HIF-1α/YAP induces interleukin 1β autocrine in hepatocytes, leading to hepatocytic fibrosis: adaptive fibrosis in nonalcoholic fatty liver

Nonalcoholic fatty-liver disease (NAFLD) has become the most common type of chronic liver disease and a global public-health problem. Fibrosis is always secondary to nonalcoholic steatohepatitis (NASH), an inflammatory fibrotic process in which hepatic stellate cells (HSCs), macrophages, and hepatic sinusoidal endothelial cells (HSECs) may all play roles. However, steatosis-associated fibrosis ( i.e. , NAFL fibrosis) and the key role of hepatocytes in liver fibrosis are not well understood. In this study, we explored the mechanisms of high-lipid microenvironment (HLME)-induced NAFL hepatocytic fibrosis and interleukin 1β (IL-1β) regulation through the hypoxia-inducible factor 1α (HIF-1α)/yes-associated protein (YAP) signaling pathway. C57BL/6J mice were fed a high-fat diet (HFD) for 1–3 months. Moreover, Hep G2 and Hepa 1-6 cells were treated with palmitic acid (PA) for 24 h to establish a NAFL model. Furthermore, we performed immunohistochemical (IHC) staining, western blot (WB) analysis, real-time quantitative polymerase chain reaction (RT-qPCR), silencing, and co-immunoprecipitation (Co-IP) experiments. The results showed that a HFD or PA induced high expression of collagen type I α1 chain and type III α1 chain (COL1A1, COL3A1), matrix metalloproteinase 2 (MMP-2), HIF-1α, YAP, and IL-1β in hepatocytes compared with the control group. IL-1β receptor was highly expressed in hepatocytes, and HIF-1α/YAP regulated the expression of IL-1β. In conclusion, hepatocytes contributed to NAFL fibrosis by IL-1β autocrine regulation via HIF-1α/YAP signaling in a HLME.