Studies in mice indicate that FGF21 is inducible and the liver is a major source of circulating FGF21 (9, 10). Parallel to serum levels, expression of hepatic FGF21 under normal physiological conditions is low; however, during prolonged fasting and starvation, both hepatic and serum FGF21 become dramatically elevated. This triggered early proposals that the physiological role of FGF21 was a starvation hormone that regulates ketogenesis essential for brain function during severe carbohydrate deficits (9, 10). A growing number of studies with animals and patients indicate that FGF21 is induced, in addition to starvation and obesity, by diverse pathogenic conditions such as liver injury, viral infection, chemical insult, specific nutritional deficiency, the hepatic regenerative response as well as liver diseases as hepatosteatosis, steatohepatitis, cirrhosis, and liver cancer (11–17). The common feature of all these conditions is that they impose stress on the liver that compromises its role in maintenance of organism metabolic homeostasis. Therefore, hepatic FGF21 appears to be an inducible hepatic stress signal.
