The Alzheimer's disease drug candidate J147 decreases blood plasma fatty acid levels via modulation of AMPK/ACC1 signaling in the liver.
The Alzheimer's disease drug candidate J147 decreases blood plasma fatty acid levels via modulation of AMPK/ACC1 signaling in the liver.
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DOI：
10.1016/j.biopha.2022.112648
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Maher P
中科院分区：
文献类型：
--
作者：
Kepchia D;Huang L;Currais A;Liang Z;Fischer W;Maher P
J147是一种用于治疗神经功能障碍的新型候选药物。许多研究已经证明了J147在细胞和动物疾病模型中的有益作用，这导致该化合物过渡到人体临床试验。然而，尚未鉴定出其靶向接合的生物标志物。在这里，我们确定了血浆中的特定代谢物是否可以指示J147的体内活性。对来自三项独立啮齿动物研究的血浆脂质组学数据以及来自其中一项研究的肝脏脂质组学数据进行了沿着评估。在独立研究中，J147持续降低血浆游离脂肪酸（FFA）水平。在J147处理的小鼠的肝脏中也发现FFA水平降低，其与血浆中的FFA水平相关性良好。肝脏中的这些变化与AMP活化蛋白激酶/乙酰辅酶A羧化酶1信号通路的激活相关。在HepG 2细胞中证实了J147引起的FFA水平降低，其中观察到AMPK/ACC 1途径的激活沿着与增强的细胞生物能量学相关的乙酰辅酶A和ATP水平的增加。我们的数据表明，J147靶向肝细胞激活AMPK/ACC 1信号通路，并以抑制FFA合成为代价保存能量。
J147 is a novel drug candidate developed to treat neurological dysfunction. Numerous studies have demonstrated the beneficial effects of J147 in cellular and animal models of disease which has led to the transitioning of the compound into human clinical trials. However, no biomarkers for its target engagement have been identified. Here, we determined if specific metabolites in the plasma could be indicative of J147’s activity in vivo. Plasma lipidomics data from three independent rodent studies were assessed along with liver lipidomics data from one of the studies. J147 consistently reduced plasma free fatty acid (FFA) levels across the independent studies. Decreased FFA levels were also found in the livers of J147-treated mice that correlated well with those in the plasma. These changes in the liver were associated with activation of the AMP-activated protein kinase/acetyl-CoA carboxylase 1 signaling pathway. A reduction in FFA levels by J147 was confirmed in HepG2 cells, where activation of the AMPK/ACC1 pathway was seen along with increases in acetyl-CoA and ATP levels which correlated with enhanced cellular bioenergetics. Our data show that J147 targets liver cells to activate the AMPK/ACC1 signaling pathway and preserve energy at the expense of inhibiting FFA synthesis.
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DOI：
10.18632/aging.100838
发表时间：
2015-11
期刊：
Aging
影响因子：
--
作者：
Currais A;Goldberg J;Farrokhi C;Chang M;Prior M;Dargusch R;Daugherty D;Armando A;Quehenberger O;Maher P;Schubert D
通讯作者：
Schubert D
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
4.3
作者：
Bertolotti, Marco;Lonardo, Amedeo;Loria, Paola
通讯作者：
Loria, Paola
影响因子：
3.7
作者：
Chen Q;Prior M;Dargusch R;Roberts A;Riek R;Eichmann C;Chiruta C;Akaishi T;Abe K;Maher P;Schubert D
通讯作者：
Schubert D
影响因子：
14.9
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.