Premium
Cross‐talk between AMP‐activated Kinase and Mitogen/extracellular‐regulated Kinase through p21‐activated Kinase Contributes to Cholesterol Homeostasis
Author(s) -
Wang HsiangMing,
Bidwai Anil,
Korrapati Sasi,
Huang Wei,
Mehta Kamal D
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a239-c
Subject(s) - ampk , protein kinase a , microbiology and biotechnology , amp activated protein kinase , kinase , chemistry , energy homeostasis , map kinase kinase kinase , biology , biochemistry , receptor
The highly conserved serine/threonine kinase AMP‐ activated protein kinase (AMPK) is a critical energy sensing kinase known to regulate cellular metabolic pathways. More recent evidence has shown that energy independent stimuli also regulate AMPK activity. Since the physiological effect of AMPK activation resembles that of exercise, the roles of AMPK on lipid metabolism have recently been the focus of attention. In this report, we provided evidence of cross‐talk between AMPK, p42/44 MAPK , and low density lipoprotein receptor (LDL‐R) expression‐ a novel pathway of AMPK in regulating hepatic cholesterol homeostasis. Activation of AMPK by 5‐aminoimidazole‐4‐carboxamide‐1‐α‐D‐ribofuranoside (AICAR) resulted in LDL‐R induction via p42/44 MAPK activation. Using chemical inhibitor and RNA silencing technique, we pinpoint that the α2 subtype of AMPKα, but not α1, is involved in this regulation. The activation of Raf‐1/MEK/p42/44 MAPK by AMPK is indirect and requires phosphatidylinositol‐3‐kinase (PI‐3K) and p21‐activated kinase (Pak). Silencing the expression of Pak or inhibition of PI‐3K attenuated, whereas their overexpression enhanced, p42/44 MAPK activity. Our results demonstrate a novel function of AMPK in regulating Raf‐1/MEK/p42/44 MAPK pathway and further introduce new players to our evolving understanding of the mechanisms controlling cholesterol homeostasis.