Effect of thyroxine on low density lipoprotein oxidation another thyroid hormone nongenomic effect.

I was most interested to read the paper by Sundaram et al. (1) and would like to comment on it. This paper complements the study by Dieckman et al. (2), who found that overt hypothyroidism increases both the lipid [total fatty acids (FA)] and apolipoprotein (apoB-100) content of the low density lipoprotein (LDL). I do agree with Sundaram et al. (1) that the increased LDL susceptibility to oxidation in hypothyroidism is a risk factor for atherosclerosis. In addition, hypothyroidism increases plasma Lp(a) levels and induces changes in the high density lipoprotein (HDL) heterogeneity as well as in thyroid hormone distribution to the HDL subfractions (3). Incidentally, because subclinical hypothyroidism is also associated with all these HDL variations (data not shown in ref. 3) and with increased oxidation of LDL (1), I concur with Sundaram et al. (1) that subclinical hypothyroidism deserves substitutive L-T4 therapy. Both studies (1, 2) conclude that the increase in LDL oxidation is secondary to less T4 available for binding to LDL, since L-T4 functions as an anti-oxidant of LDL in vitro (4, 5) and LDLs contain specific thyroid hormone binding sites (6). In normal persons, thyroid hormone binding to LDL is directly proportional to plasma LDL levels (7). Because hypothyroidism increases plasma LDL levels, it is surprising that “hypothyroid” LDLs accounted for only 1.0% (vs. 7.8% of “euthyroid” LDL) of the binding of radioactive T4 to the total lipoprotein fraction of plasma (3). This altered pattern of binding reversed upon L-T4 therapy (3). Based on the above data (1, 2) and on the fact that fatty acids inhibit thyroid hormone binding to apolipoproteins (8, 9), I think that the explanation for the said surprising finding (3) is that oxidized LDLs bind thyroid hormone less well. If so, then a vicious cycle takes place, a cycle that is disrupted by the L-T4 substitutive therapy. How to explain the increased LDL oxidation in the opposite situation— hyperthyroidism (1)? I offer one possible explanation— namely, the apoB-T4 complex is subnormal in either dysfunction. The structural thyroid hormone binding protein of LDL, apoB-100, is reduced in hyperthyroidism, but is increased in hypothyroidism (2, 10). The apoB-T4 complex is subnormal in hypothyroidism because of the scarcity of thyroid hormone that is not compensated by the increase in the apoB-100 concentration. It is subnormal in hyperthyroidism because of the scarcity of the protein, which is not compensated by the increase in thyroid hormones. In addition, the increased FA content of oxidized LDL in either thyroid dysfunction inhibits the apoB-T4 binding. However, the different kinetics of LDL oxidation in hypothyroidism vs. hyperthyroidism (1) may indicate other mechanisms. Thyroid hormone binding induces conformational changes in either free or lipid-associated apolipoproteins (9, 11). If, as it seems, the antioxidant effect of T4 is the result of the occupation of the specific binding sites in apoB-100 per se, then this effect is another example of nongenomic action of thyroid hormone. In a number of nongenomic effects of thyroid hormones, T4 is as active as T3 (12) or much more active than T3 (13), and Hanna et al. (4, 5) have shown that T4, T3, and reverse T3 are equipotent in protecting LDL from oxidation. There are other examples of nongenomic action of thyroid hormones that are pertinent to lipidology. The structural apolipoprotein of HDL, apoA-I, is a co-activator of lecithin-cholesterol-acyl-transferase (LCAT) (cf 14). LCAT activity is stimulated by thyroid hormones (14), and the LCAT activating domain of apoA-I is adjacent to the thyroid hormone binding domain (14, 15). The previously reported (14 –17) facilitation of the thyroid hormone (i.) entero-hepatic circulation, (ii.) transplacental passage, (iii.) entry into cells, and (iv.) exit from cells (S Benvenga and J Robbins, manuscript submitted) are other effects resulting from simple occupancy of thyroid hormone binding sites in apolipoproteins. Finally, considering that apolipoproteins represent the first plasma transport for thyroid hormones to appear in the animal world and that preservation of the structure of the hormone site appears to be more important than preservation of other sites (15), I underscore again that the term “apo-thyro-lipoprotein” (15) is more appropriate than “apolipoprotein.”