Calpain-mediated proteolytic production of free amino acids in vascular endothelial cells augments obesity-induced hepatic steatosis.
Calpain-mediated proteolytic production of free amino acids in vascular endothelial cells augments obesity-induced hepatic steatosis.
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DOI：
10.1016/j.jbc.2022.101953
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Miyazaki, Akira
中科院分区：
文献类型：
--
作者：
Akasu, Risako;Miyazaki, Takuro;Elhussiny, Mohamed Z.;Sugiura, Yuki;Tomitsuka, Yuki;Haraguchi, Shogo;Otsu, Kinya;Chowdhury, Vishwajit S.;Miyazaki, Akira
糖尿病和肥胖患者血浆中积累的游离氨基酸影响肝脏中的脂质代谢和蛋白质合成。应激诱导的细胞内蛋白酶钙蛋白酶蛋白水解血管内皮细胞（EC）中的各种底物，尽管其对肝脏微环境中游离氨基酸供应的贡献仍然是个谜。在本研究中，我们发现，钙蛋白酶与游离氨基酸的生产在培养的EC。此外，条件培养基来自钙蛋白酶激活的内皮细胞促进核糖体蛋白S6激酶（S6K）的磷酸化和从头脂肪生成的肝细胞，这是废除的氨基酸转运蛋白抑制剂，JPH 203，和哺乳动物的雷帕霉素复合物1的目标抑制剂，雷帕霉素。同时，在高脂饮食喂养的小鼠的肝脏中观察到过表达钙蛋白酶的毛细血管样EC。EC/造血Capns1（编码钙蛋白酶调节亚基）的条件性KO降低了肝脏微环境中支链氨基酸的水平，而不改变血浆氨基酸水平。同时，Capns1的条件性KO减轻了肝脂肪变性，而没有以氨基酸转运蛋白依赖性方式使体重和血浆脂蛋白谱正常化。具有靶向Capns1 KO的小鼠在肝细胞中表现出S6K磷酸化减少和脂肪生成因子固醇调节元件结合蛋白1成熟。最后，我们表明，骨髓移植否定造血钙蛋白酶系统的贡献。我们的结论是钙蛋白酶系统的过度激活可能是负责在EC中的游离氨基酸的生产，这可能是足以增强S6K/固醇调节元件结合蛋白1诱导的周围肝细胞中的脂肪生成。
Free amino acids that accumulate in the plasma of patients with diabetes and obesity influence lipid metabolism and protein synthesis in the liver. The stress-inducible intracellular protease calpain proteolyzes various substrates in vascular endothelial cells (ECs), although its contribution to the supply of free amino acids in the liver microenvironment remains enigmatic. In the present study, we showed that calpains are associated with free amino acid production in cultured ECs. Furthermore, conditioned media derived from calpain-activated ECs facilitated the phosphorylation of ribosomal protein S6 kinase (S6K) and de novo lipogenesis in hepatocytes, which were abolished by the amino acid transporter inhibitor, JPH203, and the mammalian target of rapamycin complex 1 inhibitor, rapamycin. Meanwhile, calpain-overexpressing capillary-like ECs were observed in the livers of high-fat diet–fed mice. Conditional KO of EC/hematopoietic Capns1, which encodes a calpain regulatory subunit, diminished levels of branched-chain amino acids in the hepatic microenvironment without altering plasma amino acid levels. Concomitantly, conditional KO of Capns1 mitigated hepatic steatosis without normalizing body weight and the plasma lipoprotein profile in an amino acid transporter–dependent manner. Mice with targeted Capns1 KO exhibited reduced phosphorylation of S6K and maturation of lipogenic factor sterol regulatory element–binding protein 1 in hepatocytes. Finally, we show that bone marrow transplantation negated the contribution of hematopoietic calpain systems. We conclude that overactivation of calpain systems may be responsible for the production of free amino acids in ECs, which may be sufficient to potentiate S6K/sterol regulatory element–binding protein 1–induced lipogenesis in surrounding hepatocytes.
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影响因子：
4.4
作者：
Miyazaki T;Miyazaki A
通讯作者：
Miyazaki A
影响因子：
5.5
作者：
Miyazaki, Takuro;Honda, Kazuo;Ohata, Hisayuki
通讯作者：
Ohata, Hisayuki
影响因子：
3.6
作者：
Miyazaki T;Miyazaki A
通讯作者：
Miyazaki A
DOI：
10.1073/pnas.2136625100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Chen, H;Polo, S;De Camilli, PV
通讯作者：
De Camilli, PV
影响因子：
29.4
作者：
Chalasani, Naga;Younossi, Zobair;Sanyal, Arun J.
通讯作者：
Sanyal, Arun J.