AKR1D1 knockout mice develop a sex-dependent metabolic phenotype.

Autor: Gathercole LL; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.; Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK., Nikolaou N; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK., Harris SE; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK., Arvaniti A; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.; Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK., Poolman TM; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK., Hazlehurst JM; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK., Kratschmar DV; Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland., Todorčević M; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK., Moolla A; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK., Dempster N; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK., Pink RC; Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK., Saikali MF; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada., Bentley L; Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, UK., Penning TM; Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA., Ohlsson C; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Cummins CL; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada., Poutanen M; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland., Odermatt A; Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland., Cox RD; Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, UK., Tomlinson JW; Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
Jazyk: angličtina
Zdroj: The Journal of endocrinology [J Endocrinol] 2022 Apr 13; Vol. 253 (3), pp. 97-113. Date of Electronic Publication: 2022 Apr 13.
DOI: 10.1530/JOE-21-0280
Abstrakt: Steroid 5β-reductase (AKR1D1) plays important role in hepatic bile acid synthesis and glucocorticoid clearance. Bile acids and glucocorticoids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. Akr1d1-/- mice were generated on a C57BL/6 background. Liquid chromatography/mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin tolerance were evaluated. Molecular changes were assessed by RNA-Seq and Western blotting. Male Akr1d1-/- mice were challenged with a high fat diet (60% kcal from fat) for 20 weeks. Akr1d1-/- mice had a sex-specific metabolic phenotype. At 30 weeks of age, male, but not female, Akr1d1-/- mice were more insulin tolerant and had reduced lipid accumulation in the liver and adipose tissue yet had hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was associated with sexually dimorphic changes in bile acid metabolism and composition but without overt effects on circulating glucocorticoid levels or glucocorticoid-regulated gene expression in the liver. Male Akr1d1-/- mice were not protected against diet-induced obesity and insulin resistance. In conclusion, this study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin tolerance and lipid homeostasis in a sex-dependent manner.
Databáze: MEDLINE