Effects of hypothyroidism on mammary and liver lipid metabolism in virgin and late-pregnant rats

Abstract

Untreated maternal hypothyroidism (hypoT) has serious consequences in offspring development that may result from the effect on lactation of maternal metabolism dysfunction. We studied the effects of prolonged propylthiouracyl (PTU)-induced hypoT (0.1% PTU in drinking water starting 8 days before mating until day 21 of pregnancy or for 30 days in virgin rats) on liver and mammary lipid metabolism and serum lipid concentrations. In virgins, hypoT reduced hepatic mRNAs associated with triglyceride (TG) and cholesterol synthesis (including fatty acid synthase and 3-hydroxy-3-methylglutaryl coenzyme A reductase), and induced lobuloalveolar mammary development. Thyroid hormones influence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure through actions on protein, carbohydrate, and lipid metabolism. With specific regard to liver lipid metabolism, thyroid hormones stimulate fatty acid and cholesterol synthesis (1, 2), increase mobilization of plasma cholesterol and triglycerides (TGs) (3, 4), and stimulate fatty acid and cholesterol degradation (5, 6). Disturbances in thyroid function are commonly associated with alterations in plasma lipid levels. Experimental hypothyroidism (hypoT) induced by propylthiouracyl (PTU) treatment is characterized by the accumulation of plasma LDL cholesterol, and decreased VLDL and plasma TGs (7), generally reflecting reduced binding activity of the hepatic LDL receptor (LDLR), which can be normalized after substitution therapy with thyroid hormone (3,8).Pregnancy is a state of dynamic changes in metabolism and nutrient utilization. The insulin-resistant condition and the increase in plasma estrogen levels occurring during late pregnancy are the main factors responsible for the development of a state of maternal hypertriglyceridemia that has been extensively studied in humans and rats (9)(10)(11). This condition benefits the progeny in two ways. First, it supplies essential fatty acids that are critical to normal fetal development and that circulate primarily esterified and associated with lipoproteins. A linear correlation between maternal and fetal plasma TGs has been described that has an important implication in newborn weight (12, 13). Second, it contributes to milk synthesis in preparation for lactation, providing circulating TG in the form of lipoprotein to the mammary gland (MG) for milk lipid synthesis (9).It has been demonstrated that the induction of hypothyroidism in dairy cows suppresses milk production during the treatment period (14). On the other hand, ad-

Hypothyroidism prolongs corpus luteum function in the pregnant rat

“…Although there is no evidence of a direct or indirect regulation of PGE2 by thyroid hormones, there is sufficient information demonstrating that the circulating concentration of PGE2 is dependent on cholesterol-low density lipoprotein (LDL) levels (Habenicht et al 1986). We have recently shown that circulating LDL-cholesterol is elevated in hypothyroid rats regardless of the reproductive state (Hapon et al 2005), and this factor may be linked with the observed elevated serum PGE2. Moreover, hypercholesterolemia may directly influence P 4 production, since in vivo and Figure 5 Effect of PTU treatment on luteal mRNA abundance of COX2, iNOS and PGF2aR on days 19 (G19) and 21 (G21) of pregnancy and 2 of lactation (L2).…”

Hypothyroidism on Lipid Metabolism

“…The mRNA levels of 7 -hydroxylase are not modified by pregnancy or by hypothyroidism. In addition, the LDL receptor mRNA, a factor involved in cholesterol uptake that is increased during late gestation, is decreased in the pregnant hypothyroid rats, contributing to the increased circulating (LDL+VLDL)-C (Hapon et al, 2005). It is well known that hypothyroidism increases cholesterol through an enhancement of LDL.…”

“…Changes in thyroid state indirectly modify the biosynthesis of cholesterol by its effects on metabolism and on the coefficient of intestinal absorption of cholesterol (Mathe & Chevallier, 1976). The mRNA levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme for de novo cholesterol biosynthesis, is increased in the liver during late gestation, but the change of 3-hydroxy-3-methylglutarylcoenzyme A reductase is not modified by hypothyroidism (Hapon et al, 2005). The mRNA levels of 7 -hydroxylase are not modified by pregnancy or by hypothyroidism.…”

“…It is known that pregnancy stimulates fatty acid synthase and glycerol-3-phosphate acyltransferase expressions in the rat liver, while a state of clinical hypothyroidism during pregnancy shows decreased hepatic triglyceride synthesis in terms of 14 C[glucose] incorporation and subsequently, decreases in triglycerides and enhanced cholesterol in the circulation (Bonet & Herrera, 1991;Lopez Luna & Morales, 1985). A decrease in the liver lipid synthesis has been also evidenced by the diminished incorporation of 3 H[H 2 O] into triglycerides and by the expression and activity of fatty acid synthase and acetyl-CoA carboxylase in pregnant hypothyroid rats, which may be responsible for the decrease in circulating triglycerides (Hapon et al, 2005). Congenitally hypothyroid mice show alterations in apoB RNA editing that switch hepatic production from apoB-100 to apoB-48 isoform (Mukhopadhyay et al, 2003), and whose conformational competence directs the assembly of hepatic VLDL more effectively.…”

“…The regulation and coordination of lipid metabolism on pregnancy and lactation are very important because of the sudden and profound physiological changes occuring during these physiological states (Hapon et al, 2003(Hapon et al, , 2005. It is known that undiagnosed hypothyroidism during pregnancy will lead to irreparable central nervous system defects in the newborn because the development of the child in utero is critically affected by the mother's thyroid status (Gartner, 2009).…”