SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin

Pradeep Kumar, Pooja Malhotra, Ke Ma, Amika Singla, Omar Hedroug, Seema Saksena, Pradeep K. Dudeja, Ravinder K. Gill, Waddah A. Alrefai

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Curcumin, the major phenolic compound in the spice turmeric, exhibits numerous biological effects, including lowering plasma cholesterol and preventing diet-induced hypercholesterolemia. The mechanisms underlying the hypocholesterolemic effect of curcumin are not fully understood. In this regard, intestinal Niemann-Pick C1-like 1 (NPC1L1) cholesterol transporter, the molecular target of intestinal cholesterol absorption inhibitor ezetimibe, plays an essential role in the maintenance of cholesterol homeostasis. The current studies were designed to investigate the effect of curcumin on NPC1L1 function, expression, and promoter activity in intestinal Caco-2 monolayers. NPC1L1 function was evaluated by the measurement of ezetimibe-sensitive [3H]cholesterol esterification. Relative abundance of NPC1L1 mRNA and protein was evaluated by real-time PCR and Western blotting, respectively. Luciferase assays were used to measure NPC1L1 promoter activity. Our results showed that curcumin significantly inhibited ezetimibe-sensitive cholesterol esterification in a dose-dependent manner with a maximum decrease (by 52% compared with control) occurring at 50 μM concentration. Curcumin treatment of Caco-2 monolayers also significantly decreased NPC1L1 mRNA and protein expression. Similarly, the promoter activity of the NPC1L1 gene was inhibitedsignificantly (55%) by 50 μM curcumin. The decrease in NPC1L1 promoter activity by curcumin was associated with a reduction in the expression and the DNA-binding activity of the sterol response element-binding protein 2 (SREBP2) transcription factor. Furthermore, the overexpression of active SREBP2 protected NPC1L1 from the inhibitory effect of curcumin. Our studies demonstrate that curcumin directly modulates intestinal NPC1L1 expression via transcriptional regulation and the involvement of SREBP2 transcription factor.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume301
Issue number1
DOIs
StatePublished - Jul 1 2011

Fingerprint

Curcumin
Response Elements
Sterols
Carrier Proteins
Cholesterol
Esterification
Transcription Factors
Anticholesteremic Agents
Curcuma
Spices
Messenger RNA
Intestinal Absorption
Hypercholesterolemia
Luciferases
Real-Time Polymerase Chain Reaction
Proteins
Homeostasis
Western Blotting
Maintenance
Diet

Keywords

  • Niemann pick type C1-like 1
  • Polyphenols
  • Sterol response element-binding protein 2

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin. / Kumar, Pradeep; Malhotra, Pooja; Ma, Ke; Singla, Amika; Hedroug, Omar; Saksena, Seema; Dudeja, Pradeep K.; Gill, Ravinder K.; Alrefai, Waddah A.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 301, No. 1, 01.07.2011.

Research output: Contribution to journalArticle

Kumar, Pradeep ; Malhotra, Pooja ; Ma, Ke ; Singla, Amika ; Hedroug, Omar ; Saksena, Seema ; Dudeja, Pradeep K. ; Gill, Ravinder K. ; Alrefai, Waddah A. / SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2011 ; Vol. 301, No. 1.
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abstract = "Curcumin, the major phenolic compound in the spice turmeric, exhibits numerous biological effects, including lowering plasma cholesterol and preventing diet-induced hypercholesterolemia. The mechanisms underlying the hypocholesterolemic effect of curcumin are not fully understood. In this regard, intestinal Niemann-Pick C1-like 1 (NPC1L1) cholesterol transporter, the molecular target of intestinal cholesterol absorption inhibitor ezetimibe, plays an essential role in the maintenance of cholesterol homeostasis. The current studies were designed to investigate the effect of curcumin on NPC1L1 function, expression, and promoter activity in intestinal Caco-2 monolayers. NPC1L1 function was evaluated by the measurement of ezetimibe-sensitive [3H]cholesterol esterification. Relative abundance of NPC1L1 mRNA and protein was evaluated by real-time PCR and Western blotting, respectively. Luciferase assays were used to measure NPC1L1 promoter activity. Our results showed that curcumin significantly inhibited ezetimibe-sensitive cholesterol esterification in a dose-dependent manner with a maximum decrease (by 52{\%} compared with control) occurring at 50 μM concentration. Curcumin treatment of Caco-2 monolayers also significantly decreased NPC1L1 mRNA and protein expression. Similarly, the promoter activity of the NPC1L1 gene was inhibitedsignificantly (55{\%}) by 50 μM curcumin. The decrease in NPC1L1 promoter activity by curcumin was associated with a reduction in the expression and the DNA-binding activity of the sterol response element-binding protein 2 (SREBP2) transcription factor. Furthermore, the overexpression of active SREBP2 protected NPC1L1 from the inhibitory effect of curcumin. Our studies demonstrate that curcumin directly modulates intestinal NPC1L1 expression via transcriptional regulation and the involvement of SREBP2 transcription factor.",
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