Functions of FGF21 and its role in cardiac hypertrophy

Fig. 1. Regulation of FGF21 expression and secretion. (1). The level of FGF21 is increased via the ATF4-PPARα pathway or SIRT1-PPARα in response to exercise. (2) FGF21 expression is increased via the IRE1α/XBP1 pathway or the PERK-eIF2α-ATF4 pathway under ERS. (3) T3 affects the expression of FGF21 via TRβ, RXR and PPARα. (4) ChREBP and PPARα cross-talk mediates the response of FGF21 to high glucose. (5) GR cooperates with PPARα to stimulate FGF21 transcription. (6) The activated CREBH protein interacts with PPARα to induce FGF21 expression in the fasting state. (7) PPARα, RARβ, or NR4A1 stimulate the transcription of FGF21 in a fasting state. (8) Activation of FXR mediates FGF21 expression. (9) IL-4/IL-13 activates STAT6, which further stimulates FGF21 transcription. (10) PPARγ can increase the FGF21 level. (11) FGF21 is upregulated by activating ATF2.

Fig. 2. FGF21 functions in tissue energy metabolism. (1) Prolonged fasting induces the generation of FGF21 in the liver, which penetrates the blood–brain barrier, causing the release of CRH in hypothalamic neurons. This subsequently activates CREB to increase gluconeogenesis in the liver. (2) FGF21 promotes glucose absorption and FAO and inhibits insulin resistance and lipogenesis in hepatic tissue. (3) FGF21 accelerates lipoprotein lipase activity and lipoprotein catabolism and inhibits lipolysis in BAT and WAT. (4) FGF21 improves β cell mass and function. (5) FGF21 promotes glucose uptake in the heart.

Fig. 3. FGF21 functions in inflammation. (1) LPS triggers the transformation of M0 to M1 macrophages and increases the levels of IL-1β, TNF-α, and IL-6, which are inhibited by FGF21. FGF21 increases IL-10 levels, further enhancing the conversion of M0 macrophages to M2 macrophages and increasing the secretion of IL-10.

Fig. 4. FGF21 functions in oxidative stress. (1) ERS and the LP-mediated PEAK-eIF2α-ATF4 pathway increase FGF21 levels, and oxLDL increases the expression of FGF21, which increases Nrf2 expression and increases the expression of SOD2, UCP3 and HO1 to decrease oxidative stress. (2) FGF21 activates ERK, which inhibits NF-κB to decrease ROS production.

Fig. 5. FGF21 functions in apoptosis. (1) FGF21 inhibits apoptosis via AKT1/MDM2 to inhibit p53, promoting the release of Bcl-2/Bcl-X and resulting in the suppression of BAX/BAK and the inhibition of apaf1 and caspases. (2) FGF21 interacts with FGFR1 and KLB to activate the PI3K-AKT1 cascade, causing BAD phosphorylation and Bcl-2/Bcl-X release, which suppresses apoptosis. (3) The FGF21-PI3K-AKT-FoxO3a pathway and the FGF21-SIRT1-FoxO1 pathway inhibit BIM, contributing to the release of Bcl-2/Bcl-X to inhibit apoptosis.

Fig. 6. FGF21 functions in autophagy. (1) FGF21 increases Beclin1 and conversion of LC3I to LC3II and decreases p62, ultimately increasing autophagy. (2) FGF21 increases Beclin1 and VPS34 levels, enhancing autophagy flux.

Fig. 7. FGF21 suppresses pathological cardiac hypertrophy. FGF21 protects against cardiac hypertrophy through the following mechanisms: (1) FGF21 inhibits IKK and IκBα phosphorylation, causing NF-κB localization in the cytosol, which inhibits TNF-α and IL-6 levels and suppresses inflammation. (2) FGF21 stimulates the SIRT1-FoxO1-SOD/CAT pathway, leading to the acceleration of ROS elimination. (3) FGF21 activates the SIRT1-PGC-1α-PPARα pathway and SIRT1-LKB1-AMPK, which upregulate mitochondrial FAO. (4) FGF21 activates SIRT1-LKB1-AMPK, inhibiting apoptosis. (5) FGF21 increases the level of miR-145 to increase the levels of Beclin1 and LC3, ultimately enhancing autophagy.