Attenuation of liver fibrosis by platelet-type 12S-lipoxygenase expressed in hepatic stellate cells involves repression of platelet-derived growth factor receptors.

Abstract

Progression of liver fibrosis is a critical determinant of the prognosis of chronic inflammatory liver disease. We previously reported that platelet-type 12S-lipoxygenase localized in hepatic stellate cells (HSCs), which are primary fibrogenic cells in the injured liver, was upregulated in a methionine-choline deficiency (MCD) diet-induced mouse liver fibrosis model. In this study, the functional contribution of platelet-type 12S-lipoxygenase to the pathological process was investigated. After feeding with an MCD diet for 8 weeks, platelet-type 12S-lipoxygenase-deficient (Alox12-/-) mice exhibited significantly greater Sirius Red-positive areas and higher expression of type I collagen genes (Col1a1 and Col1a2) than wild-type (WT) mice, indicating aggravated fibrosis. Similar results were obtained in a model induced by neonatal streptozotocin injection followed by a high-fat diet (HFD) feeding. Conversely, a human HSC line (TWNT-1) stably overexpressing human platelet-type 12S-lipoxygenase exhibited significantly reduced COL1A1 and COL1A2 expression compared to the parental and mock cells. Analysis of fibrosis-related genes revealed downregulation of platelet-derived growth factor receptors (PDGFR) α and β in platelet-type 12S-lipoxygenase-expressing TWNT-1 cells. Consistently, the hepatic expression of Pdgfra and Pdgfrb was significantly elevated in MCD diet-fed Alox12-/- mice compared to that in MCD diet-fed WT mice. The knockdown of PDGFRs in parental TWNT-1 cells using siRNAs significantly suppressed the expression of type I collagen genes. Collectively, these findings indicate that platelet-type 12S-lipoxygenase expressed in HSCs attenuates liver fibrosis, at least in part, by modulating PDGFR expression.