Hwang Byounghoon, Jeoung Nam Ho, Harris Robert A
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Biochem J. 2009 Sep 25;423(2):243-52. doi: 10.1042/BJ20090390.
The hypothesis that PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) has potential as a target for the treatment of type 2 diabetes was tested by feeding wild-type and PDHK4 knockout mice a high saturated fat diet that induces hyperglycemia, hyperinsulinaemia, glucose intolerance, hepatic steatosis and obesity. Previous studies have shown that PDHK4 deficiency lowers blood glucose by limiting the supply of three carbon gluconeogenic substrates to the liver. There is concern, however, that the increase in glucose oxidation caused by less inhibition of the pyruvate dehydrogenase complex by phosphorylation will inhibit fatty acid oxidation, promote ectopic fat accumulation and worsen insulin sensitivity. This was examined by feeding wild-type and PDHK4 knockout mice a high saturated fat diet for 8 months. Fasting blood glucose levels increased gradually in both groups but remained significantly lower in the PDHK4 knockout mice. Hyperinsulinaemia developed in both groups, but glucose tolerance was better and body weight was lower in the PDHK4 knockout mice. At termination, less fat was present in the liver and skeletal muscle of the PDHK4 knockout mice. Higher amounts of PGC-1alpha [PPARgamma (peroxisome proliferator-activated receptor gamma) coactivator 1alpha] and PPARalpha and lower amounts of fatty acid synthase and acetyl-CoA carboxylase isoenzyme 1 were present in the liver of the PDHK4 knockout mice. These findings suggest PDHK4 deficiency creates conditions that alter upstream signalling components involved in the regulation of lipid metabolism. The findings support the hypothesis that PDHK4 is a viable target for the treatment of type 2 diabetes.
通过给野生型和PDHK4基因敲除小鼠喂食能诱发高血糖、高胰岛素血症、葡萄糖不耐受、肝脂肪变性和肥胖的高饱和脂肪饮食，来验证丙酮酸脱氢酶激酶同工酶4（PDHK4）作为2型糖尿病治疗靶点的潜力。先前的研究表明，PDHK4缺乏通过限制肝脏三碳糖异生底物的供应来降低血糖。然而，有人担心，磷酸化对丙酮酸脱氢酶复合物抑制作用减弱导致的葡萄糖氧化增加会抑制脂肪酸氧化，促进异位脂肪堆积并恶化胰岛素敏感性。通过给野生型和PDHK4基因敲除小鼠喂食高饱和脂肪饮食8个月来对此进行研究。两组小鼠的空腹血糖水平均逐渐升高，但PDHK4基因敲除小鼠的空腹血糖水平仍显著较低。两组均出现高胰岛素血症，但PDHK4基因敲除小鼠的葡萄糖耐量更好且体重更低。实验结束时，PDHK4基因敲除小鼠肝脏和骨骼肌中的脂肪含量更少。PDHK4基因敲除小鼠肝脏中过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）、过氧化物酶体增殖物激活受体α（PPARα）含量较高，脂肪酸合酶和乙酰辅酶A羧化酶同工酶1含量较低。这些发现表明，PDHK4缺乏创造了改变脂质代谢调节上游信号成分的条件。这些发现支持了PDHK4是2型糖尿病可行治疗靶点的假说。
