Fig 1: KRT23 expression correlates with disease severity and key features of AH.(a) KRT23 hepatic gene expression measured by qPCR in patients with AH (n = 51), HCV (n = 10), compensated cirrhosis (n = 10) and NASH (n = 14), compared to normal livers (n = 7). (b) KRT23 peripheral serum levels are elevated in patients with AH (n = 34) when compared to patients with cirrhosis (n = 14). (c) Correlation between KRT23 hepatic gene expression (fold change vs. normal livers) and clinical features in patients with AH (n = 51). Both MELD score as well as ABIC score correlated with KRT23 hepatic gene expression. (d) Kaplan-Meier’s curve analysis illustrates the relationship between KRT23 hepatic gene expression with 90-day mortality in patients with AH. A cut-off value of 250-fold expression (fold change vs. normal livers) defined patients with low and high KRT23 gene expression with the best sensitivity and specificity. Portal hypertension (hepatic venous pressure gradient – HVPG – mmHg) was higher in patients with higher KRT23 gene expression levels (>250-fold).
Fig 2: KRT23 hepatic expression in animal models of liver injury and in LPCs.(a) Relationship between KRT23 hepatic gene expression and LPS serum levels in patients with AH (n = 39). Correlation between LPS serum levels and ABIC score in patients with AH. (b) Krt23 hepatic gene expression in a mouse model of acute liver injury. Krt23 gene expression in mice treated with LPS (n = 6) compared to control mice (n = 6). (c) Krt23 hepatic gene expression in a mouse model of advanced fibrosis. Krt23 in mice treated CCl4 plus LPS (n = 8) compared to mice treated with CCl4 alone (n = 6). (d) Gene expression of KRT23 and LPCs markers (KRT7 and EPCAM) in a model of liver progenitor cell differentiation from 3 independent experiments.
Fig 3: LPS-TLR4 induced liver damage is mediated by ductular cells in animal models of liver injury.(a) Gene expression of Krt23 and LPCs markers (Krt7 and Epcam) in WT and Tlr4-KO mice subjected to sham operation (n = 3) or BDL. BDL mice were sacrificed 5 (n = 4) or 21 days (n = 8) after operation. (b) Representative micrographs of KRT23 protein expression in WT and Tlr4-KO mice subjected to sham operation or BDL. (c) Gene expression of Krt23 and LPCs markers in WT and Tlr4-KO mice subjected to Tsukamoto-French model of ethanol damage (4 weeks, n = 6) compared to uninjured control mice (n = 4). (d) Representative micrographs of Krt23 protein expression in WT and Tlr4-KO mice subjected to Tsukamoto-French model and uninjured control mice. Bars, 100 µm.
Fig 4: KRT23 regulation by HDACs in mice liver progenitor cells and KRT23 effects on collagen synthesis.(a) Effect of HDAC inhibition by NaB administration on Krt23 gene expression in BAML cells (3 independent experiments). (b) Gene expression of Sirt1, an HDAC, in a BAML cells treated with NaB (3 independent experiments). (c) Correlation between KRT23 hepatic gene expression and COL1A1 hepatic gene expression in patients with AH (n = 39). (d) Effect of HDACs inhibition by NaB administration on Col1a1 gene expression in BAML cells. (e) Silencing of Krt23 by means of siRNA inhibited NaB induced Col1a1 gene expression in BAML cells (3 independent experiments).
Fig 5: Identification of KRT23 as a Marker of Ductular Cells in AH.(a) Representative micrographs of KRT23 protein expression in paraffin sections of liver biopsies from normal livers and from patients with AH, stained with anti-KRT23 antibody (x100 magnification). (b) Immunofluorescence staining shows co-localization of KRT23 and LPCs markers (KRT7 and EPCAM) in paraffin sections of liver biopsies from patients with AH (x100 magnification). (c) Krt23 hepatic gene expression measured in a mouse model of progenitor cell expansion (DDC diet for 4 weeks, n = 6 compared to uninjured mouse liver (control, n = 6). (d) Representative images of liver KRT23 staining in mice treated for 4 weeks with a DDC diet and in uninjured mice (x200 magnification). (e) Krt23 and LPCs markers (Epcam, Krt7, Krt19) gene expression was significantly enriched in LCP cells (n = 3) vs. a non-LPC population (n = 3).
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