BackgroundInsulin resistance with elevated glucose is a risk factor for non-alcoholic steatohepatitis (NASH). We investigated the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor luseogliflozin on NASH development using a rodent model.MethodsMice were treated with both nicotinamide and streptozotocin (NA/STZ) to reduce insulin secretory capacity, and then fed a high fat diet containing trans fatty acids (HFDT) for 8 weeks. The NA/STZ HFDT-fed mice were divided into two groups, either treated with luseogliflozin or untreated, during this period. The glucose elevations in the NA/STZ-treated and HFDT-fed mice were significantly improved by luseogliflozin administration. While HFDT feeding induced NASH development as shown by liver weight gain with lipid accumulation and increased serum alanine aminotransferase, these changes were all attenuated in the group treated with luseogliflozin. In addition, fibrotic change and increases in collagen deposition with upregulations of collagen1 and smooth muscle actin and inflammatory cytokine expressions observed in the HFDT-fed mouse livers were also normalized by luseogliflozin administration.ConclusionsTaken together, these results obtained in mice demonstrate the favorable effects of administering SGLT2 inhibitors, for the treatment of NASH associated with diabetes mellitus. We anticipate that these agents would be applicable to humans.

Objective-Hyperuricemia is common in patients with metabolic syndrome. We investigated the role of xanthine oxidoreductase (XOR) in atherosclerosis development, and the effects of the XOR inhibitor allopurinol on this process. Methods and Results-Oral administration of allopurinol to ApoE knockout mice markedly ameliorated lipid accumulation and calcification in the aorta and aortic root. In addition, allopurinol treatment or siRNA-mediated gene knockdown of XOR suppressed transformation of J774.1 murine macrophage cells, treated with acetylated LDL or very low density lipoprotein (VLDL) into foam cells. This inhibitory effect of allopurinol was also observed in primary cultured human macrophages. In contrast, overexpression of XOR promoted transformation of J774.1 cells into foam cells. Interestingly, SR-A1, SR-B1, SR-B II, and VLDL receptors in J774.1 cells were reduced by XOR knockdown, and increased by XOR overexpression. Conversely, expressions of ABCA1 and ABCG1 were increased by XOR knockdown and suppressed by XOR overexpression. Finally, productions of inflammatory cytokines accompanied by foam cell formation were also reduced by allopurinol administration. Conclusion-These results strongly suggest XOR activity and/or its expression level to contribute to macrophage foam cell formation. Thus, XOR inhibitors may be useful for preventing atherosclerosis. Key Words: atherosclerosis Ⅲ cell physiology Ⅲ cytokines Ⅲ macrophages Ⅲ xanthine oxidoreductase A relationship between serum uric acid levels and atherosclerotic disease development has been suggested. [1][2][3] In addition, there is epidemiological evidence of an association between hyperuricemia and metabolic syndrome, 1 type 2 diabetes, 4 chronic kidney diseases, 5,6 heart failure incidence in older adults, 7 and with mortality in patients undergoing percutaneous coronary intervention or with acute myocardial infarction. 8 -10 Uric acid itself reportedly functions as an antioxidant, 11 though the process of uric acid synthesis is accompanied by the generation of reactive oxygen species.Xanthine oxidoreductase (XOR) is a key enzyme in the uric acid production pathway; XOR oxidizes hypoxanthine from nucleic acid metabolites into xanthine, and xanthine into uric acid. XOR basically oxidizes a variety of purines and pterins, classified as molybdenum iron-sulfur flavin hydroxylases. XOR tissue and cellular distributions are high in the mammalian liver and intestine due to XOR-rich parenchymal cells. 12 XOR activity is low in human serum, brain, heart, and skeletal muscle, though a recent study revealed microvascular endothelial cells to be rich in XOR activity. 13 It seems that XOR does not induce harmful reactive oxygen species production under normal conditions but in pathological states such as ischemic congestive heart failure, XOR activity increases drastically and XOR localizes within CD68 positive macrophages. 14 Allopurinol, a xanthine oxidase (XO) inhibitor, has been widely used for hyperuricemia treatment. Oxypurinol, a hydroxide and the main met...

Uric acid (UA) is the end product of purine metabolism and can reportedly act as an antioxidant. However, recently, numerous clinical and basic research approaches have revealed close associations of hyperuricemia with several disorders, particularly those comprising the metabolic syndrome. In this review, we first outline the two molecular mechanisms underlying inflammation occurrence in relation to UA metabolism; one is inflammasome activation by UA crystallization and the other involves superoxide free radicals generated by xanthine oxidase (XO). Importantly, recent studies have demonstrated the therapeutic or preventive effects of XO inhibitors against atherosclerosis and nonalcoholic steatohepatitis, which were not previously considered to be related, at least not directly, to hyperuricemia. Such beneficial effects of XO inhibitors have been reported for other organs including the kidneys and the heart. Thus, a major portion of this review focuses on the relationships between UA metabolism and the development of atherosclerosis, nonalcoholic steatohepatitis, and related disorders. Although further studies are necessary, XO inhibitors are a potentially novel strategy for reducing the risk of many forms of organ failure characteristic of the metabolic syndrome.