Department of Internal Medicine, School of Medicine (T.S., M.W., Y.H., N.K.I., E.A., K.M., J.I., H.I.), Health Science Laboratory, and Graduate School of Media and Governance (M.W.), Keio University, Tokyo, 160-8582 Japan; and Center for Collaborative Research (T.M., A.H.), Tokyo Medical University Ibaraki Medical Center, Ibaraki, 300-0332 Japan.
Endocrinology. 2014 Aug;155(8):2810-9. doi: 10.1210/en.2013-2143. Epub 2014 Apr 28.
Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-A(y) mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.
患有糖尿病的血脂异常患者，包括代谢综合征患者，患冠心病的风险增加。据报道，胆固醇吸收抑制剂依折麦布可改善小鼠和人类的代谢疾病。然而，其潜在机制尚不清楚。在这里，我们研究了依折麦布对脂类和葡萄糖稳态的影响。雄性 KK-A(y) 小鼠喂食高脂肪饮食，这是代谢综合征的小鼠模型，用或不用依折麦布喂养 14 周。依折麦布改善了血脂异常、脂肪变性和胰岛素抵抗。依折麦布降低了肝氧化固醇，即肝 X 受体 (LXR) 的内源性激动剂，从而降低了肝内源性基因表达，特别是硬脂酰辅酶 A 去饱和酶-1 (SCD1)，导致肝油酸含量显著减少，这有助于通过减少甘油三酯和胆固醇酯来改善脂肪变性。同时，肝β-氧化、NADPH 氧化酶和细胞色素 P450 2E1 (CYP2E1) 减少，因此活性氧 (ROS) 和炎性细胞因子也减少。与这些变化一致，依折麦布减少了肝 c-Jun N-末端激酶 (JNK) 磷酸化并改善了肝胰岛素信号。使用雄性 SD 大鼠原代肝细胞进行的体外研究表明，用油酸和 LXR 激动剂处理后，细胞内脂质堆积过多，氧化应激增加，胰岛素信号受损。因此，在肥胖人群中，依折麦布通过降低肝氧化固醇来降低肝油酸含量，从而降低 LXR 活性。这改善了脂肪变性并减少了氧化应激，这种减少改善了肝内的胰岛素信号。这些结果为代谢综合征的发病机制和治疗策略提供了新的见解。
