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. 2023 Feb 28;24(5):4682. doi: 10.3390/ijms24054682

Figure 3.

Figure 3

Role of hepatocyte SP/KLF transcription factors in non-metabolic functions: KLF6 indirectly increases expression of the rate-limiting enzyme for bile acid synthesis (Cyp7a1) by repressing FXR-mediated transcription of SHP. KLF15 indirectly promotes Cyp7a1 transcription via transcriptional repression of FGF15 expression in enterocytes. KLF5 enhances transcription of the Gpbar1, whereas SP1 inhibits it. KLF6 promotes AhR-mediated transcription of the Cyp1a family, and KLF9 promotes HNF4α-mediated transcription of Cyp2d6. SP1 induces transcription of phase 1 (Cyp1a1, Cyp2b10, Cyp3a4) and phase 2 (Ugt1a8, Ugt1a10, Sult1a1, Sult2b1b, Nags, Gst) metabolic enzymes. SP1 also increases the transcription of clotting (Prothrombin, Factor X, Factor VII, TF) and anti-coagulation (Protein S) proteins. KLF2 and KLF4 prevent thrombosis and inflammation-induced prothrombotic gene (TF, PAI-1) expression and inhibitory influence on anti-thrombotic (TM, eNOS) gene expression. Endothelial KLF15 promotes thrombosis. In hepatocyte injury, endothelial KLF2 indirectly inhibits hepatic regeneration by leading to Activin A secretion. KLF4 and KLF10 promote hepatic regeneration by regulating the expression of cell cycle genes (AhR: Aryl hydrocarbon receptor, c-Myc: c-Myc oncoprotein, Cyp1a1: Cytochrome P450 Family 1 Subfamily A Member 1, Cyp2b10: Cytochrome P450, family 2, subfamily b, polypeptide 10, Cyp2d6: Cytochrome P450 family 2 subfamily D member 6, Cyp3a4: Cytochrome P450 family 3 subfamily A member 4, Cyp7a1: Cytochrome P450 family 7 subfamily A member 1, eNOS: Endothelial nitric oxide synthase, FGF15: Fibroblast growth factor 15, FXR: Farnesoid X receptor, Gpbar1: G protein-coupled bile acid receptor 1, Gst: Glutathione-s-transferase, HNF4α: Hepatocyte nuclear factor-4 alpha, KLFs: Krupple like family transcription factors, Nags: N-acetylglutamate synthase, Oct-4: Octamer-binding transcription factor 4, PAI-I: Plasminogen activator inhibitor 1, SHP: Small heterodimer partner, Sox2: SRY-Box transcription factor 2, SP: Specificity protein family transcription factors, Sult1a1: Sulfotransferase family 1A member 1, Sult2b1b: Sulfotransferase family cytosolic 2B member 1, TGR-5: Takeda G-protein receptor 5, TNF-α: Tumor necrosis factor α, Ugt1a8: UDP glucuronosyltransferase family 1 member A8, Ugt1a10: UDP glucuronosyltransferase family 1 member A10).