Protein kinase A suppresses sterol regulatory element-binding protein-1C expression via phosphorylation of liver X receptor in the liver.
Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls synthesis of fatty acids and triglycerides in the liver and is highly regulated by nutrition and hormones. In the current studies we show that protein kinase A (PKA), a mediator of glucagon/cAMP, a fasting signaling, suppresses SREBP-1c by modulating the activity of liver X receptor alpha (LXRalpha), a dominant activator of SREBP-1c expression. Activation of PKA repressed LXR-induced SREBP-1c expression both in rat primary hepatocytes and mouse livers. Promoter analyses revealed that the LXRalpha-binding site in the SREBP-1c promoter is responsible for PKA inhibitory effect on SREBP-1c transcription. In vitro and in vivo PKA directly phosphorylated LXRalpha, and the two consensus PKA target sites (195, 196 serines and 290, 291 serines) in its ligand binding/heterodimerization domain were crucial for the inhibition of LXR signaling. PKA phosphorylation of LXRalpha caused impaired DNA binding activity by preventing LXRalpha/RXR dimerization and decreased its transcription activity by inhibiting recruitment of coactivator SCR-1 and enhancing recruitment of corepressor NcoR1. These results indicate that LXRalpha is regulated not only by oxysterol derivatives but also by PKA-mediated phosphorylation, which suggests that nutritional regulation of SREBP-1c and lipogenesis could be regulated at least partially through modulation of LXR.
Yamamoto
Takashi
T
Department of Internal Medicine, Metabolism and Endocrinology, Graduate School of Comprehensive Human Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Shimano
Hitoshi
H
Inoue
Noriyuki
N
Nakagawa
Yoshimi
Y
Matsuzaka
Takashi
T
Takahashi
Akimitsu
A
Yahagi
Naoya
N
Sone
Hirohito
H
Suzuki
Hiroaki
H
Toyoshima
Hideo
H
Yamada
Nobuhiro
N
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D017868:Cyclic AMP-Dependent Protein Kinases