Dysregulation of Δ4-3-oxosteroid 5β-reductase in diabetic patients: Implications and mechanisms. (15th July 2018)

• Record Type: Journal Article
• Authors: Valanejad, Leila; Ghareeb, Mwlod; Shiffka, Stephanie; Nadolny, Christina; Chen, Yuan; Guo, Liangran; Verma, Ruchi; You, Sangmin; Akhlaghi, Fatemeh; Deng, Ruitang
• Is Part Of: Molecular and cellular endocrinology. Volume 470(2018)
• Page Start: 127
• Page End: 141
• Publication Date: 2018-07-15
• Subjects: AKR1D1 -- Diabetes -- Bile acid synthesis -- Steroid hormone metabolism -- PPARα signaling; AKR1D1 aldo-keto reductase family 1, member D1 -- BMI body mass index -- BSEP bile salt export pump -- CA cholic acid -- CDCA chenodeoxycholic acid -- CPT1A carnitine palmitoyltransferase-1A -- CYP7A1 cholesterol 7α-hydroxylase or cytochrome P450 family 7 subfamily A member 1 -- CYP7B1 cytochrome P450 family 7 subfamily B member 1 -- CYP8B1 sterol 12α-hydroxylase or CYP family 8 subfamily B member 1 -- CYP27A1 cytochrome P450 family 27 subfamily A member 1 -- DCA deoxycholic acid -- FXR farnesoid x receptor -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- LCA lithocholic acid -- LXR liver x receptor -- LC-MS/MS liquid chromatography tandem-mass spectrometry -- LLOD low limit of quantification -- LLOQ low limit of detection -- MRP3 multidrug resistance-associated protein 3 -- MRP4 multidrug resistance-associated protein 4 -- NADPH nicotinamide adenine dinucleotide phosphate -- NTCP sodium-taurocholate cotransporting polypeptide -- OATP1B1 organic anion-transporting polypeptide member 1B1 -- PGZN pioglitazone -- PPARα peroxisome proliferator-activated receptor alpha -- SEM standard error of mean -- TGR5 Takeda G-protein receptor 5 -- UDCA ursodeoxycholic acid; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2017.10.005
• Languages: English
• ISSNs: 0303-7207

Abstract

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. Highlights: AKR1D1 expression was markedly repressed in diabetic patients. Hepatic bile acids were significantly reduced in diabetic patients. AKR1D1 was transcriptionally down-regulated by PPARα signaling. PPARα signaling was enhanced in diabetic patients.