Abulizi Abudukadier, Perry Rachel J, Camporez João Paulo G, Jurczak Michael J, Petersen Kitt Falk, Aspichueta Patricia, Shulman Gerald I
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), Leioa, Spain.
FASEB J. 2017 Jul;31(7):2916-2924. doi: 10.1096/fj.201700001R. Epub 2017 Mar 22.
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-ε and PKC-θ 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-1α, -β, -2, -4, -6, -10, -12, CD69, and caspase 3 and attenuated activation of the IRE-1α 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.
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。脂肪营养不良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的NASH的努力取得了有限的成功。我们研究了一种产生轻度肝脏靶向性线粒体解偶联的控释线粒体质子载体（CRMP）是否能降低严重脂肪营养不良和糖尿病小鼠模型（无脂肪AZIP/F-1小鼠）中的高甘油三酯血症，并逆转NASH和糖尿病。在口服CRMP（每天2mg/kg体重）或赋形剂治疗4周后，小鼠接受高胰岛素-正常血糖钳夹试验并结合放射性标记葡萄糖，以评估肝脏和肌肉的胰岛素反应性以及组织脂质测量。CRMP治疗逆转了肝脏和骨骼肌中的高甘油三酯血症和胰岛素抵抗。胰岛素抵抗的逆转可分别归因于肝脏和肌肉中二酰甘油含量的降低以及PKC-ε和PKC-θ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；肝脏脂肪变性；以及肝脏中IL-1α、-β、-2、-4、-6、-10、-12、CD69和半胱天冬酶3的表达，并减弱了未折叠蛋白反应的IRE-1α分支的激活。综上所述，这些结果为开发肝脏靶向性线粒体解偶联剂作为治疗脂肪营养不良相关高甘油三酯血症、NASH和糖尿病的潜在新疗法提供了概念验证。-阿卜力孜，A.，佩里，R.J.，坎波雷兹，J.P.G.，尤尔扎克，M.J.，彼得森，K.F.，阿斯皮楚埃塔，P.，舒尔曼，G.I.一种控释线粒体质子载体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。
