Regulation Of Hepatic Expression Of FGF21in Diabetic Mice By The RXRα Agonist Bexarotene And Its Effects On Atherosclerosis

Aims: To explore the role of the regulation of retinoid X receptor alpha (RXRα) bythe synthetic agonist bexarotene (Bex) on the hepatic expression of fibroblast growthfactor21(FGF21) in streptozotocin (STZ)-induced diabetic apolipoprotein E knockout(ApoE-/-) mice and Bex’s effect on atherosclerosis.Methods: Eight C57mice composed the control group, and fifty-two ApoE-/-micewere randomly divided into the following four groups: ApoE-/-; STZ-ApoE-/-;STZ-ApoE-/-+Bex (10mg/kg/d) or STZ-ApoE-/-+Bex (30mg/kg/d). Intraperitonealinjection of streptozotocin was used to produce a diabetic animal model. Bloodglucose levels were determined with the glucose oxidase method. Blood lipid levelswere detected with the enzymic method or the selective homogeneous method.Real-time PCR was used to measure FGF21mRNA levels, and western blotting wasused to detect FGF21protein levels. Thoracic aorta lipid plaques were observed withSudan Ⅲ staining. The plaque area in the thoracic aorta was measured with H-Estaining. In vitro, hepatic cells were exposed to glucose (25mM) and9-cis-RA (10-7M), to observe FGF21mRNA and protein levels.Results:(1) Compared to the C57mice, blood glucose levels in the STZ-ApoE-/-mice were greatly elevated. Bexarotene dose-dependently decreased fasting plasmaglucose levels in the STZ-induced ApoE-/-mice. Blood glucose levels in theSTZ-ApoE-/-+Bex (30mg/kg/d) mice were much lower than those of theSTZ-ApoE-/-mice (14.7±2.68mM vs.17.82±2.26mM，P<0.05).(2) Compared tothe ApoE-/-mice, FGF21levels were elevated in the STZ-ApoE-/-mice. Furthermore,bexarotene remarkably decreased the expression of hepatic FGF21mRNA and proteinin a dose-dependent manner, and the FGF21mRNA and protein levels in theSTZ-ApoE-/-+Bex (10mg/kg/d) mice were lower than the levels in the STZ-ApoE-/- mice (FGF21mRNA:17.54±3.15vs.40.15±6.26, respectively, P<0.05; FGF21protein:0.192±0.030vs.0.426±0.095, respectively, P<0.05).(3) Compared to theC57mice, triglyceride (TG), total cholesterol (TCHO), and low-densitylipoprotein-cholesterol (LDL-C) levels were increased in the ApoE-/-mice. Moreover,lipid levels in the STZ-ApoE-/-mice were greatly elevated compared to the ApoE-/-mice. Bexarotene reduced TG, TCHO and LDL-C levels and increased high-densitylipoprotein-cholesterol (HDL-C) levels. Bexarotene also inhibited fat deposits andreduced the plaque area in the thoracic arteries. Compared to the STZ-ApoE-/-mice,the plaque areas of the STZ-ApoE-/-+Bex (10mg/kg/d) and STZ-ApoE-/-+Bex (30mg/kg/d) mice were all significantly reduced (78.72±4.62um2and46.13±7.56um2vs.94.06±8.04um2, P<0.05).(4) Exposure to a high concentration of glucose (25mM) increased hepatic cell FGF21levels in a time-dependent manner, and theselevels peaked at eight hours after exposure; the RXRα agonist9-cis-RA(10-7M)decreased FGF21levels after exposure to high-concentration glucose (25mM) at theeight-hour time point.Conclusion: The RXRα agonist bexarotene improved glucolipid metabolism andatherosclerosis in the STZ-ApoE-/-mice. High-concentration glucose could inducethe expression of hepatic FGF21mRNA and protein in the ApoE-/-mice. TheRXRα agonist bexarotene down-regulate liver FGF21levels, which may be associatedwith improved glucose metabolism.