The Potential Role of Fibroblast Growth Factor 21 in Lipid Metabolism and Hypertension

Fibroblast growth factor (FGF) 21 belongs to the FGF superfamily that is involved in cell proliferation and differentiation, neural development, angiogenesis, and metabolism. FGF21 requires beta-Klotho as a co-receptor. Tissues involved in metabolism such as the liver, adipose tissues, skeletal muscle, and pancreas express FGF21. Starvation increases hepatic expression of FGF21, which then acts centrally to increase hepatic gluconeogenesis. FGF21 also increases fatty acid oxidation. This may be relevant in cold exposure, when expression of FGF21 is induced. Chronic treatment with recombinant FGF21 reduces serum and hepatic triglyceride levels and ameliorates fatty liver in obese mice, through the suppression of the lipogenic gene, Srebp-1. FGF21 reduces hepatic cholesterol production by inhibiting Srebp-2, a transactivator of proprotein convertase subtilisin/kexin type 9 (PCSK9). LY2045319, an FGF21 analog, reduces LDL-C and triglycerides and increases HDL-C in obese human subjects with type 2 diabetes. FGF21 does not seem to lower blood pressure acutely. In rats fed with high-fructose water to induce mild hypertension, 4-week treatment with recombinant FGF21 led to normalization of systolic blood pressure and improved serum lipid profile. FGF receptors and beta-Klotho are expressed on the nucleus tractus solitarii and nodose ganglion in the baroreflex afferent pathway. Moreover, FGF21 acts on the hypothalamus to release corticosterone and induces in adipocytes the production of adiponectin, an adipokine with antihypertensive activities. Therefore, FGF21 may decrease blood pressure indirectly, through its actions in the liver, brain, and adipose tissues.