A novel regulatory pathway for cholesterol degradation via lactostatin.
Our group previously discovered a novel hypocholesterolemic pentapeptide (IIAEK: Ile-Ile-Ala-Glu-Lys, or what we describe as "lactostatin") derived from bovine milk beta-lactoglobulin. To clarify the mechanism of the hypocholesterolemic action of lactostatin, we screened the target gene and signal transducing pathway induced by lactostatin in HepG2, a human liver cell line. Unexpectedly, we found that water-soluble lactostatin can activate cholesterol 7alpha-hydroxylase (CYP7A1) gene expression. Treatment with mitogen-activated protein kinase (MAPK) inhibitor or calcium (Ca2+) channel blocker blocked this activation. We also found that lactostatin regulates the phosphorylation of extracellular signal-regulated kinase (ERK) and intracellular Ca2+ concentration. Here, we show the involvement of a new regulatory pathway in the calcium-channel-related MAPK signaling pathway of lactostatin-mediated cholesterol degradation. Oligopeptide shows promise as a new molecule for the development of medicines and functional foods to prevent and improve hypercholesterolemia and atherosclerosis.
Morikawa
Kensei
K
Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan.
Kondo
Itsuo
I
Kanamaru
Yoshihiro
Y
Nagaoka
Satoshi
S
D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D015220:Calcium Channels; D009842:Oligopeptides; C516979:lactostatin; D002784:Cholesterol; D020928:Mitogen-Activated Protein Kinases