Hepatocyte HIF2α Downregulates the Urea Cycle Through Suppression of HNF4α

Hypoxia contributes to chronic liver diseases such as metabolic dysfunction-associated steatotic liver disease through the activation of hypoxia-inducible factors (HIFs). Hif2α has been shown to drive a severe steatohepatitis and fibrosis phenotype in mice. How Hif2α drives this injury is not fully known. We identified a core regulatory pathway that was disrupted in hepatocytes in a Hif2α-dependent fashion to identify a possible common signaling pathway that may predispose to progression of inflammation and fibrosis.

We utilized mouse primary hepatocytes and mouse liver tissue from genetic models of chronic hypoxia along with standard molecular methods and ammonia assays to identify abnormal nitrogen metabolism.

The urea cycle is significantly depressed in a HIF2α-dependent fashion, which leads to elevation of ammonia. The urea cycle is controlled by a master regulator of hepatocyte function called hepatocyte nuclear factor 4 alpha (HNF4α), which is suppressed by Hif2α.

Hif2α suppresses expression of a master regulator of hepatocyte biology, HNF4α, leading to significant disruption in hepatocyte-specific pathways such as the urea cycle. How Hif2α regulates HNF4α remains a point of active investigation, but inhibition of Hif2α may represent a therapeutic target to maintain the full function of a mature hepatocyte.