Thyroid hormone regulates the hypotriglyceridemic gene APOA5.
The apolipoprotein AV gene (APOA5) is a key determinant of plasma triglyceride levels, a major risk factor for coronary artery disease and a biomarker for the metabolic syndrome. Since thyroid hormones influence very low density lipoprotein triglyceride metabolism and clinical studies have demonstrated an inverse correlation between thyroid status and plasma triglyceride levels, we examined whether APOA5 is regulated by thyroid hormone. Here we report that 3,5,3'-triiodo-L-thyronine (T3) and a synthetic thyroid receptor beta (TRbeta) ligand increase APOA5 mRNA and protein levels in hepatocytes. Our data revealed that T3-activated TR directly regulates APOA5 promoter through a functional direct repeat separated by four nucleotides (DR4). Interestingly, we show that upstream stimulatory factor 1, a transcription factor associated with familial combined hyperlipidemia and elevated triglyceride levels in humans, and upstream stimulatory factor 2 cooperate with TR, resulting in a synergistic activation of APOA5 promoter in a ligand-dependent manner via an adjacent E-box motif. In rats, we observed that apoAV levels declines with thyroid hormone depletion but returned to normal levels upon T3 administration. In addition, treatments with a TRbeta-selective agonist increased apoAV and diminished triglyceride levels. The identification of APOA5 as a T3 target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis. Additionally, these data suggest that TRbeta may be a potential pharmacological target for the treatment of hypertriglyceridemia.
Prieur
Xavier
X
GlaxoSmithKline, 25 Avenue du Québec, 91951 Les Ulis cedex, France.
Huby
Thierry
T
Coste
Hervé
H
Schaap
Frank G
FG
Chapman
M John
MJ
Rodríguez
Joan C
JC
D020816:Amino Acid Motifs; D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000378:metabolism*; D001054:Apolipoproteins A; D001483:Base Sequence; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037042:Thyroid Hormone Receptors beta; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*; D015854:Up-Regulation; D051720:Upstream Stimulatory Factors
C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D004268:DNA-Binding Proteins; D008024:Ligands; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014280:Triglycerides; D051720:Upstream Stimulatory Factors; D014284:Triiodothyronine; D012313:RNA