Yu Yue, Tamai Miho, Tagawa Yoh-Ichi
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
School of Life Science and Technology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
Exp Anim. 2017 Oct 30;66(4):293-302. doi: 10.1538/expanim.17-0017. Epub 2017 May 18.
Nitric oxide (NO), generated from L-arginine by three different isoforms of nitric oxide synthase (NOS), is a pleiotropic factor to regulate physiological functions in almost every organ and tissue. Each knockout mouse of iNOS or eNOS has been used to suggest that NO has a crucial role in liver regeneration after partial hepatectomy (PH), for NO may inhibit caspase 3 activity and is required for EGFR signaling. In previous reports, defective mitochondrial β-oxidation was observed in eNOS KO mice, and hepatic steatosis was often correlated to deficient liver regeneration, so we focused on metabolic perspective and hypothesized that NO depletion in PH mice would affect hepatocytic lipolysis and impair hepatocytes proliferation. We inhibited all NOS isoforms by administrating L-N-nitroarginine methyl ester (L-NAME) to PH mice, and hepatocyte DNA synthesis was severely inhibited at 40-44 h post PH in L-NAME (+) group. IL-6 was robustly secreted into circulating blood in L-NAME (-) group, but not in L-NAME (+) group. Down-regulation of carnitine palmytoyltransferase 1A, massive lipid accumulation and elevated endoplasmic reticulum (ER) stress relative genes expression level were observed in L-NAME (+) group mouse liver. The expression level of C/EBP homologous protein, a mediator of ER stress induced apoptosis, significantly increased in L-NAME (+) group. Our findings suggest the lack of NO affected IL-6 induction and hepatocyte lipolysis after PH, consequently leading to excessive hepatic lipid accumulation, elevated ER stress and impaired hepatocyte proliferation.
一氧化氮（NO）由一氧化氮合酶（NOS）的三种不同同工型从L-精氨酸生成，是一种多效性因子，可调节几乎每个器官和组织的生理功能。iNOS或eNOS的每种基因敲除小鼠已被用于表明NO在部分肝切除术后（PH）的肝再生中起关键作用，因为NO可能抑制半胱天冬酶3活性，并且是EGFR信号传导所必需的。在先前的报道中，在eNOS基因敲除小鼠中观察到线粒体β-氧化缺陷，肝脂肪变性常与肝再生不足相关，因此我们从代谢角度进行了研究，并假设PH小鼠中NO的消耗会影响肝细胞脂肪分解并损害肝细胞增殖。我们通过向PH小鼠施用L-N-硝基精氨酸甲酯（L-NAME）来抑制所有NOS同工型，在PH后40-44小时，L-NAME（+）组的肝细胞DNA合成受到严重抑制。在L-NAME（-）组中，IL-6大量分泌到循环血液中，但在L-NAME（+）组中则没有。在L-NAME（+）组小鼠肝脏中观察到肉碱棕榈酰转移酶1A的下调、大量脂质积累和内质网（ER）应激相关基因表达水平升高。ER应激诱导凋亡的介质C/EBP同源蛋白的表达水平在L-NAME（+）组中显著增加。我们的研究结果表明，NO的缺乏影响了PH后IL-6的诱导和肝细胞脂肪分解，从而导致肝脏脂质过度积累、ER应激升高和肝细胞增殖受损。
