Genetic Loss of HIF-Prolyl-Hydroxylase 1, but Not Pharmacological Inhibition, Mitigates Hepatic Fibrosis

Abstract

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