Thyroid Hormone Regulates the Hypotriglyceridemic Gene APOA5

Abstract

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-Lthyronine (T 3 ) and a synthetic thyroid receptor ␤ (TR␤) ligand increase APOA5 mRNA and protein levels in hepatocytes. Our data revealed that T 3 -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 T 3 administration. In addition, treatments with a TR␤-selective agonist increased apoAV and diminished triglyceride levels. The identification of APOA5 as a T 3 target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis. Additionally, these data suggest that TR␤ may be a potential pharmacological target for the treatment of hypertriglyceridemia.

Glucose Regulates the Expression of the Apolipoprotein A5 Gene

“…This work showed for the first time the phosphorylation-dependent binding of USF1/2 to a functional E-box element within the APOA5 promoter. Interestingly, in agreement with our study, Prieur et al 19 have reported that the thyroid hormone regulates the hypotriglyceridemic gene APOA5 through a synergistic activation with USF. Their report combinated with ours raises the possibility of a cross talk between insulin and thyroid signals on the same element in APOA5.…”

Recent advances in physiological lipoprotein metabolism

“…Thyroid hormones can influence lipid metabolism by: 1) inducing HMG CoA reductase; 2) controlling SREBP-2 which regulates LDL receptor expression; 3) increasing CETP activity; and 4) upregulating the synthesis of apoAV [313][314][315][316]. ANGPTL3 gene is negatively regulated by triodothyronine leading to the speculation that triodothyronine can lower plasma triglycerides by suppressing the ANGPTL3 gene thus activating LPL which plays a central role in lipid metabolism [317].…”

Impact of Thyroid Dysfunction on Natural Course of Coronary Artery Disease

“…The most important mechanisms of thyroid hormone action on lipid metabolism are shown in (Prieur et al, 2005) Inhibition of TGs production Increased TG levels, acceleration of atherosclerosis and CAD T3 and its acetic derivative protect LDL from oxidation (Faureet al, 2004) Protection from oxidation of LDL Burden of oxidative stress, acceleration of atherosclerosis and CAD Increased cholesteryl ester transfer protein activity Increased exchange of cholesteryl esters from HDL2 to VLDL and TGs to the opposite direction (Rizos et al, 2011) Not definitely established, due to this mechanism plasma HDL levels may be elevated…”