Genetic Loss of HIF-Prolyl-Hydroxylase (PHD) 1, but not pharmacological Inhibition, mitigates hepatic fibrosis.

Abstract

Liver fibrosis is characterized by excessive deposition of extracellular-matrix (ECM) due to chronic inflammation of the liver. HSCs become activated and produce excessive amounts of ECM. Previously, we showed that loss of HIF-prolyl-hydroxylase 1 (PHD1) attenuates HSC activation and fibrotic tissue remodeling in a murine model of biliary liver fibrosis. We thus validated the protective effect of PHD1 deficiency (PHD1^-/-) in an additional (toxic) model of liver fibrosis and evaluated the effect of dimethyloxalylglycine (DMOG), a pan-HIF-prolyl-hydroxylase inhibitor, on the development of liver fibrosis. Liver fibrosis was induced utilizing carbon tetrachloride (CCl₄) in WT, PHD1^-/-, vehicle-, and DMOG-treated mice. Livers were further analyzed by Sirius red staining and gene expression analysis of pro-fibrotic genes to assess fibrosis development. When compared to WT mice, PHD1^-/- mice developed less severe liver fibrosis. In contrast, DMOG treatment did not prevent liver fibrosis. PHD1^-/- mice showed a lower number of α SMA⁺ cells and less macrophage infiltration when compared to WT mice. Gene expression of profibrogenic and proinflammatory genes was reduced in livers from CCl₄-exposed PHD1^-/- mice. In vitro analyses of in PHD1-deficient human HSCs revealed attenuated mRNA-levels of profibrotic genes as well as impaired migration and invasion. While PHD1 deficiency attenuates activation of HSCs, pharmacological PHD inhibition does not ameliorate fibrosis development. Selective PHD1 inhibitors could prove effective in preventing and treating liver fibrosis.