on October 12, 2006
Published online before print October 12, 2006, doi: 10.1161/01.ATV.0000249861.80471.96
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Submitted on December 14, 2005
Accepted on September 27, 2006
MEK-ERK Inhibition Corrects the Defect in VLDL Assembly in HepG2 Cells. Potential Role of ERK in VLDL-ApoB100 Particle Assembly
Julie Tsai ;
From the Division of Clinical Biochemistry, Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
* To whom correspondence should be addressed. E-mail: khosrow.adelii{at}sickkids.ca.
Objective--Hepatic VLDL assembly is defective in HepG2 cells, resulting in the secretion of immature triglyceride-poor LDL-sized apoB particles. We investigated the mechanisms underlying defective VLDL assembly in HepG2 and have obtained evidence implicating the MEK-ERK pathway.
Methods and Results--HepG2 cells exhibited considerably higher levels of the ERK1/2 mass and activity compared with primary hepatocytes. Inhibition of ERK1/2 using the MEK1/MEK2 inhibitor, U0126 (but not the inactive analogue) led to a significant increase in apoB secretion. In the presence of oleic acid, ERK1/2 inhibition caused a major shift in the lipoprotein distribution with a majority of particles secreted as VLDL, an effect independent of insulin. In contrast, overexpression of constitutively active MEK1 decreased apoB and large VLDL secretion. MEK1/2 inhibition significantly increased both cellular and microsomal TG mass, and mRNA levels for DGAT-1 and DGAT-2. In contrast to ERK, modulation of the PI3-K pathway or inhibition of the p38 MAP kinase, had no effect on lipoprotein density profile. Modulation of the MEK-ERK pathway in primary hamster hepatocytes led to changes in apoB secretion and altered the density profile of apoB-containing lipoproteins.
Conclusion--Inhibition of the overactive ras-MEK-ERK pathway in HepG2 cells can correct the defect in VLDL assembly leading to the secretion of large, VLDL-sized particles, similar to primary hepatocytes, implicating the MEK-ERK cascade in VLDL assembly in the HepG2 model. Modulation of this pathway in primary hepatocytes also regulates apoB secretion and appears to alter the formation of VLDL-1 sized particles.
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