In the Zone: How a Hepatocyte Knows Where It Is

The molecular regulation of metabolic zonation in the liver. Hepatocytes near the portal vein are exposed to a very different environment and fulfill different functions than those near the central vein. In perivenous hepatocytes, a local Wnt signal of yet unknown nature binds to frizzled receptors (Frz) on the hepatocyte surface and activates the Wnt/APC/β-catenin pathway. Stabilization of β-catenin leads to its nuclear translocation, activation of the transcription factor Lef1, and activation of glutamine synthetase (GS) and cytochrome p450 enzymes (Cyp1A1). Conversely, in periportal hepatocytes, which are not exposed to a Wnt signal, β-catenin is degraded via the APC complex, and periportal genes such as glutaminase 2 (Gls2) are activated by HNF4α, whereas perivenous genes seem to be repressed by the same factor.⁷ Action of the Wnt/APC/β-catenin pathway in metabolic zonation of the liver does not require activation of c-Myc.⁸