Kusunoki Jun, Kanatani Akio, Moller David E
Department of Metabolic Disorders, Banyu-Tsukuba Research Institute, Tsukuba, Japan.
Endocrine. 2006 Feb;29(1):91-100. doi: 10.1385/ENDO:29:1:91.
Increased de novo lipogenesis and reduced fatty acid oxidation are probable contributors to adipose accretion in obesity. Moreover, these perturbations have a role in leading to non-alcoholic steatohepatitis, dyslipidemia, and insulin resistance--via "lipotoxicity"-related mechanisms. Research in this area has prompted an effort to evaluate several discrete enzymes in these pathways as targets for future therapeutic intervention. Acetyl-CoA carboxylase 1 (ACC1) and ACC2 regulate fatty acid synthesis and indirectly control fatty acid oxidation via a key product, malonyl CoA. Based on mouse genetic and preclinical pharmacologic evidence, inhibition of ACC1 and/or ACC2 may be a useful approach to treat obesity and metabolic syndrome. Similarly, available data suggest that inhibition of other enzymes in this pathway, including fatty acid synthase, stearoyl CoA desaturase, and diacylglycerol acytransferase 1, will have beneficial effects. AMP-activated protein kinase is a master regulator of nutrient metabolism, which controls several aspects of lipid metabolism. Activation of AMPK in selected tissues is also a potential therapeutic approach. Inhibition of hormone-sensitive lipase is another possible approach. The rationale for modulating the activity of these enzymes and their relative merits (and downsides) as possible therapeutic targets are further discussed.
肥胖状态下，脂肪生成增加及脂肪酸氧化减少可能是脂肪堆积的原因。此外，这些紊乱通过“脂毒性”相关机制，在导致非酒精性脂肪性肝炎、血脂异常和胰岛素抵抗方面发挥作用。该领域的研究促使人们努力评估这些途径中的几种离散酶，作为未来治疗干预的靶点。乙酰辅酶A羧化酶1（ACC1）和ACC2调节脂肪酸合成，并通过关键产物丙二酰辅酶A间接控制脂肪酸氧化。基于小鼠遗传学和临床前药理学证据，抑制ACC1和/或ACC2可能是治疗肥胖和代谢综合征的有效方法。同样，现有数据表明，抑制该途径中的其他酶，包括脂肪酸合酶、硬脂酰辅酶A去饱和酶和二酰甘油酰基转移酶1，将产生有益效果。AMP激活的蛋白激酶是营养代谢的主要调节因子，它控制脂质代谢的多个方面。在选定组织中激活AMPK也是一种潜在的治疗方法。抑制激素敏感性脂肪酶是另一种可能的方法。本文将进一步讨论调节这些酶活性的基本原理及其作为潜在治疗靶点的相对优点（和缺点）。
