Activation of testicular orphan receptor 4 by fatty acids.
Nuclear receptors can be activated by chemicals, metabolites, hormones or environmental compounds to regulate gene expression. Bioassay-guided screening of mouse tissue extracts found that natural fatty acids of a certain carbon length and level of unsaturation could activate the mouse orphan nuclear receptor, testicular orphan receptor 4 (TR4). Subsequent experiments focused on gamma-linoleic acid, a compound identified during screening of mouse tissues that exerts regulatory activity in TR4 transactivation assays. gamma-linoleic acid positively modulates TR4 activity to promote the expression of downstream genes such as apolipoprotein E (ApoE) and phosphoenolpyruvate carboxykinase, and to activate a reporter carrying direct repeat 1 from the ApoE promoter. It also induced the interaction of TR4 with transcription coregulators such as RIP140 and PCAF. Comparisons of transactivation by TR4 and the metabolism-related peroxisome proliferator-activated nuclear receptors indicate that gamma-linoleic acid regulation is specific to TR4. The data suggest that TR4 might exert its physiological function by sensing certain lipids. Identifying these compounds could be useful for examining the physiological pathways in which TR4 and its target genes are involved.
Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455-0217, USA.
Nien-Pei
NP
Tsai
Mostaqul
M
Huq
Pawan
P
Gupta
Keiko
K
Yamamoto
Hiroyuki
H
Kagechika
Li-Na
LN
Wei
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000078723:Nuclear Receptor Interacting Protein 1; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2 / Q000235:genetics* / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000737:chemistry / Q000378:metabolism; D014020:Tissue Extracts / Q000737:chemistry / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D020798:Two-Hybrid System Techniques; D017965:gamma-Linolenic Acid / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; D005227:Fatty Acids; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2; D047492:Peroxisome Proliferator-Activated Receptors; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D014020:Tissue Extracts; D017965:gamma-Linolenic Acid; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000627127:NRIP1 protein, human