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Inhibition of Microsomal Triglyceride Transfer Protein Expression and Apolipoprotein B100 Secretion by the Citrus Flavonoid Naringenin and by Insulin Involves Activation of the Mitogen-Activated Protein Kinase Pathway in Hepatocytes
- Source :
- Diabetes. 54:1676-1683
- Publication Year :
- 2005
- Publisher :
- American Diabetes Association, 2005.
-
Abstract
- Microsomal triglyceride transfer protein (MTP) is necessary for hepatocyte assembly and secretion of apolipoprotein (apo)B100-containing lipoproteins. The citrus flavonoid naringenin, like insulin, decreased MTP expression in HepG2 cells, resulting in inhibition of apoB100 secretion; however, the mechanism for naringenin is independent of insulin receptor substrate-1/2. Recently, it was reported that insulin decreased MTP expression in HepG2 cells via the mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) (MAPKerk) pathway. We hypothesized that naringenin acts via a similar mechanism. Inhibition of MAPK kinase (MEK) 1/2 in HepG2 cells significantly attenuated the naringenin- and insulin-induced reduction in MTP expression. Both naringenin and insulin increased ERK1/2 phosphorylation, which was completely inhibited by MEK1/2 inhibition and enhanced by inhibition of MAPKp38, a negative regulator of MAPKerk activity. Inhibition of MEK1/2 significantly attenuated both the naringenin- and insulin-induced decrease in apoB100 secretion demonstrating a direct link between MAPKerk activation and apoB100 secretion. Furthermore, both compounds increased MAPKp38 activation, and therefore inhibition of MAPKp38 amplified thenaringenin- and insulin-induced decrease in apoB100 secretion. We conclude that MAPKerk signaling in hepatocytes is critical for inhibition of apoB100 secretion by naringenin and insulin. Therefore, naringenin may prove useful for activating insulin-signaling pathways important for regulation of hepatocyte lipid homeostasis.
- Subjects :
- Naringenin
MAPK/ERK pathway
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
p38 mitogen-activated protein kinases
Gene Expression
Microsomal triglyceride transfer protein
Cell Line
chemistry.chemical_compound
Internal medicine
Internal Medicine
medicine
Animals
Insulin
RNA, Messenger
Protein kinase A
Apolipoproteins B
Phosphoinositide-3 Kinase Inhibitors
biology
Kinase
food and beverages
Cell biology
Insulin receptor
Endocrinology
chemistry
Mitogen-activated protein kinase
Apolipoprotein B-100
Flavanones
Hepatocytes
biology.protein
Mitogen-Activated Protein Kinases
Carrier Proteins
Signal Transduction
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....23bff251dd2df5e5f3fa21841cfb44aa