Expression data from livers of high fat fed rats treated with ACC inhibitor PF-04923503

Fundamental alterations in lipid metabolism including increased rates of de novo lipogenesis (DNL), reduced fatty acid oxidation (FAOX) and ectopic lipid accumulation in skeletal muscle and liver are characteristic of type 2 diabetes mellitus (T2DM) and have been hypothesized to directly contribute to the molecular pathogenesis of the disease. Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, the rate limiting substrate for DML and key regulator of FAOX. ACC inhibitors have the potential to pharmacologically rebalance these metabolic alterations. In the present study, PF-04923503, a potent dual ACC1/ACC2 inhibitor with properties optimized for in vivo studies, suppressed levels of malonyl-CoA in primary hepatocytes, rat skeletal muscle ex vivo, as well as rat liver and skeletal muscle in vivo. This impact on malonyl-CoA was directly correlated (r2>0.9) with reduced hepatic DNL and inversely correlated with incresed rates of FAOX (r2>0.9). The pharmacological eccfect of PF-04923503 persisted with chronic treatment. High-fat fed rats treated with PF-04923503 for six weeks showed dose-dependent reductions in skeletal muscle and liver lipid accumulation. These changes correlated directly with markers for improved insulin sensitization. However, liver gene expression indicates that pharmacological inhibition results in compensation by up-regualtion of genes involved with DNL. These results suggest that pharmacological inhibition of ACC may have utility to help rebalance metabolic abnormalities in T2DM and improve insulin sensitivity.2型糖尿病（type 2 diabetes mellitus, T2DM）的典型特征为脂质代谢发生根本性改变，包括从头脂肪生成（de novo lipogenesis, DNL）速率升高、脂肪酸氧化（fatty acid oxidation, FAOX）降低以及骨骼肌与肝脏出现异位脂质蓄积；已有研究假说指出，这些改变可直接参与疾病的分子致病过程。乙酰辅酶A羧化酶（acetyl-CoA carboxylase, ACC）可催化丙二酰辅酶A的生成，后者是DNL的限速底物，同时也是FAOX的关键调控因子。ACC抑制剂具备通过药理学手段重新平衡上述代谢紊乱的潜力。本研究中，PF-04923503是一种强效的ACC1/ACC2双重抑制剂，其特性经过优化以适配体内研究，该化合物可在原代肝细胞、离体大鼠骨骼肌以及活体大鼠的肝脏与骨骼肌中降低丙二酰辅酶A水平。其对丙二酰辅酶A的影响与肝脏DNL的降低呈直接正相关（决定系数r²>0.9），与FAOX速率的升高呈显著负相关（r²>0.9）。PF-04923503的药理学效应在长期给药后仍可维持。对高脂饮食喂养的大鼠连续6周给予PF-04923503后，其骨骼肌与肝脏的脂质蓄积呈现剂量依赖性降低，这些变化与胰岛素增敏相关标志物的改善呈直接关联。不过肝脏基因表达分析显示，ACC的药理学抑制会引发代偿效应，参与DNL的相关基因出现上调。上述结果表明，ACC的药理学抑制或可用于重新平衡T2DM患者的代谢异常，并改善胰岛素敏感性。