Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.

中文翻译：

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乙酰辅酶A羧化酶抑制作用可减少小鼠和人类的肝脂肪变性，但可升高血浆甘油三酸酯：从床旁进行临床研究。

抑制脂肪生成可防止具有胰岛素抵抗的啮齿动物肝脂肪变性。为了确定降低脂肪生成的功能是否类似地在人类中发挥作用，我们开发了MK-4074，这是一种肝脏特异性的乙酰辅酶A羧化酶（ACC1）和（ACC2）酶，后者可以产生丙二酰辅酶A来合成脂肪酸。对患有肝脂肪变性的受试者给药1个月的MK-4074可降低脂肪生成，增加酮和将肝甘油三酸酯降低36％。出乎意料的是，MK-4074使血浆甘油三酸酯增加了200％。为了进一步研究，生成了在肝细胞中缺乏ACC1和ACC2的小鼠（ACC dLKO）。由于减少了丙二酰-CoA，ACC的缺失降低了肝脏中多不饱和脂肪酸（PUFA）的浓度，而丙二酰-CoA的减少是必需脂肪酸延长所必需的。PUFA缺乏诱导SREBP-1c，从而增加GPAT1表达和VLDL分泌。PUFA补充或GPAT1标准化的血浆甘油三酸酯的siRNA介导的敲除。因此，抑制人的脂肪生成减少了肝脂肪变性，但抑制ACC则由于SREBP-1c的激活和VLDL分泌的增加而导致高甘油三酸酯血症。