Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan.
Tokyo New Drug Research Laboratories, Kowa Co., Ltd., Tokyo, Japan.
J Diabetes Investig. 2018 Nov;9(6):1261-1269. doi: 10.1111/jdi.12860. Epub 2018 Jun 5.
AIMS/INTRODUCTION: Recent data showed that dipeptidyl peptidase 4 (DPP-4) inhibitors exert a lipid-lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non-diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol-lowering action.
Male apolipoprotein E (ApoE)-deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of C-labeled cholesterol ( C-Chol). In additional experiments, effects of exendin-4 in mice and of anagliptin in DPP-4-deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice.
The serum total and non-high-density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE-deficient mice. The cholesterol-lowering effect was predominantly observed in the chylomicron fraction. The plasma C-Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal C-Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP-4 activity, and exendin-4 had no effect on the C-Chol transport in ApoE-deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport-related microsomal triglyceride transfer protein, acyl-coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin.
These findings suggest that anagliptin might exert a cholesterol-lowering action through DPP-4-dependent and glucagon-like peptide 1-independent suppression of intestinal cholesterol transport.
目的/引言：最近的数据表明，二肽基肽酶 4（DPP-4）抑制剂在糖尿病患者中具有降脂作用。然而，其作用机制尚不清楚。我们使用非糖尿病高脂血症动物研究了阿格列汀对小肠胆固醇代谢和转运的影响，以阐明其降脂作用的机制。
雄性载脂蛋白 E（ApoE）缺陷小鼠给予阿格列汀口服正常饮食。测量血清胆固醇水平和脂蛋白谱，并通过测量口服 C 标记胆固醇（ C-Chol）后组织中的放射性来评估胆固醇转运。在额外的实验中，评估了 exendin-4 在小鼠中的作用和 anagliptin 在 DPP-4 缺陷大鼠中的作用。在正常小鼠中通过定量聚合酶链反应分析肠道中靶基因的表达。
阿格列汀治疗后，ApoE 缺陷小鼠的血清总胆固醇和非高密度脂蛋白胆固醇浓度降低。降脂作用主要发生在乳糜微粒部分。胆固醇负荷后 2 小时，血浆 C-Chol 放射性显著降低 26%，72 小时粪便 C-Chol 排泄量显著增加 38%。在缺乏 DPP-4 活性的大鼠中，上述胆固醇转运作用被消除，exendin-4 对 ApoE 缺陷小鼠的 C-Chol 转运没有影响。此外，在重复给予阿格列汀的小鼠中，观察到肠道胆固醇转运相关的微粒体甘油三酯转移蛋白、酰基辅酶 A：胆固醇酰基转移酶 2、ApoA2 和 ApoC2 信使核糖核酸表达显著降低。
这些发现表明，阿格列汀可能通过 DPP-4 依赖性和胰高血糖素样肽 1 非依赖性抑制肠道胆固醇转运发挥降脂作用。
