A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice
A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice
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DOI：
10.1096/fj.201700001r
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发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Abulizi, Abudukadier;Perry, Rachel J.;Shulman, Gerald I.
脂肪营养不良是一种罕见的疾病，其特征是脂肪组织完全或部分丧失。脂肪代谢障碍患者表现出高甘油三酯血症、严重胰岛素抵抗、2 型糖尿病和非酒精性脂肪性肝炎 (NASH)。使用药物改善脂肪营养不良中 NASH 的努力取得了有限的成功。我们在严重脂肪营养不良和糖尿病的小鼠模型（无脂肪 AZIP/F-1 小鼠）中检查了产生轻度肝脏靶向线粒体解偶联的控释线粒体质子载体（CRMP）是否可以降低高甘油三酯血症并逆转 NASH 和糖尿病。口服 CRMP（每天 2 毫克/公斤体重）或载体治疗 4 周后，小鼠接受高胰岛素正常血糖钳夹结合放射性标记的葡萄糖，以评估肝脏和肌肉的胰岛素反应性和组织脂质测量。 CRMP 治疗逆转了肝脏和骨骼肌的高甘油三酯血症和胰岛素抵抗。胰岛素抵抗的逆转可归因于二酰甘油含量的减少以及肝脏和肌肉中 PKC-E 和 PKC-0 活性的降低。 CRMP 治疗还逆转了 NASH，表现为血浆天冬氨酸转氨酶和丙氨酸转氨酶浓度降低；肝脂肪变性； IL-1a、-13、-2、4、-6、-10、-12、CD69和半胱天冬酶3的肝脏表达以及未折叠蛋白反应的IRE-1a分支的激活减弱。总而言之，这些结果为开发肝脏靶向线粒体解偶联剂作为治疗脂肪营养不良相关的高甘油三酯血症、NASH 和糖尿病的潜在新疗法提供了概念证明。 Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. 控释线粒体质子载体可逆转脂肪营养不良小鼠的高甘油三酯血症、非酒精性脂肪性肝炎和糖尿病。
Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled -release mitochondrial protonophore (CRMP) that produces mild liver targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP/F-1 mice) of severe lipodystrophy and diabetes. After 4 wk of oral CRMP (2 mg/kg body weight per day) or vehicle treatment, mice underwent hyperinsulinemic-euglycemic clamps combined with radiolabeled glucose to assess liver and muscle insulin responsiveness and tissue lipid measurements. CRMP treatment reversed hypertriglyceridemia and insulin resistance in liver and skeletal muscle. Reversal of insulin resistance could be attributed to reductions in diacylglycerol content and reduced PKC-E and PKC-0 activity in liver and muscle respectively. CRMP treatment also reversed NASH as reflected by reductions in plasma aspartate aminotransferase and alanine aminotransferase concentrations; hepatic steatosis; and hepatic expression of IL -la, -13, -2, 4, -6, -10, -12, CD69, and caspase 3 and attenuated activation of the IRE -la branch of the unfolded protein response. Taken together, these results provide proof of concept for the development of liver -targeted mitochondrial uncoupling agents as a potential novel therapy for lipodystrophy-associated hypertriglyceridemia, NASH and diabetes. Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. A controlled release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice.