RGD Reference Report - Thyroid hormone regulates the hypotriglyceridemic gene APOA5. - Rat Genome Database

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Thyroid hormone regulates the hypotriglyceridemic gene APOA5.

Authors: Prieur, X  Huby, T  Coste, H  Schaap, FG  Chapman, MJ  Rodriguez, JC 
Citation: Prieur X, etal., J Biol Chem. 2005 Jul 29;280(30):27533-43. Epub 2005 Jun 7.
RGD ID: 1601661
Pubmed: PMID:15941710   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M503139200   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypothyroidism  ISOApoa5 (Rattus norvegicus)1601661; 1601661protein:decreased expression:liverRGD 
hypothyroidism  IEP 1601661protein:decreased expression:liverRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation of lipid metabolic process  IDA 1601661 RGD 
response to hormone  IEP 1601661 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Apoa5  (apolipoprotein A5)
Thrb  (thyroid hormone receptor beta)

Genes (Mus musculus)
Apoa5  (apolipoprotein A-V)

Genes (Homo sapiens)
APOA5  (apolipoprotein A5)


Additional Information