Abstract
ObjectivesThe study of sex differences in hyperuricemia can provide not only a theoretical basis for this clinical phenomenon but also new therapeutic targets for urate-lowering therapy. In the current study, we aimed to confirm that estradiol can promote intestinal ATP binding cassette subfamily G member 2 (ABCG2) expression to increase urate excretion through the PI3K/Akt pathway.MethodsThe estradiol levels of hyperuricemia/gout patients and healthy controls were compared, and a hyperuricemia mouse model was used to observe the urate-lowering effect of estradiol and the changes in ABCG2 expression in the kidney and intestine. In vivo and in vitro intestinal urate transport models were established to verify the urate transport function regulated by estradiol. The molecular pathway by which estradiol regulates ABCG2 expression in intestinal cells was explored.ResultsThe estradiol level of hyperuricemia/gout patients was significantly lower than that of healthy controls. Administering estradiol benzoate (EB) to both male hyperuricemic mice and female mice after removing the ovaries confirmed the urate-lowering effect of estradiol, and hyperuricemia and estradiol upregulated the expression of intestinal ABCG2. Estradiol has been confirmed to promote urate transport by upregulating ABCG2 expression in intestinal urate excretion models in vivo and in vitro. Estradiol regulates the expression of intestinal ABCG2 through the PI3K/Akt pathway.ConclusionOur study revealed that estradiol regulates intestinal ABCG2 through the PI3K/Akt pathway to promote urate excretion, thereby reducing serum urate levels.
Highlights
In humans, urate is the terminal metabolite of purine metabolism
Serum estradiol and urate levels in patients and healthy controls The 18 patients with gout and hyperuricemia in the study were all males of 53.3 ± 15.2 years old, and the healthy controls were males of 49.0 ± 12.3 years old
The results suggest that PI3K/Akt blocked the effect of ATP binding cassette subfamily G member 2 (ABCG2) upregulation by estradiol, which simultaneously phosphorylated two important sites of Akt
Summary
Increased levels (> 420 μmol/L) of serum urate are defined as hyperuricemia [1]. Hyperuricemia may lead to saturation and precipitation of weakly soluble urate as monosodium urate crystals (MSU crystals). Urate in the human body is synthesized mainly by the liver and excreted through the kidneys and intestines [2]. Any abnormality in this process can disturb the urate balance and cause hyperuricemia. Hyperuricemia is thought to be caused mainly by decreased urate excretion. The balance between reabsorption and secretion determines the level of urate in the body.
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