27‐Hydroxycholesterol regulates human SLC22A12 gene expression through estrogen receptor action

Abstract

The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27‐hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC‐activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

“…The previous study [ 9 , 37 ] as well as the present study suggested that tissue URAT1 action is enhanced in the insulin-resistant state, as represented by metabolic syndrome, presumably via persistent exposure to hyperinsulinemia. Conversely, the present study indicates that enhanced URAT1 action induces insulin resistance in metabolic syndrome, leading to a vicious cycle (see the Graphical Abstract).…”

Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut–Kidney Axis Dysfunction

“…In addition to the UA overproduction caused by dietary factors and subsequent activation of xanthine oxidase (XOD) in liver tissue, the impaired urate excretion also plays an important role in the development of HUA . Daily UA that generated and excreted in the human body is 600–700 mg, of which one-third is eliminated via the intestine and two-thirds by the kidney, respectively .…”

Susceptibility genes of hyperuricemia and gout

“…Consistent with previous studies, pavelcova et al also found that SLC22A12 gene variant rs3825017 (p.N82N) increased the risk of gout [ 51 ]. However, Toyoda et al [ 53 ] found that dysfunctional mutations of SLC22A12 gene have prominent anti-gout effect. Even in the presence of ABCG2 pathogenic mutations, these mutations still have a protective effect on gout.…”

“…It can be seen that the vast majority of SLC22A12 gene mutations inhibit the function of URAT1 and reduce the risk of gout. In addition, 27-Hydroxycholesterol (a metabolite of cholesterol) can activate SLC22A12 gene promoter via estrogen response elements (EREs), and then up-regulate the expression of SLC22A12 [ 53 ].…”