Glucose transporter (Glut) 9 plays an important role in maintaining the homeostasis of uric acid in the body. Although the physiologic functions of Glut9 have been well established, the regulation of Glut9 expression is less well understood. In this study, we showed that the mRNA and protein expression of Glut9 in mouse liver and kidney are female predominant. Ontogeny studies further revealed that the female-predominant Glut9 expression in mouse liver only occurs in adult mice, which is primarily attributable to the fact that Glut9 expression sustains in females but gradually decreases in males after it reaches the peak level at day 22. Hormone replacement studies in gonadectomized mice, lit/lit mice, and hypophysectomized mice demonstrated that female-predominant Glut9 expression in mouse liver and kidney are primarily due to the inhibitory effects of male-pattern growth hormone secretion, but not sex hormones. In silico analysis of DNA sequences revealed that conserved response elements of signal transducer and activator of transcription 5b, which is an established relay molecule in the growth hormone signaling pathway, are present in mouse and human Glut9/GLUT9 gene promoters, suggesting that Glut9/GLUT9 is a potential target gene of growth hormone. Analysis of mice treated with a panel of chemicals revealed that agonists of the aryl hydrocarbon receptor and the peroxisome proliferator-activated receptor a induced Glut9 mRNA expression in the liver, which is further supported by the presence of conserved xenobiotic response elements and direct repeat 1 DNA motifs in the mouse Glut9 gene promoter. In summary, Glut9 expression is downregulated by male-pattern growth hormone secretion but is upregulated by activation of aryl hydrocarbon receptor and peroxisome proliferator-activated receptor a signaling in mice.

Epalrestat (EPS), an aldose reductase inhibitor, is widely prescribed to manage diabetic neuropathy. It is generally believed that EPS is beneficial to diabetic patients because it can protect endothelial cells, Schwann cells, or other neural cells from oxidative stress. However, several clinical studies revealed that EPS therapy led to liver dysfunction, which limited its clinical applications. Currently, the underlying mechanism by which EPS causes liver dysfunction is unknown. This study aimed to investigate the mechanism responsible for EPS-induced liver injury. In mouse liver, EPS 1) increased oxidative stress, indicated by increased expression of manganese superoxide dismutase, Ho-1, and Nqo1, 2) induced inflammation, indicated by infiltration of inflammatory cells, and induced expression of tumor necrosis factor-alpha, CD11b, and CD11c, as well as 3) predisposed to induce fibrosis, evidenced by increased mRNA and protein expression of early profibrotic biomarker genes procollagen I and alpha-smooth muscle actin, and by increased collagen deposition. In cultured mouse and human hepatoma cells, EPS treatment induced oxidative stress, decreased cell viability, and triggered apoptosis evidenced by increased Caspase-3 cleavage/activation. In addition, EPS increased mRNA and protein expression of cytoglobin in mouse liver, indicating that EPS activated hepatic stellate cells (HSCs). Furthermore, EPS treatment in cultured human HSCs increased cell viability. In summary, EPS administration induced oxidative stress and inflammation in mouse liver, and stimulated liver fibrogenesis. Therefore, cautions should be exercised during EPS therapy.

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