Gender-specific changes in thyroid hormone-glucuronidating enzymes in rat liver during short-term fasting and long-term food restriction

Abstract

Glucuronidation is a major pathway of thyroid hormone metabolism in rats, involving at least three different hepatic UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT and androsterone UGT. We have studied the effects of short-term (3 days) fasting and long-term (3 weeks) food restriction to one-third of normal intake (FR33) on hepatic UGT activities for thyroxine (T4), triiodothyronine (T3), bilirubin and androsterone in male and female Wistar rats with either a functional (high activity, HA) or a defective (low activity, LA) androsterone UGT gene. Because food deprivation is known to induce centrally mediated hypothyroidism in rats, results were compared with those obtained in methimazole (MMI)-induced hypothyroid rats. Both fasting and FR33 produced largely parallel increases in T4 and bilirubin UGT activities. These effects were greater in males than in females, and were reproduced in MMI-treated rats. In male and female HA rats, fasting induced insignificant increases in T3 UGT activity and had no effect on androsterone UGT activity. In male HA rats, FR33 was associated with an increase in T3 UGT activity, while androsterone UGT activity showed little change. However, in female HA rats both T3 and androsterone UGT activities were markedly decreased by FR33. Triiodothyronine UGT activity in LA rats was strongly decreased compared with HA rats, but was not further decreased by FR33 in female LA rats, supporting the importance of androsterone UGT for T3 glucuronidation. These results demonstrate different sex-dependent effects of food deprivation on hepatic T4 and T3 glucuronidation that are associated with changes in the expression of bilirubin UGT and androsterone UGT, respectively. For the increased T4 and bilirubin UGT activities at least, these effects appear to be mediated by the hypothyroid state of the (semi)starved animals.

Involvement of Thyroid Hormones and Cortisol in the Stress Response and their Possible Effects on Fertility in the Pig

“…experiment I, seems to be in agreement with findings of van Haasteren et al (1996). These authors concluded that thyroid-stimulating hormone (TSH) release might be lowered by increased corticosterone secretion, although the mechanism of this effect may differ between acute starvation and prolonged food reduction in rats.…”

Fasting Induces Nuclear Factor E2-Related Factor 2 and ATP-Binding Cassette Transporters via Protein Kinase A and Sirtuin-1 in Mouse and Human

“…For example, mouse and human ABCC2 are known to be high affinity transporters for bilirubin-glucuronide and contribute to bilirubin excretion to bile (21). Fasting increases bilirubin glucuronidation (51) and Abcc2 induction could be in response to increase bilirubin clearance. Second, as ABCC2-4 contributes to bile acid efflux from hepatocytes, induction might aid in decreasing the increased bile acid load that occurs with fasting.…”

Clofibrate Increases Hepatic Triiodothyronine (T3)- and Thyroxine (T4)-Glucuronosyltransferase Activities and Lowers Plasma T3and T4Concentrations in Pigs

“…It has further been shown that some UGT isoforms (UGT1A9, UGT2B4) are PPAR␣ target genes (Barbier et al, 2003a,b). PPAR␣ is naturally activated during fasting, and Visser et al (1996) showed that food restriction resulted in increased bilirubin and thyroid hormone UGT activities in rats. These findings suggest that UGT catalyzing the glucuronidation of thyroid hormones may be transcriptionally upregulated by activation of PPAR␣.…”