Hepatic FGF21: Its Emerging Role in Inter-Organ Crosstalk and Cancers

Abstract

Fibroblast growth factor (FGF) 21 is one of the FGF members with special endocrine properties. In the last twenty years, it has attracted intense research and development for its physiological functions that respond to dietary manipulation, pharmacological benefits of improving the macronutrient metabolism, and clinical values as a biomarker of various human diseases. Generally, FGF21 can be produced by major metabolic organs, but only the subgroup from the liver shows canonical endocrine properties, which emphasizes the special value of delineating the unique secretory and functional characteristics of hepatic FGF21. There has been a growth in literature to address the extra-hepatic activities of FGF21, and many striking findings have therefore been published. Yet, they are fragmented and scattered, and controversies are raised from divergent findings. For this reason, there is a need for a systematic and critical evaluation of current research in this aspect. In this review, we focus on the current knowledge about the molecular biology of endocrine FGF21, especially present details on the regulation of circulating levels of FGF21. We also emphasize its emerging roles in inter-organ crosstalk and cancer development.

Keywords: Cancer; Endocrine FGF21; Fibroblast growth factor 21; Hepatic FGF21; Inter-organ crosstalk; Liver.

Figure 1

Timeline figure showing the milestones in the history and development of FGF21. Since 2000, FGF21 has attracted great interest due to its pleiotropic effects in response to diverse physiological and pathological stress. With the knowledge of FGF21 expanding exponentially, our understanding of its biology is constantly undergoing modification, and the therapeutic value of FGF21 is being hotly discussed.

Figure 2

The regulation of hepatic FGF21. The expression of FGF21 is tightly connected with circadian rhythm, diet intervention, exercise, and cold exposure. The circadian rhythm of FGF21 is controlled by several clock proteins. PPARα and RORα positively activate the expression of FGF21 while REV-ERBα and E4BP4 repress its transcription; Exercise stimulates FGF21 expression via the increased plasma glucagon to insulin ratio, and this process positively correlated with the elevated lipolysis and decreased glucose levels; Diet regimen has magnificent impacts on FGF21 levels, both nutrient proportions and food timing are implicated in the complex regulation system of FGF21; Increased FGF21 is also observed under cold exposure which may be cooperated with the thermogenic response of BAT to maintain body temperature.

Figure 3

Hepatic FGF21 is a modulator in liver-participated inter-organ crosstalk. The aberrant expressions of FGF21 have been associated with brain, eye, and heart diseases and implicated in various liver-participated inter-organ crosstalk. As a modulator, hepatic FGF21 has displayed an important role in mediating brain-regulated adaptive response and adipose tissue-performed energy metabolism.

Figure 4

Hepatic FGF21 is a promising biomarker for cancers. Aberrant expression of FGF21 has been correlated with cancer development. Accumulating data indicated the predictive and diagnostic values of FGF21 as a promising biomarker for human cancers, for some of which its underlying mechanisms have been discussed.