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p16 INK4A drives non-alcoholic fatty liver disease phenotypes in high fat diet fed mice via biliary e2f1/foxo1/igf-1 signaling

Kundu D, Kennedy L, Zhou T, Ekser B, Meadows V, Sybenga A, Kyritsi K, Chen L, Ceci L, Wu N, Wu C, Glaser S, Carpino G, Onori P, Gaudio E, Alpini G, Francis H
Hepatology. 2023 Feb 20. doi: 10.1097/HEP.0000000000000307. Online ahead of print
Backgroundand aim: Non-alcoholic fatty liver disease (NAFLD) is characterized by steatosis, hepatic inflammation, and fibrosis which can develop into non-alcoholic steatohepatitis (NASH). NAFLD/NASH patients have increased ductular reaction (DR) and biliary senescence. High fat/high cholesterol diet (HFD) feeding increases biliary senescence, DR, and biliary insulin-like growth factor-1 (IGF-1) expression in mice. p16/IGF-1 converges with fork-head box transcription factor O1 (FOXO1) via E2F1. We evaluated p16 inhibition on NAFLD phenotypes and biliary E2F1/FOXO1/IGF-1 signaling. Approach: 4 wk wild-type (WT, C57BL/6J) male mice were fed control diet (CD) or HFD and received either p16 or control Vivo Morpholino (VM) by tail vein injection 2x during the 16th wk of feeding. We confirmed p16 knockdown and examined (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling. Human normal, NAFLD, and NASH liver samples and isolated cholangiocytes treated with control or p16 VM, were evaluated for p16/E2F1/FOXO1/IGF-1 signaling. Results: p16 VM treatment reduced cholangiocyte and hepatocyte p16. In WT HFD mice with control VM, there was increased (i) NAFLD phenotypes, (ii) DR and biliary senescence, (iii) serum metabolites, and (iv) biliary E2F1/FOXO1/IGF-1 signaling; however, p16 VM treatment reduced these parameters. Biliary E2F1/FOX-O1/IGF-1 signaling increased in human NAFLD/NASH but was blocked by p16 VM. In vitro, p16 VM reduced biliary E2f1 and Foxo1 transcription by inhibiting RNA pol II binding and E2F1 binding at the Foxo1 locus, respectively. Inhibition of E2F1 reduced biliary FOXO1, in vitro. Conclusion: Attenuating hepatic p16 expression may be a therapeutic approach for improving NAFLD/NASH phenotypes.
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