Role of Hypoxia-Inducible Factors in the Development of Liver Fibrosis.

Liver fibrosis remains a significant clinical problem in the United States and throughout the world. Although important advances in the understanding of this disease have been made, no effective pharmacologic agents have been developed that directly prevent or reverse the fibrotic process. Many of the successes in liver fibrosis treatment have been targeted toward treating the cause of fibrosis, such as the development of new antivirals that eradicate hepatitis virus.

Hepatic stellate cells orchestrate clearance of necrotic cells in a hypoxia-inducible factor-1α-dependent manner by modulating macrophage phenotype in mice.

Hypoxia-inducible factor-1α (HIF-1α) is activated in hepatic stellate cells (HSCs) by hypoxia and regulates genes important for tissue repair. Whether HIF-1α is activated in HSCs after acute injury and contributes to liver regeneration, however, is not known. To investigate this, mice were generated with reduced levels of HIF-1α in HSCs by crossing HIF-1α floxed mice with mice that express Cre recombinase under control of the glial fibrillary acidic protein (GFAP) promoter (i.