5β-Reduced Steroids and Human Δ4-3-Ketosteroid 5β-Reductase (AKR1D1)
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Recently, δ-aminolevulinate synthase, the rate limiting enzyme of porphyrin-heme synthesis, has also been identified as a gene regulated by FXR, indicating a role of bile acids and their precursors in regulating hepatic heme biosynthesis [19]. The secondary bile acid, lithocholic acid activates PXR [20] and the vitamin D receptor [21, 22]. PXR in turn regulates the expression of CYP3A4, which encodes the major drug and xenobiotic catabolizing P450 isozyme in human liver. The secondary bile acid, ursodeoxycholic acid activates the glucocorticoid receptor and exerts immunomodulatory effects [23–25]. Bile acids also activate several signaling pathways including the c-Jun NH2- terminal kinase (JNK) 1/2 pathway (to feedback inhibit bile acid biosynthesis) [8], the protein kinase B (AKT) pathway (to regulate glucose metabolism) [8, 26], FXR, short heterodimer partner (SHP), liver X receptor (LXR), and the sterol regulatory element- binding protein (SREBP)-1c pathway (to regulate lipid metabolism) [8, 27], the extracellular-signal-regulated kinases (ERK) pathway (to prevent apoptosis) [28, 29], and the epidermal growth factor receptor (to modulate intestinal permeability) [30]. A recently identified G protein-coupled bile acid receptor (TGR5) [31] further expands the function of bile acids and their roles in energy metabolism [32], inflammation [33, 34], and gallbladder contractility [35]. Bile acids also affect cardiac function by regulating vascular tone and myocardial contractility, but the underlying mechanism for this remains largely unknown [36].
