Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance.

Abstract

OBJECTIVE:

Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.

RESEARCH DESIGN AND METHODS:

Lipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor-deficient mice (Ldlr(-/-)) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.

RESULTS:

In HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal-related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr(-/-) mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator-activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.

CONCLUSIONS:

Nobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.

• Authors: Erin E Mulvihill, Julia M Assini, Justin K Lee, Emma M Allister, Brian G Sutherland, Julie B Koppes, Cynthia G Sawyez, Jane Y Edwards, Dawn E Telford, Alexandre Charbonneau, Philippe St-Pierre, André Marette, Murray W Huff
• Journal: Diabetes (Diabetes) Vol. 60 Issue 5 Pg. 1446-57 (May 2011) ISSN: 1939-327X [Electronic] United States
• PMID: 21471511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Butadienes
• Enzyme Inhibitors
• Flavones
• Insulin
• Insulin Receptor Substrate Proteins
• Lipoproteins, VLDL
• Nitriles
• Triglycerides
• U 0126
• very low density lipoprotein triglyceride
• nobiletin
• MAP2K2 protein, human
• Receptor, Insulin
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Animals
• Atherosclerosis (drug therapy, metabolism)
• Butadienes (pharmacology)
• Diet (adverse effects)
• Dyslipidemias (drug therapy, metabolism)
• Electrophoresis, Polyacrylamide Gel
• Energy Metabolism (drug effects)
• Enzyme Inhibitors (pharmacology)
• Flavones (therapeutic use)
• Hep G2 Cells
• Humans
• Insulin (pharmacology)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance (physiology)
• Lipoproteins, VLDL (metabolism)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Mutant Strains
• Nitriles (pharmacology)
• Phosphorylation (drug effects)
• Receptor, Insulin (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Triglycerides (metabolism)