Molecular mechanism for nobiletin to enhance ABCA1/G1 expression in mouse macrophages
Tomoe Tsuboi1, Rui Lu1, Takayuki Yonezawa2
1Bioscience and Biotechnology, Chubu University, Kasaugai, Aichi, 487-8501, Japan.
Background And Aims:
Nobiletin (NOB), a functional ingredient found in citrus peel, is said to act against diabetes, obesity, and atherosclerosis. It has been reported to activate AMPK pathway, as well as increase SREBP1c, PPARα and PPARγ expression. However, no molecular mechanism has been elucidated to be able to integrate these sporadic findings with some controversies to lead to concrete outcomes. In this study, regulation of HDL biogenesis by NOB was investigated modulating ABCA1 and ABCG1 expression.
Methods And Results:
Regulation of ABCA1/G1 by NOB was investigated in mouse macrophages J774.1. NOB increased mRNA and protein levels of ABCA1/G1, and cell cholesterol release by these factors. It also increased mRNA of PPARγ and LXRα but not PPARα. The increase in ABCA1/G1 mRNA levels by NOB was suppressed by antagonists of PPARγ and LXRα. The increase in PPARγ mRNA levels by NOB was suppressed by an LXRα antagonist, and the increase in LXRα mRNA levels was suppressed by a PPARγ antagonist. NOB increased CD36 mRNA and this was suppressed by an LXRα antagonist. The increase in ABCA1 mRNA by a PPARγ agonist was also suppressed by an LXRα antagonist. NOB did not influence LPL1 mRNA expression levels. NOB stimulated AMPK phosphorylation, and the increase in ABCA1/G1, LXRα and PPARγ mRNA levels and ABCA1/G1 protein levels by NOB was reversed by an AMPK inhibitor. AMPK siRNA suppressed ABCA1 expression.
Conclusions:
NOB activates AMPK and subsequently LXRα to promote the expression of ABCA1 and ABCG1, and an LXRα - PPARγ loop pathway amplifies these signals.
Insights
Nobiletin (NOB) activates AMPK and LXRα to boost ABCA1/ABCG1 expression, enhancing HDL biogenesis. An LXRα-PPARγ loop further amplifies these cholesterol-regulating signals.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Nobiletin (NOB), a citrus peel compound, shows potential against metabolic diseases.
- NOB's reported effects on AMPK, SREBP1c, PPARα, and PPARγ lack a clear molecular mechanism.
- Understanding NOB's role in HDL biogenesis via ABCA1 and ABCG1 is crucial.
Purpose of the Study:
- To investigate the molecular mechanism of Nobiletin (NOB) in regulating HDL biogenesis.
- To elucidate NOB's effect on ABCA1 and ABCG1 expression in macrophages.
- To determine the signaling pathways involved in NOB-mediated cholesterol regulation.
Main Methods:
- Utilized mouse macrophages (J774.1) to study NOB's effects.
- Assessed mRNA and protein levels of ABCA1, ABCG1, PPARγ, LXRα, CD36, and LPL1.
- Investigated the roles of AMPK, LXRα, and PPARγ using inhibitors and siRNA.
Main Results:
- NOB increased ABCA1/G1 mRNA and protein levels, promoting cholesterol release.
- NOB upregulated LXRα and PPARγ, but not PPARα.
- NOB-induced ABCA1/G1 expression was dependent on AMPK, LXRα, and PPARγ signaling, involving an LXRα-PPARγ feedback loop.
Conclusions:
- NOB activates AMPK, which then promotes LXRα expression.
- LXRα and PPARγ form a loop that amplifies ABCA1 and ABCG1 expression.
- This pathway highlights NOB's potential in modulating HDL biogenesis and cholesterol homeostasis.
More Related Videos
11:03Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
Published on: September 9, 2021
07:55A Macrophage Reporter Cell Assay to Examine Toll-Like Receptor-Mediated NF-kB/AP-1 Signaling on Adsorbed Protein Layers on Polymeric Surfaces
Published on: January 7, 2020