Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation.
Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation.
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DOI：
10.1016/j.cmet.2017.07.009
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发表时间：
2017-08-01
期刊：
影响因子：
29
通讯作者：
Horton JD
中科院分区：
文献类型：
--
作者：
Kim CW;Addy C;Kusunoki J;Anderson NN;Deja S;Fu X;Burgess SC;Li C;Ruddy M;Chakravarthy M;Previs S;Milstein S;Fitzgerald K;Kelley DE;Horton JD
抑制脂肪生成可预防胰岛素抵抗啮齿动物的肝脂肪变性。为了确定减少脂肪生成在人类中是否具有类似的功能，我们开发了MK-4074，一种乙酰辅酶A羧化酶（ACC 1）和（ACC 2）的肝脏特异性抑制剂;产生丙二酰辅酶A用于脂肪酸合成的酶。对肝脂肪变性受试者给予MK-4074 1个月，可降低脂肪生成，增加酮体，并使肝脏甘油三酯降低36%。出乎意料的是，MK-4074使血浆甘油三酯增加了200%。为了进一步研究，产生肝细胞中缺乏ACC 1和ACC 2的小鼠（ACC dLKO）。ACCs的缺失降低了肝脏中多不饱和脂肪酸（PUFA）的浓度，这是由于丙二酰辅酶A的减少，而丙二酰辅酶A是延长必需脂肪酸所必需的。PUFA缺乏诱导SREBP-1c，增加GPAT 1表达和VLDL分泌。PUFA补充或siRNA介导的GPAT 1敲低使血浆甘油三酯正常化。因此，抑制人类脂肪生成可减少肝脂肪变性，但抑制ACC可导致高脂血症，这是由于SREBP-1c的激活和VLDL分泌增加。Kim等人描述了乙酰辅酶A羧化酶（ACC）1和2的抑制剂，其减少患有脂肪肝的个体的肝脏甘油三酯，但增加血浆甘油三酯。在缺乏ACC的小鼠中，丙二酰辅酶A水平降低抑制多不饱和脂肪酸合成，导致SREBP-1c和GPAT 1表达增加，VLDL分泌增加和高脂血症。
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. Kim et al. describe an inhibitor of acetyl-CoA carboxylase (ACC) 1 and 2 that reduces liver triglycerides in individuals with fatty livers, but increases plasma triglycerides. In mice lacking ACCs, reduced malonyl-CoA levels suppress polyunsaturated fatty acid synthesis leading to increased SREBP-1c and GPAT1 expression, increased VLDL secretion, and hypertriglyceridemia.
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影响因子：
13.5
作者：
Browning, JD;Szczepaniak, LS;Hobbs, HH
通讯作者：
Hobbs, HH
影响因子：
7.1
作者：
Aarsland, A;Chinkes, D;Wolfe, RR
通讯作者：
Wolfe, RR
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH
DOI：
10.1074/jbc.m109.064501
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
He S;McPhaul C;Li JZ;Garuti R;Kinch L;Grishin NV;Cohen JC;Hobbs HH
通讯作者：
Hobbs HH
影响因子：
29.4
作者：
Chalasani, Naga;Younossi, Zobair;Sanyal, Arun J.
通讯作者：
Sanyal, Arun J.