Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice
Yiling Mi, … , Dorothy Fiete, Jacques U. Baenziger
Yiling Mi, … , Dorothy Fiete, Jacques U. Baenziger
Published April 22, 2008
Citation Information: J Clin Invest. 2008;118(5):1815-1824. https://doi.org/10.1172/JCI32467.
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Research Article Reproductive biology

Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice

Abstract

Luteinizing hormone (LH), produced in the anterior lobe of the pituitary, is a member of the hypothalamic-pituitary-gonad axis that is required for production of the sex hormones estradiol, progesterone, and testosterone. Perturbations in levels of hormones associated with this axis can result in defects in sexual development and maturity. LH bears unique N-linked carbohydrate units that terminate with a sulfated N-acetylgalactosamine structure (GalNAc-4-SO4) that mediates its clearance from the blood. To determine the significance of this terminal structure, we ablated the gene encoding the sulfotransferase responsible for sulfate addition to GalNAc on LH, GalNAc-4-sulfotransferase-1 (GalNAc-4-ST1) in mice. Mice lacking GalNAc-4-ST1 exhibited increased levels of circulating LH. In male mice, this resulted in elevated levels of testosterone and precocious maturation of testis and seminal vesicles. Female mice lacking GalNAc-4-ST1 demonstrated elevated estrogen levels and exhibited precocious sexual maturation and increased fecundity. Female mice remained in estrus for prolonged periods and produced almost 50% more litters per mouse than wild-type mice over the same period of time. Thus, sulfate modification of the terminal glycosylation of LH plays a central role in regulating the hypothalamic-pituitary-gonad axis in vivo.

Authors

Yiling Mi, Dorothy Fiete, Jacques U. Baenziger

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Figure 1

Schematic of HPG axis.

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Schematic of HPG axis. The LH synthesized by WT mice bears N-linked olig...
The LH synthesized by WT mice bears N-linked oligosaccharides that terminate predominantly with SO4-4-GalNAc. Following GnRH-stimulated release into the blood, LH is rapidly removed from the blood by the Man/GalNAc-4-SO4-R expressed by endothelial cells in the liver, resulting in a half-life of 7.2 minutes in the blood. The amount of LH that reaches the LH receptor in the ovary and, as a result, the amount of estrogen/progesterone produced is determined by the half-life of LH. In the absence of GalNAc-4-4-ST1, the N-linked oligosaccharides on LH synthesized in the pituitary are predominantly modified with terminal Siaα2,6GalNAc. LH-bearing terminal Siaα2,6GalNAc is cleared by the ASGP-R expressed by hepatocytes, resulting in a longer half-life of 10.1 minutes. The longer half-life results in higher levels of LH in the blood and increased production of estrogen/progesterone by the ovary in GalNAc-4-ST1–/– mice as compared with WT mice. Thus, the rate of LH clearance and the concentration that LH attains in the blood are determined by the structures of its carbohydrate moieties. The strength of the signal produced by the same amount of LH released is determined by the structure of its terminal sugars. The impact of altered half-life appears to be superimposed on the other feedback mechanisms that normally regulate estrogen/progesterone levels. The same effects are seen in males with respect to T production.