Fibroblast Growth Factor Binding Protein 3: A Novel Target for Glucose Intolerance and Nonalcoholic Fatty Liver Disease Treatment
Garman, Khalid A
ABSTRACTEndocrine Fibroblast Growth Factor 21 (FGF21) has been shown to improve insulin sensitivity, glucose tolerance, and hepatosteatosis in many species. Previous studies have demonstrated that Fibroblast Growth Factor Biding Proteins (FGFBPs) protect FGFs from proteolytic degradation and enhance their binding to their cognate receptors. In our studies, we report that FGFBP3-/- mice suffer insulin resistance and impaired glucose homeostasis, which was further aggravated by diet-induced obesity. In FGFBP3-/- mice, we further report on the scant liver fat content in lean regular diet mice and the paradoxical high-fat diet-induced hepatosteatosis. We show that endogenous FGFBP3 controls liver fat content through its effect on fatty acid synthesis (Fasn, ACAC, ACLY, AACS, ACAS2, and SCD1), fatty acid uptake (SLC27A5), long-chain fatty acid activation (ACSL1 and ACSL5), and triglyceride synthesis (Dgat1 and Dgat2). In contrast, we demonstrate that exogenous FGFBP3 administration ameliorates hepatosteatosis in leptin-deficient ob/ob mice via promotion of peroxisomal fatty acid oxidation (EHHADH) and triglyceride secretion (MTTP). We also describe the high-fat diet-induced upregulation of hepatic and white adipose tissue FGF21 and KL in the FGFBP3-/- mice. Our studies indicate a more prominent FGFBP3 effect on the liver compared to white adipose tissue. Collectively, our studies indicate a possible collaboration between FGFBP3 and FGF21 on blood glucose and liver fat content homeostasis.
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