Dysregulation of Δ 4 -3-oxosteroid 5β-reductase in diabetic patients: Implications and mechanisms
Document Type
Article
Date of Original Version
7-15-2018
Abstract
Aldo-keto reductase family 1 member D1 (AKR1D1) is a Δ 4 -3-oxosteroid 5β-reductase required for bile acid synthesis and steroid hormone metabolism. Both bile acids and steroid hormones, especially glucocorticoids, play important roles in regulating body metabolism and energy expenditure. Currently, our understanding on AKR1D1 regulation and its roles in metabolic diseases is limited. We found that AKR1D1 expression was markedly repressed in diabetic patients. Consistent with repressed AKR1D1 expression, hepatic bile acids were significantly reduced in diabetic patients. Mechanistic studies showed that activation of peroxisome proliferator-activated receptor-α (PPARα) transcriptionally down-regulated AKR1D1 expression in vitro in HepG2 cells and in vivo in mice. Consistently, PPARα signaling was enhanced in diabetic patients. In summary, dysregulation of AKR1D1 disrupted bile acid and steroid hormone homeostasis, which may contribute to the pathogenesis of diabetes. Restoring bile acid and steroid hormone homeostasis by modulating AKR1D1 expression may represent a new approach to develop therapies for diabetes.
Publication Title, e.g., Journal
Molecular and Cellular Endocrinology
Volume
470
Citation/Publisher Attribution
Valanejad, Leila, Mwlod Ghareeb, Stephanie Shiffka, Christina Nadolny, Yuan Chen, Liangran Guo, Ruchi Verma, Sangmin You, Fatemeh Akhlaghi, and Ruitang Deng. "Dysregulation of Δ 4 -3-oxosteroid 5β-reductase in diabetic patients: Implications and mechanisms." Molecular and Cellular Endocrinology 470, (2018): 127-141. doi: 10.1016/j.mce.2017.10.005.