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Background <p>Niemann-Pick C1-like 1 (NPC1L1) mediates cholesterol absorption and plays major roles in cholesterol homeostasis. Our previous study showed that curcumin reduced NPC1L1 expression and cholesterol absorption in Caco-2 cells. This study aimed to investigate whether curcumin could prevent hypercholesterolemia by transcriptionally suppressing intestinal and hepatic NPC1L1 expression via inhibition of sterol regulatory element binding protein-2 (SREBP-2) and hepatocyte nuclear factor 1α (HNF1α) transcriptional activity.</p> Methods <p>Male hamsters were fed a high-fat diet (HFD) with or without 0.1% w/w curcumin for 12 weeks. Additionally, Caco-2 cells and HepG2 cells were treated with 6, 12, 25, or 50 µmol/L curcumin for 24&#xa0;h. The cholesterol absorption was determined with 22-NBD-cholesterol assay, the promoter activity of NPC1L1 and the transcriptional activity of SREBP-2 and HNF1α were determined with luciferase assay, and the gene expression of NPC1L1, SREBP-2, and HNF1α and the nuclear abundance of SREBP-2 and HNF1α were measured by RT-qPCR and Western blotting, respectively.</p> Results <p>Compared to HFD-fed hamsters, curcumin supplementation significantly lowered cholesterol levels in the serum (20.2%,) and liver (26.1%), and increased fecal neutral sterol excretion (114.5%). In addition, curcumin significantly reduced the gene expression of NPC1L1, SREBP-2, and HNF1α and the nuclear abundance of SREBP-2 and HNF1α in the small intestine and liver of HFD-fed hamsters. Furthermore, the dual luciferase assay showed that the promoter activity of NPC1L1 and the transcriptional activity of SREBP-2 and HNF1α in Caco-2 and HepG2 cells were dose-dependently inhibited after 24&#xa0;h curcumin treatment, and maximally inhibited by 50 µmol/L curcumin. Additionally, the gene expression of NPC1L1, SREBP-2, and HNF1α and the nuclear abundance of SREBP-2 and HNF1α in Caco-2 and HepG2 cells were consistently suppressed by curcumin. Curcumin also significantly reduced the cholesterol uptake in both Caco-2 and HepG2 cells.</p> Conclusions <p>Our findings indicate that curcumin prevents HFD-induced hypercholesterolemia by transcriptionally suppressing intestinal and hepatic NPC1L1 expression and cholesterol absorption via inhibition of SREBP-2 and HNF1α transcriptional activity. Our research provides evidence for curcumin as a potential nutraceutical for hypercholesterolemia treatment by regulating NPC1L1 and enterohepatic circulation metabolism of cholesterol.</p>

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Dietary curcumin prevents hypercholesterolemia by inhibiting the transcriptional activity of SREBP-2 and HNF1α and reducing intestinal and hepatic NPC1L1 expression in high-fat diet-fed hamsters

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月28日

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  • Zhuo Cao,
  • Jie Yang,
  • Haiyan Mai,
  • Ting Hong,
  • Xiaobing Chen,
  • Dan Feng

摘要

Background

Niemann-Pick C1-like 1 (NPC1L1) mediates cholesterol absorption and plays major roles in cholesterol homeostasis. Our previous study showed that curcumin reduced NPC1L1 expression and cholesterol absorption in Caco-2 cells. This study aimed to investigate whether curcumin could prevent hypercholesterolemia by transcriptionally suppressing intestinal and hepatic NPC1L1 expression via inhibition of sterol regulatory element binding protein-2 (SREBP-2) and hepatocyte nuclear factor 1α (HNF1α) transcriptional activity.

Methods

Male hamsters were fed a high-fat diet (HFD) with or without 0.1% w/w curcumin for 12 weeks. Additionally, Caco-2 cells and HepG2 cells were treated with 6, 12, 25, or 50 µmol/L curcumin for 24 h. The cholesterol absorption was determined with 22-NBD-cholesterol assay, the promoter activity of NPC1L1 and the transcriptional activity of SREBP-2 and HNF1α were determined with luciferase assay, and the gene expression of NPC1L1, SREBP-2, and HNF1α and the nuclear abundance of SREBP-2 and HNF1α were measured by RT-qPCR and Western blotting, respectively.

Results

Compared to HFD-fed hamsters, curcumin supplementation significantly lowered cholesterol levels in the serum (20.2%,) and liver (26.1%), and increased fecal neutral sterol excretion (114.5%). In addition, curcumin significantly reduced the gene expression of NPC1L1, SREBP-2, and HNF1α and the nuclear abundance of SREBP-2 and HNF1α in the small intestine and liver of HFD-fed hamsters. Furthermore, the dual luciferase assay showed that the promoter activity of NPC1L1 and the transcriptional activity of SREBP-2 and HNF1α in Caco-2 and HepG2 cells were dose-dependently inhibited after 24 h curcumin treatment, and maximally inhibited by 50 µmol/L curcumin. Additionally, the gene expression of NPC1L1, SREBP-2, and HNF1α and the nuclear abundance of SREBP-2 and HNF1α in Caco-2 and HepG2 cells were consistently suppressed by curcumin. Curcumin also significantly reduced the cholesterol uptake in both Caco-2 and HepG2 cells.

Conclusions

Our findings indicate that curcumin prevents HFD-induced hypercholesterolemia by transcriptionally suppressing intestinal and hepatic NPC1L1 expression and cholesterol absorption via inhibition of SREBP-2 and HNF1α transcriptional activity. Our research provides evidence for curcumin as a potential nutraceutical for hypercholesterolemia treatment by regulating NPC1L1 and enterohepatic circulation metabolism of cholesterol.