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<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Steroid 5β-reductase (AKR1D1) plays important roles in hepatic glucocorticoid clearance and bile acid synthesis. Glucocorticoids and bile acids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype <jats:italic>in vivo</jats:italic> is unknown.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p><jats:italic>Akr1d1-/-</jats:italic>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 sensitivity were evaluated. Molecular changes were assessed by RNASeq and western blotting. <jats:italic>Male Akr1d1-/-</jats:italic>mice were challenged with a 60% high fat diet.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>Akr1d1-/-</jats:italic>mice had a sex specific metabolic phenotype. At 30-weeks of age male, but not female, <jats:italic>Akr1d1-/-</jats:italic>mice were more insulin sensitive and had reduced lipid accumulation in the liver and adipose tissue, concomitant with hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was underpinned by sexually dimorphic changes in bile acid metabolism and composition, but without overt effects on glucocorticoid action. Male <jats:italic>Akr1d1-/-</jats:italic>mice were not protected against diet induced obesity and insulin resistance.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>This study shows that AKR1D1 controls bile acid homeostasis <jats:italic>in vivo</jats:italic> and that altering its activity can affect insulin sensitivity and lipid homeostasis in a sex dependent manner.</jats:p></jats:sec>

Original publication

DOI

10.1101/2021.02.02.429227

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

03/02/2021