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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:211.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

MEK–ERK Inhibition Corrects the Defect in VLDL Assembly in HepG2 Cells

Potential Role of ERK in VLDL-ApoB100 Particle Assembly

Julie Tsai; Wei Qiu; Rita Kohen-Avramoglu; Khosrow Adeli

From the Division of Clinical Biochemistry, Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.

Correspondence to Khosrow Adeli, Division of Clinical Biochemistry, Hospital for Sick Children, University of Toronto, Ontario, Canada M5G 1X8. E-mail khosrow.adeli{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.

Inhibition of the overactive ras-MEK–ERK pathway in HepG2 cells was found to correct the defect in VLDL assembly (that normally secrete immature triglyceride-poor LDL-sized apoB particles) leading to the secretion of large, VLDL-sized particles, similar to primary hepatocytes. Our data implicate the MEK–ERK pathway in regulating the VLDL assembly process in HepG2 cells.

Key Words: apolipoprotein B100 • MEK–ERK • HepG2 • VLDL

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