TY - JOUR
T1 - Metabolite regulation of nuclear localization of carbohydrate-response element-binding protein (ChREBP)
T2 - Role of amp as an allosteric inhibitor
AU - Sato, Shogo
AU - Jung, Hunmin
AU - Nakagawa, Tsutomu
AU - Pawlosky, Robert
AU - Takeshima, Tomomi
AU - Lee, Wan Ru
AU - Sakiyama, Haruhiko
AU - Laxman, Sunil
AU - Wynn, R. Max
AU - Tu, Benjamin P.
AU - MacMillan, John B.
AU - De Brabander, Jef K.
AU - Veech, Richard L.
AU - Uyeda, Kosaku
N1 - Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
PY - 2016/5/13
Y1 - 2016/5/13
N2 - The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/ cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branchedchain α-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-α2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis.
AB - The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/ cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branchedchain α-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-α2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis.
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U2 - 10.1074/jbc.M115.708982
DO - 10.1074/jbc.M115.708982
M3 - Article
C2 - 26984404
AN - SCOPUS:84969132762
SN - 0021-9258
VL - 291
SP - 10515
EP - 10527
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -