Homocysteine Activates cAMP-response Element Binding Protein in HepG2 Through cAMP/PKA Signaling Pathway

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 5; pp. 1043 - 1050
• Main Authors: Woo, Connie W.H, Siow, Yaw L, O, Karmin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.05.2006; Hagerstown, MD Lippincott
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Cells, Cultured; Cyclic AMP - physiology; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - physiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; General and cellular metabolism. Vitamins; Hepatocytes - metabolism; Homocysteine - pharmacology; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hyperhomocysteinemia - metabolism; Male; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; homocysteine; Thiol; HMG; Enzyme; PKA; Cardiovascular disease; Gonadotropin; cAMP; Sulfur containing aminoacid; Vascular disease; Binding protein; CREB; Homocystein; HMG-CoA reductase; Atherosclerosis; Oxidoreductases; Reductase
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000214981.58499.32

OBJECTIVE—Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Our previous studies demonstrated that hyperhomocysteinemia not only elicited inflammatory responses in the vascular endothelium but also induced fatty liver and hypercholesterolemia via transcriptional regulation. One of the transcription factors activated in the liver during hyperhomocysteinemia was cAMP-response element binding protein (CREB). CREB regulates the expression of many genes including those involved in lipid and glucose metabolism. In this study, we investigated the molecular mechanism by which Hcy activated CREB in rat liver and in hepatocytes (HepG2). METHOD AND RESULTS—Hyperhomocysteinemia was induced in rats by feeding high-methionine diet for 4 weeks. There was a significant increase in hepatic cAMP levels, protein kinase A (PKA) activity and an activation of CREB. Incubation of HepG2 cells with Hcy (50 to 100 μmol/L) significantly enhanced CREB phosphorylation and subsequently increased CREB/DNA binding activity. PKA was activated in Hcy-treated cells as a result of increased cellular cAMP level. Inhibition of adenylyl cyclase not only reduced the intracellular cAMP levels elevated by Hcy treatment but also inhibited PKA activation and prevented Hcy-induced CREB phosphorylation. CONCLUSION—These results suggest that the cAMP/PKA signaling pathway plays an important role in mediating Hcy-induced CREB activation in hepatocyte.