Thyroid hormone status regulates the expression of secretory phospholipases.
Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRβ). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRβ agonists may ameliorate inflammation and hyperlipidemia.
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, United States.
Pragya
P
Sharma
Department of Infectious Diseases and Immunity, Faculté de Médecine de l'Université Laval, CHUQ Research Center and Division of Rheumatology, CHUQ, Quebec City, QC G1V 4G2, Canada.
Tania
T
Levesque
Department of Infectious Diseases and Immunity, Faculté de Médecine de l'Université Laval, CHUQ Research Center and Division of Rheumatology, CHUQ, Quebec City, QC G1V 4G2, Canada.
Eric
E
Boilard
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, United States. Electronic address: epark@uthsc.edu.
Edwards A
EA
Park
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D054501:Group II Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D006980:Hyperthyroidism / Q000235:genetics / Q000378:metabolism; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054497:Phospholipases A2, Secretory / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D037042:Thyroid Hormone Receptors beta / Q000819:agonists / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*
C526273:3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid; D000813:Anilides; D012333:RNA, Messenger; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human; D054497:Phospholipases A2, Secretory; C516288:Pla2g2a protein, mouse; C516289:Pla2g2a protein, rat
Eprotirome; PLA2g2a; Secretory phospholipase A2; Thyroid hormone