Curcumin protects against bisphenol A-induced hepatic steatosis by inhibiting cholesterol absorption and synthesis in CD-1 mice

Abstract

Curcumin is a polyphenol extracted from the rhizome of turmeric, and our previous research showed that curcumin inhibited cholesterol absorption and had cholesterol-lowering effect. Bisphenol A (BPA), a common plasticizer, is widely used in the manufacture of food packaging and is associated with non-alcoholic fatty liver disease (NAFLD). We hypothesized that curcumin could protect against BPA-induced hepatic steatosis by inhibiting cholesterol absorption and synthesis. Male CD-1 mice fed BPA-contaminated diet with or without curcumin for 24 weeks were used to test our hypothesis. We found that chronic low-dose BPA exposure significantly increased the levels of serum triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol and the contents of liver TG and TC, resulting in liver fat accumulation and hepatic steatosis while curcumin supplementation could alleviate BPA-induced dyslipidemia and hepatic steatosis. Moreover, the anti-steatosis and cholesterol-lowering effects of curcumin against BPA coincided with a significant reduction in intestinal cholesterol absorption and liver cholesterol synthesis, which was modulated by suppressing the expression of sterol regulatory element-binding protein-2 (SREBP-2), Niemann-Pick C1-like 1 (NPC1L1), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the small intestine and liver. In addition, the expression levels of liver lipogenic genes such as liver X receptor alpha (LXRα), SREBP-1c, acetyl-CoA carboxylase 1 (ACC1), and ACC2 were also markedly down-regulated by curcumin. Overall, our findings indicated that curcumin inhibited BPA-induced intestinal cholesterol absorption and liver cholesterol synthesis by suppressing SREBP-2, NPC1L1, and HMGCR expression, subsequently reducing liver cholesterol accumulation and fat synthesis, thereby preventing hepatic steatosis and NAFLD.

Keywords: 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase; Niemann–Pick C1‐like 1; bisphenol A; curcumin; hepatic steatosis.

FIGURE 1

Bar plot of serum biochemical markers in CD‐1 mice. Male CD‐1 mice were fed BPA‐contaminated diet with or without curcumin for 24 weeks. (a–d) Serum TG, TC, LDL‐C, and HDL‐C levels; (e, f) Serum ALT and AST activity. Results are expressed as mean ± SEM (n = 8), *p < .05 versus control group, and ^# p < .05 versus BPA group.

FIGURE 2

Curcumin improved liver histological changes and hepatic steatosis induced by BPA in CD‐1 mice. Male CD‐1 mice were fed BPA‐contaminated diet with or without curcumin for 24 weeks. (a) Representative pictures of H&E staining showing the liver morphological changes (200 × magnifications, 400 × magnifications); (b) Representative pictures of Oil Red O staining showing the liver fat accumulation (200 × magnifications, 400 × magnifications). The arrows refer to hepatocytes with significant histopathological changes.

FIGURE 3

Curcumin inhibited the expression of SREBP‐2, HMGCR, and NPC1L1 induced by BPA in CD‐1 mice. Male CD‐1 mice were fed BPA‐contaminated diet with or without curcumin for 24 weeks. (a) The protein expression levels of SREBP‐2 and HMGCR in the liver; (b, c) The quantitative analysis of Western blotting assay for SREBP‐2 and HMGCR expression. (d) The protein expression levels of SREBP‐2 and NPC1L1 in the small intestine; (e, f) The quantitative analysis of Western blotting assay for SREBP‐2 and NPC1L1 expression. Results are expressed as mean ± SEM (n = 8), *p < .05 versus control group, and ^# p < .05 versus BPA group.

FIGURE 4

Curcumin inhibited the expression of liver lipogenic genes induced by BPA in CD‐1 mice. Male CD‐1 mice were fed BPA‐contaminated diet with or without curcumin for 24 weeks. (a–d) The mRNA expression levels of LXRα, SREBP‐1c, ACC1, and ACC2 in the liver; (e) The protein expression levels of LXRα, SREBP‐1c, ACC1, and ACC2 in the liver; (f–i) The quantitative analysis of western blotting assay for LXRα, SREBP‐1c, ACC1, and ACC2 expression. Results are expressed as mean ± SEM (n = 8), *p < .05 versus control group, and ^# p < .05 versus BPA group.