Fibroblast Growth Factor 21 Prevents Atherosclerosis by Suppression of Hepatic Sterol Regulatory Element-Binding Protein-2 and Induction of Adiponectin in Mice
Background—Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor (PPAR) α and PPARγ, the agonists of which have been used for lipid-lowering and insulin-sensitization respectively. However, the role of FGF21 in cardiovascular system remains elusive.
Methods and Results—The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apoE-/- mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apoE-/- mice, which was accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apoE-/- mice via two independent mechanisms: inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor Sterol regulatory Element-Binding Protein-2 (Srebp-2), thereby leading to reduced cholesterol synthesis and attenuation of hypercholeseterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apoE-/- mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of Srebp-2.
Conclusions—FGF21 protects against atherosclerosis via fine-tuning the multi-organ crosstalk between liver, adipose tissue and blood vessels.
- Received January 7, 2015.
- Revision received March 10, 2015.
- Accepted March 13, 2015.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.