The lipoprotein lipase inhibitor ANGPTL3 is negatively regulated by thyroid hormone.
Whereas the role of thyroid hormone is clearly established in the regulation of cholesterol homeostasis, its involvement in the control of serum triglyceride (TG) levels remains largely debated. Angiopoietin-like proteins 3 and 4 have recently been characterized as potent lipoprotein lipase inhibitors and therefore as important components of plasma triglyceride homeostasis. In the present study, the role of thyroid hormone in the regulation of both ANGPTL4 and ANGPTL3 gene expression was investigated. In vivo studies revealed that thyroid hormone down-regulates ANGPTL3 but not ANGPTL4 gene expression in hypothyroid rats. Using thyroid hormone receptor (TR)-deficient mice, we show that thyroid hormone regulates ANGPTL3 gene expression in a TRbeta-dependent manner. Transfection studies revealed that this inhibition occurs at the transcriptional level in a DNA binding-independent fashion and requires the proximal (-171 to +66) region of the ANGPTL3 gene promoter. Moreover, site-directed mutagenesis experiments indicate that the HNF1 site within this proximal region mediates this TRbeta-dependent repression. Finally, co-transfection studies and electrophoretic mobility shift assays suggest that TRbeta antagonizes the HNF1alpha signaling pathway by inhibiting its transcriptional activity without interfering with its DNA-binding capacity. Taken together, our results lead to the identification of ANGPTL3 as a novel TRbeta target gene and provide a new potential mechanism to explain the hypotriglyceridemic properties of TRbeta agonists in vivo.
Fugier
Charlotte
C
GlaxoSmithKline, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, 25 Avenue du Quebec, Les Ulis 91951, France.
Tousaint
Jean-Jacques
JJ
Prieur
Xavier
X
Plateroti
Michelina
M
Samarut
Jacques
J
Delerive
Philippe
P
D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology; D020218:Response Elements; D015398:Signal Transduction; D013489:Suppression, Genetic; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000502:physiology; D013963:Thyroid Hormones / Q000494:pharmacology*; D014158:Transcription, Genetic; D014162:Transfection
C479896:ANGPTL3 protein, human; C474772:ANGPTL4 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; C407088:Angptl4 protein, mouse; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D051537:Hepatocyte Nuclear Factor 1; D008071:Lipoprotein Lipase