The significance of metabolic reprogramming during hepatic fibrosis

Background Hepatic stellate cells (HSCs) and chronic hypoxia play a central role during liver fibrosis. We previously showed that loss of the HIF prolyl hydroxylase 1 (PHD1 -/- ) mitigates liver fibrosis. Upon activation, HSCs utilize anaerobic glycolysis stimulating profibrotic processes. PHD1 inhibition stimulates the expression of pyruvate dehydrogenase kinases (PDK) 1 and 4, thereby regulating anaerobic glycolysis. We thus investigated the significance of pharmacologic PHD inhibition and PDK stimulation during metabolic reprogramming of activated HSCs to treat liver fibrosis. Methods Biliary fibrosis was induced by treating mice with DDC. HSC activation was investigated in-vitro utilizing primary HSCs and human HSC cell lines (LX2 cells). Gene and protein expression of myofibroblast markers were analyzed applying RT-PCR and western blotting, respectively. Metabolic reprogramming of HSCs was examined by gene expression analysis and ATP-content-assays. In patient-derived liver biopsies, the expression of PHD1 and PDK1-4 was detected by immunohistochemistry and correlated with different stages of liver fibrosis and cirrhosis. Results Unspecific PHD inhibition bydimethyloxalylglycine (DMOG) attenuated DDC-induced hepatic fibrosis in mice. InhumanHSCs, siRNA-elicited PHD1 knockdown or DMOG treatment reduced the expression of COL1A1 and COL3A1. Moreover, PHD inhibition mitigated the migratory potential of HSCs, suggesting decreased HSC activation. Gene expression analysis suggested that metabolic reprogramming of HSCs was stimulated by both knockdown of PHD1 and DMOG. PDK stimulation by fenofibrate treatment showed comparable effects. In liver biopsies, PHD1, PDK1, and PDK4 inversely correlated with higher stages of liver fibrosis compared to patients with lower stages or no fibrosis at all. Conclusion Targeting metabolic reprogramming of HSCs by pharmacologic PHD inhibition or direct PDK stimulation could represent a promising treatment option in patients with liver fibrosis . Publication History Article published online: 19 August 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany