Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.
Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.
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乙酰辅酶A羧化酶1（ACC1）在胰高血糖素分泌中起关键作用。
DOI：
10.1038/s42003-022-03170-w
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发表时间：
2022-03-18
影响因子：
5.9
通讯作者：
Cantley J
中科院分区：
文献类型：
--
作者：
Veprik A;Denwood G;Liu D;Bany Bakar R;Morfin V;McHugh K;Tebeka NN;Vetterli L;Yonova-Doing E;Gribble F;Reimann F;Hoehn KL;Hemsley PA;Ahnfelt-Rønne J;Rorsman P;Zhang Q;de Wet H;Cantley J
胰腺α细胞胰高血糖素分泌失调是1型和2型糖尿病（T1 D和T2 D）的一个关键特征，但相对于胰岛素分泌β细胞，我们对α细胞功能的机制理解尚不充分。在这里，我们表明，乙酰辅酶A羧化酶1（ACC 1），这对葡萄糖代谢脂肪生成，在胰高血糖素分泌的调节中起着关键作用。小鼠胰岛或α TC 9细胞中ACC 1的药理学抑制在低葡萄糖（1 mmol/l）下损害胰高血糖素分泌。同样，在小鼠α细胞中缺失ACC 1在分离的胰岛中在低葡萄糖下减少胰高血糖素分泌，并且在体内响应于禁食或胰岛素诱导的低血糖。电生理记录确定受损的KATP通道活性和P/Q-和L-型钙电流缺乏ACC 1的α-细胞，解释了葡萄糖敏感的损失。通过酰基生物素交换试验鉴定了KATP通道亚基Kir6.2的S-酰化的ACC依赖性改变。组织学分析确定，ACC 1的缺失导致胰腺α细胞面积、胰高血糖素含量和单个α细胞大小的减少，进一步损害分泌能力。ACC 1的缺失也减少了原发性胃肠道隐窝中胰高血糖素样肽1（GLP-1）的释放。总之，这些数据揭示了ACC 1偶联途径在表达胰高血糖素原的营养反应性内分泌细胞功能和全身葡萄糖稳态中的作用。Veprik等人表明，乙酰辅酶A羧化酶1（ACC 1），一种将葡萄糖代谢与脂肪生成偶联的酶，参与胰高血糖素分泌并调节关键葡萄糖敏感蛋白的S-酰化。胰腺α细胞中ACC 1的缺失对大小和数量以及胰高血糖素含量都有负面影响，而在肠道肠内分泌细胞中，ACC 1的缺失导致胰高血糖素样肽1的释放减少。
Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis. Veprik et al. show that Acetyl-CoA-carboxylase 1 (ACC1), an enzyme that couples glucose metabolism to lipogenesis, is involved in glucagon secretion and regulates S-acylation of critical glucose-sensing proteins. Loss of ACC1 in pancreatic alpha-cells negatively affects both size and number, as well as glucagon content, while in gut enteroendocrine cells leads to reduced release of glucagon-like peptide 1.
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影响因子：
8.2
作者：
Cantley J;Davenport A;Vetterli L;Nemes NJ;Whitworth PT;Boslem E;Thai LM;Mellett N;Meikle PJ;Hoehn KL;James DE;Biden TJ
通讯作者：
Biden TJ
影响因子：
8.2
作者：
Parker, H. E.;Adriaenssens, A.;Rogers, G.;Richards, P.;Koepsell, H.;Reimann, F.;Gribble, F. M.
通讯作者：
Gribble, F. M.
影响因子：
4.8
作者：
Chien, AJ;Gao, TY;Hosey, MM
通讯作者：
Hosey, MM
影响因子：
2.2
作者：
Albrechtsen, Nicolai J. Wewer;Kuhre, Rune E.;Holst, Jens J.
通讯作者：
Holst, Jens J.
影响因子：
7.7
作者：
Lee Y;Wang MY;Du XQ;Charron MJ;Unger RH
通讯作者：
Unger RH