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. 2017;2017:8234507.
doi: 10.1155/2017/8234507. Epub 2017 Jul 9.

PEGylated Curcumin Derivative Attenuates Hepatic Steatosis via CREB/PPAR- γ/CD36 Pathway

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Free PMC article

PEGylated Curcumin Derivative Attenuates Hepatic Steatosis via CREB/PPAR- γ/CD36 Pathway

Yu Liu et al. Biomed Res Int. .
Free PMC article

Abstract

Curcumin has the potential to cure dyslipidemia and nonalcoholic fatty liver disease (NAFLD). However, its therapeutic effects are curbed by poor bioavailability. Our previous work has shown that modification of curcumin with polyethylene glycol (PEG) improves blood concentration and tissue distribution. This study sought to investigate the role of a novel PEGylated curcumin derivative (Curc-mPEG454) in regulating hepatic lipid metabolism and to elucidate the underlying molecular mechanism in a high-fat-diet- (HFD-) fed C57BL/6J mouse model. Mice were fed either a control chow diet (D12450B), an HFD (D12492) as the NAFLD model, or an HFD with Curc-mPEG454 administered by intraperitoneal injection at 50 mg/kg or 100 mg/kg for 16 weeks. We found that Curc-mPEG454 significantly lowered the body weight and serum triglyceride (TG) levels and reduced liver lipid accumulation in HFD-induced NAFLD mice. It was also shown that Curc-mPEG454 suppressed the HFD-induced upregulated expression of CD36 and hepatic peroxisome proliferator activated receptor-γ (PPAR-γ), a positive regulator of CD36. Moreover, Curc-mPEG454 dramatically activated cAMP response element-binding (CREB) protein, which negatively controls hepatic PPAR-γ expression. These findings suggest that Curc-mPEG454 reverses HFD-induced hepatic steatosis via the activation of CREB inhibition of the hepatic PPAR-γ/CD36 pathway, which may be an effective therapeutic for high-fat-diet-induced NAFLD.

Figures

Figure 1
Figure 1
The chemical structure of Curc-mPEG454.
Figure 2
Figure 2
Curc-mPEG454 reduced hepatic steatosis and hepatic lipid levels after 16-week treatment. Compared with the livers in the chow group, HFD-induced typical steatosis was evidenced by H&E staining (a) and oil red O staining (b) of lipids in representative liver section; a test system containing 36 test points was superimposed on HE-stained images, and the degree of steatosis was assessed by point counting (c), the degree of steatosis of each group (d), and the content of liver TG (e). Curc-mPEG454 treatment significantly reversed the changes. Quantified date are mean ± SD. ∗∗∗P < 0.001 versus chow group; ##P < 0.01 and ###P < 0.001 versus HFD group.
Figure 3
Figure 3
Effects of Curc-mPEG454 on CD36 expression and hepatic lipid metabolic relative genes in mice after 16-week treatment. qPCR analysis of mRNA levels of genes involved in hepatic lipogenesis, FA oxidation, lipid uptake, TG secretion, and bile acid synthesis (a). Western blot analysis and quantification of CD36 protein; β-actin served as an internal control ((b) and (c)). The immunohistochemical staining of CD36 in liver tissue; the black arrows indicate positive expression of CD36 (d). All figures are representative of at least 3 independent experiments. Quantified date are mean ± SD. P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus chow group; ##P < 0.01 and ###P < 0.001 versus HFD group.
Figure 4
Figure 4
Effects of Curc-mPEG454 on lipid accumulation and PPAR-γ expression in liver. qPCR analysis of mRNA levels of genes involved in regulation of CD36 (a). Western blot analysis and quantification of PPAR-γ protein; β-actin served as an internal control ((b) and (c)). All figures are representative of at least 3 independent experiments. Quantified date are mean ± SD. ∗∗∗P < 0.001 versus chow group; ###P < 0.001 versus HFD group.
Figure 5
Figure 5
Curc-mPEG454 activated CREB phosphorylation in liver. qPCR analysis of CREB expression (a). Western blot analysis and quantification of phospho-CREB and CREB protein; β-actin served as an internal control ((b) and (c)). The immunohistochemical staining of phospho-CREB in liver tissue (d). All figures are representative of at least 3 independent experiments. Quantified data are the mean ± SD. P < 0.05 and ∗∗∗P < 0.001 versus chow group; #P < 0.05 and ###P < 0.001 versus HFD group.
Figure 6
Figure 6
Schematic illustration of molecular mechanism involved in antisteatosis of Curc-mPEG454. The red arrows indicate that Curc-mPEG454 may coordinate hepatic lipid through activation of CREB phosphorylation and then inhibition of PPAR-γ and CD36 expression. The pathway of CREB/PPAR-γ/CD36 plays a crucial role in lipid metabolism in HFD-induced NAFLD.

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