Exendin-4 regulates lipid metabolism and fibroblast growth factor 21 in hepatic steatosis.

Metabolism: clinical and experimental (2014-06-17)
Jinmi Lee, Seok-Woo Hong, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee
RESUMEN

Hepatokine fibroblast growth factor (FGF) 21 takes part in the regulation of lipid metabolism in the liver and adipose tissue. We investigated whether exendin-4 regulates the expression of FGF21 in the liver, and whether the effects of exendin-4 on the regulation of FGF21 expression are mediated via silent mating type information regulation 2 homolog (SIRT) 1 or SIRT6. The C57BL/6J mice were fed a low fat diet, high fat diet, or high fat diet with 1 nmol/kg/day exendin-4 intraperitoneal injection for 10 weeks. HepG2 used in vitro study was treated with palmitic aicd (0.4 mM) with or without exendin-4 (100 nM) and FGF21 (50 nM) for 24 hours. The change of FGF21 and its receptors expression by exendin-4 were measured using quantitative real-time RT-PCR and Western blot. The intracellular lipid content in HepG2 cells was evaluated by Oil Red O staining. Inhibition of FGF21, SIRT1 and SIRT6, by 10 nM siRNA was performed to establish the signaling pathway of exendin-4 action in hepatic lipid metabolism. Exendin-4 increased the expression of FGF21 and its receptors in high fat diet-induced obese mice. In addition, recombinant FGF21 treatment reduced lipid content in palmitic acid-treated HepG2 cells. We also observed significantly decreased expression of peroxisomal proliferator-activated receptor (PPAR) α and medium-chain acyl-coenzyme A dehydrogenase (MCAD) in hepatocytes transfected with FGF21 siRNA. In cells treated with exendin-4, inhibition of SIRT1, but not SIRT6, by siRNA significantly repressed the expression of FGF21 mRNA, whereas decreased SIRT1 expression by inhibition of FGF21 was not observed. These data suggest that exendin-4 could improve fatty liver by increasing SIRT1-mediated FGF21.

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Sigma-Aldrich
Palmitic acid, ≥99%
Sigma-Aldrich
Palmitic acid, BioXtra, ≥99%
Supelco
Palmitic acid, analytical standard
Supelco
Palmitic acid, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Palmitic acid, ≥95%, FCC, FG
Sigma-Aldrich
Palmitic acid, natural, 98%, FG
USP
Palmitic acid, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Palmitic acid, ≥98% palmitic acid basis (GC)
Palmitic acid, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Fibroblast Growth Factor from bovine pituitary, suitable for cell culture
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Palmitic acid, certified reference material, TraceCERT®