Science子刊：靶向肝脏线粒体的药物或能改善多种代谢紊乱
- ①在两种代谢紊乱猴子模型中，研究控释线粒体质子载体（CRMP）药物对代谢的影响；
- ②每日单剂量5mg/kg的CRMP治疗，可使肝脏线粒体脂肪氧化率提高40%；
- ③6周CRMP治疗降低了猴子的肝脏甘油三酯，但不影响动物的体重、摄食量和体温，且无不良反应发生；
- ④同时使空腹血浆甘油三酯和低密度脂蛋白胆固醇降低20%-30%；
- ⑤口服CRMP可使内源性葡萄糖产量减少18%，可归因于肝乙酰辅酶A含量和丙酮酸羧化酶通量减少了20%。
主编推荐语
线粒体解偶联剂2,4-二硝基酚（DNP）具有治疗非酒精性脂肪肝的潜力，但由于其毒性作用而未能进行临床应用。基于此，研究人员对DNP进行药物改良，开发了一种肝脏特异性的控释型线粒体解偶联剂（CRMP），并在小鼠中验证了药物作用。Science Translational Medicine近期发表了CRMP在两种猴子模型中的研究结果，证实了这种药可安全的改善胰岛素敏感性、血脂紊乱和脂肪肝，为进一步展开临床试验提供更多证据。
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Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates
在代谢紊乱的非人类灵长类动物中，控释线粒体质子载体（CRMP）逆转血脂异常和肝脂肪变性
10.1126/scitranslmed.aay0284
2019-10-02, Article
Abstract & Authors:展开
Abstract:收起
Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides. Although we previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, hepatic inflammation, and fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess its safety and efficacy in a model highly relevant to humans. Here, we evaluated the impact of longer-term CRMP treatment on hepatic mitochondrial oxidation and on the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in high-fat, fructose-fed cynomolgus macaques (n = 6) and spontaneously obese dysmetabolic rhesus macaques (n = 12). Using positional isotopomer nuclear magnetic resonance tracer analysis (PINTA), we demonstrated that acute CRMP treatment (single dose, 5 mg/kg) increased rates of hepatic mitochondrial fat oxidation by 40%. Six weeks of CRMP treatment reduced hepatic triglycerides in both nonhuman primate models independently of changes in body weight, food intake, body temperature, or adverse reactions. CRMP treatment was also associated with a 20 to 30% reduction in fasting plasma triglycerides and low-density lipoprotein (LDL)–cholesterol in dysmetabolic nonhuman primates. Oral administration of CRMP reduced endogenous glucose production by 18%, attributable to a 20% reduction in hepatic acetyl–coenzyme A (CoA) content [as assessed by whole-body β-hydroxybutyrate (β-OHB) turnover] and pyruvate carboxylase flux. Collectively, these studies provide proof-of-concept data to support the development of liver-targeted mitochondrial uncouplers for the treatment of metabolic syndrome in humans.
First Authors:
Leigh Goedeke
Correspondence Authors:
Gerald I Shulman
All Authors:
Leigh Goedeke,Liang Peng,Valle Montalvo-Romeral,Gina M Butrico,Sylvie Dufour,Xian-Man Zhang,Rachel J Perry,Gary W Cline,Paul Kievit,Keefe Chng,Kitt Falk Petersen,Gerald I Shulman
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