Berberine Reduces Pyruvate-driven Hepatic Glucose Production by Limiting Mitochondrial Import of Pyruvate through Mitochondrial Pyruvate Carrier 1.
Berberine Reduces Pyruvate-driven Hepatic Glucose Production by Limiting Mitochondrial Import of Pyruvate through Mitochondrial Pyruvate Carrier 1.
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DOI：
10.1016/j.ebiom.2018.07.039
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发表时间：
2018-08
期刊：
影响因子：
11.1
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Li A;Liu Q;Li Q;Liu B;Yang Y;Zhang N
线粒体丙酮酸通过线粒体丙酮酸载体（MPC）输入是肝脏再生的中心步骤。黄连素抑制肝纤维化，但其机制尚不完全清楚。本研究的目的是探讨黄连素是否可以减少过量的肝葡萄糖的生产（HGP）通过限制线粒体输入丙酮酸通过MPC 1。高脂饮食（HFD）喂养增强HGP。研究了小檗碱对肝脏脂肪酸氧化、沉默调节蛋白3（SIRT 3）诱导和线粒体丙酮酸载体1（MPC 1）功能的影响。HFD喂养增加了肝脏乙酰辅酶A（乙酰CoA）的积累，丙酮酸脱氢酶（PDH）活性受损，丙酮酸羧化酶（PC）诱导增加。小檗碱通过限制脂肪酸氧化减少乙酰辅酶A的积累，并通过羧化阻止线粒体丙酮酸从氧化转变为异生。在丙酮酸应答后，SIRT3结合到MPC 1并通过脱乙酰化修饰稳定MPC 1蛋白，促进丙酮酸的线粒体输入。小檗碱通过抑制SIRT3的诱导来保护MPC 1的乙酰化，并通过蛋白质降解来破坏MPC 1蛋白质的稳定性，从而限制线粒体丙酮酸的供应以供胚胎发生。小檗碱通过限制脂肪酸氧化降低乙酰辅酶A含量，通过保护乙酰化增加MPC 1降解，从而通过阻断丙酮酸的线粒体输入抑制HGP。这些结果表明，限制线粒体丙酮酸输入可能是一种治疗策略，以防止过度的肝脏葡萄糖的生产。
Mitochondrial pyruvate import via mitochondrial pyruvate carrier (MPC) is a central step in hepatic gluconeogenesis. Berberine inhibits hepatic gluconeogenesis, but the mechanism is incompletely understood. This study aims to investigate whether berberine could reduce excessive hepatic glucose production (HGP) by limiting mitochondrial import of pyruvate through MPC1. High-fat diet (HFD) feeding augmented HGP. The effects of berberine on hepatic fatty acid oxidation, sirtuin3 (SIRT3) induction and mitochondrial pyruvate carrier 1 (MPC1) function were examined. HFD feeding increased hepatic acetyl coenzyme A (acetyl CoA) accumulation with impaired pyruvate dehydrogenase (PDH) activity and increased pyruvate carboxylase (PC) induction. Berberine reduced acetyl CoA accumulation by limiting fatty acid oxidation and prevented mitochondrial pyruvate shift from oxidation to gluconeogenesis through carboxylation. Upon pyruvate response, SIRT3 binded to MPC1 and stabilized MPC1 protein via deacetylation modification, facilitating mitochondrial import of pyruvate. Berberine preserved the acetylation of MPC1 by suppression of SIRT3 induction and impaired MPC1 protein stabilization via protein degradation, resultantly limiting mitochondrial pyruvate supply for gluconeogenesis. Berberine reduced acetyl CoA contents by limiting fatty acid oxidation and increased MPC1 degradation via preserving acetylation, thereby restraining HGP by blocking mitochondrial import of pyruvate. These findings suggest that limitation of mitochondrial pyruvate import might be a therapeutic strategy to prevent excessive hepatic glucose production.
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影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
抑制线粒体复合物 I 可改善葡萄糖代谢，与 AMPK 激活无关
影响因子：
5.3
作者：
Hou WL;Yin J;Alimujiang M;Yu XY;Ai LG;Bao YQ;Liu F;Jia WP
通讯作者：
Jia WP
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1056/nejm197003052821026
发表时间：
1970-03-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cahill, G F Jr
通讯作者：
Cahill, G F Jr
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X