TY - JOUR
T1 - Insulin induction of SREBP-1c in rodent liver requires LXRα-c/EBPβ complex
AU - Tian, Jing
AU - Goldstein, Joseph L.
AU - Brown, Michael S.
N1 - Funding Information:
We thank Guosheng Liang and Shijie Li for helpful suggestions; Joyce Repa, Steven Kliewer, and David Mangelsdorf for providing the LXR??-/-mice and for critical comments on the manuscript; Christina Li, Linda Donnelly, Angela Carroll, and Jeff Cormier for excellent technical assistance; and Lisa Beatty for invaluable help with tissue culture. This work was supported by NIH Grant HL20948 and the Moss Heart Foundation. J.T. was the recipient of a postdoctoral fellowship from the American Diabetes Association.
PY - 2016/7/19
Y1 - 2016/7/19
N2 - Insulin increases lipid synthesis in liver by activating transcription of the gene encoding sterol regulatory element-binding protein-1c (SREBP-1c). SREBP-1c activates the transcription of all genes necessary for fatty acid synthesis. Insulin induction of SREBP-1c requires LXRα, a nuclear receptor. Transcription of SREBP-1c also requires transcription factor C/EBPβ, but a connection between LXRα and C/EBPβ has not been made. Here we show that LXRα and C/EBPβ form a complex that can be immunoprecipitated from rat liver nuclei. Chromatin immunoprecipitation assays showed that the LXRα-C/EBPβ complex binds to the SREBP-1c promoter in a region that contains two binding sites for LXRα and is known to be required for insulin induction. Knockdown of C/EBPβ in fresh rat hepatocytes ormouse livers in vivo reduces the ability of insulin to increase SREBP-1c mRNA. The LXRα-C/EBPβ complex is bound to the SREBP-1c promoter in the absence or presence of insulin, indicating that insulin acts not by increasing the formation of this complex, but rather by activating it.
AB - Insulin increases lipid synthesis in liver by activating transcription of the gene encoding sterol regulatory element-binding protein-1c (SREBP-1c). SREBP-1c activates the transcription of all genes necessary for fatty acid synthesis. Insulin induction of SREBP-1c requires LXRα, a nuclear receptor. Transcription of SREBP-1c also requires transcription factor C/EBPβ, but a connection between LXRα and C/EBPβ has not been made. Here we show that LXRα and C/EBPβ form a complex that can be immunoprecipitated from rat liver nuclei. Chromatin immunoprecipitation assays showed that the LXRα-C/EBPβ complex binds to the SREBP-1c promoter in a region that contains two binding sites for LXRα and is known to be required for insulin induction. Knockdown of C/EBPβ in fresh rat hepatocytes ormouse livers in vivo reduces the ability of insulin to increase SREBP-1c mRNA. The LXRα-C/EBPβ complex is bound to the SREBP-1c promoter in the absence or presence of insulin, indicating that insulin acts not by increasing the formation of this complex, but rather by activating it.
KW - Chromatin immunoprecipitation
KW - Fasting and refeeding
KW - Fatty acid synthesis
KW - Rat hepatocytes
KW - Transcription
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U2 - 10.1073/pnas.1608987113
DO - 10.1073/pnas.1608987113
M3 - Article
C2 - 27382175
AN - SCOPUS:84978910589
SN - 0027-8424
VL - 113
SP - 8182
EP - 8187
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -