of several members of the major urinary protein family of proteins, which have recently been shown to be altered during endoplasmic reticulum stress.; (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.) |
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| Grant Information: | Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse); UTU | Institute of Biomedicine, University of Turku (Biolääketieteen laitos); Jalmari ja Rauha Ahokkaan Säätiö (Jalmari and Rauha Ahokas Foundation) |
| Contributed Indexing: | Keywords: 17‐hydroxysteroid dehydrogenases; computer assisted image analysis; lipid droplets; liver steatosis; nonalcoholic fatty liver disease |
| Substance Nomenclature: | EC 1.1.- (17-Hydroxysteroid Dehydrogenases); 0 (Fatty Acids) |
| Entry Date(s): | Date Created: 20240909 Date Completed: 20240909 Latest Revision: 20240909 |
| Update Code: | 20260130 |
| DOI: | 10.1096/fj.202400333RR |
| PMID: | 39248019 |
| Database: | MEDLINE |
Journal Article