Figure 7. Schematic illustration of cellular and molecular events underlying hepatocyte DKK1-regulated hepatic steatosis.

In response to continuous challenge with HFD, (1) the DKK1 expression is mainly induced in hepatocytes and the increased serum DKK1 could have served as a diagnostic bio-marker for steatohepatitis progression. (2) DKK1 enhances hepatic CD36 expression by activating ERK-PPARγ signaling and consequently leads to increased hepatic fatty acid uptake and hepatocyte steatosis. (3) DKK1 activates JNK to decrease the phosphorylation of AKT and FOXO1, leading to insulin resistance. Hepatic fatty acid uptake and insulin resistance synergistically exacerbate fatty acid accumulation and the resultant hepatic steatosis.