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Curcumin Prevents High-Fat Diet-Induced Hepatic Steatosis in ApoE -/- Mice by Improving Intestinal Barrier Function and Reducing Endotoxin and Liver TLR4/NF-κB Inflammation

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Curcumin Prevents High-Fat Diet-Induced Hepatic Steatosis in ApoE -/- Mice by Improving Intestinal Barrier Function and Reducing Endotoxin and Liver TLR4/NF-κB Inflammation

Dan Feng et al. Nutr Metab (Lond).

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and has become a public health concern worldwide. The hallmark of NAFLD is hepatic steatosis. Therefore, there is an urgent need to develop new therapeutic strategies that are efficacious and have minimal side effects in hepatic steatosis and NAFLD treatment. The present study aimed to investigate the effect of dietary supplement of curcumin on high-fat diet (HFD)-induced hepatic steatosis and the underlying mechanism.

Methods: ApoE-/- mice were fed a normal diet, high-fat diet (HFD) or HFD supplemented with curcumin (0.1% w/w) for 16 weeks. Body and liver weight, blood biochemical.parameters, and liver lipids were measured. Intestinal permeability, hepatic steatosis and mRNA and protein expressions of TLR4-related inflammatory signaling molecule were analyzed.

Results: The administration of curcumin significantly prevented HFD-induced body weight gain and reduced liver weight. Curcumin attenuated hepatic steatosis along with improved serum lipid profile. Moreover, curcumin up-regulated the expression of intestinal tight junction protein zonula occluden-1 and occludin, which further improved gut barrier dysfunction and reduced circulating lipopolysaccharide levels. Curcumin also markedly down-regulated the protein expression of hepatic TLR4 and myeloid differentiation factor 88 (MyD88), inhibited p65 nuclear translocation and DNA binding activity of nuclear factor-κB (NF-κB) in the liver. In addition, the mRNA expression of hepatic tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) as well as the plasma levels of TNF-α and IL-1β were also lowered by curcumin treatment.

Conclusion: These results indicated that curcumin protects against HFD-induced hepatic steatosis by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-κB inflammation. The ability of curcumin to inhibit hepatic steatosis portrayed its potential as effective dietry intervention for NAFLD prevention.

Keywords: Curcumin; Hepatic steatosis; Lipopolysaccharide; Nuclear factor-κB; Tight junction protein; Toll like receptor 4.

Conflict of interest statement

Competing interestsConflict of interest On behalf of all authors, the corresponding author states. that there is no conflict of interest.

Figures

Fig. 1
Fig. 1
Effects of curcumin on liver histology and hepatic TG content in HFD-fed ApoE−/− mice. ApoE−/− mice were fed a normal diet, high-fat diet and high-fat diet supplemented with 0.1% curcumin (w/w) for 16 weeks, histological analysis of steatosis in liver sections stained with H&E (a) or Oil Red O (b) (magnification 200 ×). Hepatic TG content (c). Histological changes of steatosis in the liver were semi-quantitative and expressed as steatosis scores (d). Results are mean ± SEM (n = 10 per group). ##P < 0.01 versus control group; *P < 0.05, **P < 0.01 versus HF group. Control, normal diet; HF, high-fat diet; HF + Curcumin, high-fat diet supplemented with curcumin
Fig. 2
Fig. 2
Effects of curcumin on circulating LPS levels in HFD-fed ApoE−/− mice. ApoE−/− mice were fed a normal diet, high-fat diet and high-fat diet supplemented with 0.1% curcumin (w/w) for 16 weeks, the serum LPS levels were measured by ELISA. Results are mean ± SEM (n = 10 per group). ##P < 0.01 versus control group; **P < 0.01 versus HF group. Control, normal diet; HF, high-fat diet; HF + Curcumin, high-fat diet supplemented with curcumin
Fig. 3
Fig. 3
Effects of curcumin on intestinal permeability in HFD-fed ApoE−/− mice. ApoE−/− mice were fed a normal diet, high-fat diet and high-fat diet supplemented with 0.1% curcumin (w/w) for 16 weeks. (a) The protein expression of ZO-1 and occludin in ileal tissues was measured by Western blotting. (Top panel) Representative blot, (Bottom panel) Quantitative analysis of panel A. Results are mean ± SEM (n = 10 per group). ##P < 0.01 versus control group; *P < 0.05, **P < 0.01 versus HF group. (b) Ultrastructural observation of the tight junctions in the ileal mucosa and the width of the tight junction gap (transmission electron microscopy, 4000× or 8000×) (n = 10 per group). (c) The width of the tight junction gap (n = 10 per group). #P < 0.05 versus control group; *P < 0.05 versus HF group. Control, normal diet; HF, high-fat diet; HF + Curcumin, high-fat diet supplemented with curcumin
Fig. 4
Fig. 4
Effects of curcumin on hepatic TLR4 and MyD88 expression in HFD-fed ApoE−/− mice. ApoE−/− mice were fed a normal diet, high-fat diet and high-fat diet supplemented with 0.1% curcumin (w/w) for 16 weeks. (a) TLR4 expression in the liver was measured by immunohistochemical staining. Representative images of the control, HF and HF + curcumin groups (200 × magnification). (b) The protein expression levels of hepatic TLR4 and MyD88 were analyzed by Western blotting. (Top panel) Representative blot, (Bottom panel) Quantitative analysis of panel B. Results are mean ± SEM (n = 10 per group). #P < 0.05 versus control group, *P < 0.05 versus HF group. Control, normal diet; HF, high-fat diet; HF + Curcumin, high-fat diet supplemented with curcumin
Fig. 5
Fig. 5
Effects of curcumin on hepatic NF-κB activation in HFD-fed ApoE−/− mice. ApoE−/− mice were fed a normal diet, high-fat diet and high-fat diet supplemented with 0.1% curcumin (w/w) for 16 weeks. Nuclear extracts from liver tissue were prepared for Western blotting of the p65 subunit of NF-κB (a) or NF-κB binding activity assay (b). For panel A, (Top panel) Representative blot, (Bottom panel) Quantitative analysis of panel A. Results are mean ± SEM (n = 10 per group). #P < 0.05 versus control group, *P < 0.05 versus HF group. Control, normal diet; HF, high-fat diet; HF + Curcumin, high-fat diet supplemented with curcumin
Fig. 6
Fig. 6
Effects of curcumin on hepatic TNF-α and IL-1β expression in HFD-fed ApoE−/− mice. ApoE−/− mice were fed a normal diet, high-fat diet and high-fat diet supplemented with 0.1% curcumin (w/w) for 16 weeks. (a) Hepatic TNF-α and IL-1β mRNA expression was analyzed by quantitative real-time PCR as described in the Materials and Methods. Expression values were normalized to housekeeping gene GAPDH. Results are mean ± SEM (n = 10 per group). #P < 0.05 versus control group, *P < 0.05 versus HF group. (b) The plasma TNF-α and IL-1β levels were measured by ELISA. Results are mean ± SEM (n = 10 per group). #P < 0.05 versus control group, *P < 0.05 versus HF group. Control, normal diet; HF, high-fat diet; HF + Curcumin, high-fat diet supplemented with curcumin

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