Kudo Maya, Yamagishi Yoshie, Suguro Shiori, Nishihara Masaaki, Yoshitomi Hisae, Hayashi Misa, Gao Ming
School of Pharmaceutical Science Mukogawa Women's University Nishinomiya Japan.
Protein Chemical Co., Ltd. Tokyo Japan.
Food Sci Nutr. 2021 Jul 16;9(9):4893-4904. doi: 10.1002/fsn3.2439. eCollection 2021 Sep.
Body weight gain is a social issue all over the world. When body weight increased, hepatic fat accumulation also increased and it causes fatty liver disease. Therefore, developing a new treatment method and elucidating its mechanism is necessary. L-citrulline (L-Cit) is a free amino acid found mainly in watermelon. No reports regarding its effects on the improvement of hepatic steatosis and fibrogenesis are currently available. The aim of this study was to clarify the effect and the mechanism of L-Cit on inhibition of body weight gain and hepatic fat accumulation in high-fat and high-cholesterol fed SHRSP5/Dmcr rats.
L-Cit or water (controls) was administered to six-week-old male SHRSP5/Dmcr rats by gavage for nine weeks. We recorded the level of body weight and food intake while performing the administration and sacrificed rats. After that, the blood and lipid metabolism-related organs and tissues were collected and analyzed.
L-Cit treatment reduced body weight gain and hepatic TC and TG levels, and serum levels of AST and ALT. L-Cit enhanced AMPK, LKB1, PKA, and hormone-sensitive lipase (HSL) protein phosphorylation levels in the epididymal fat. L-Cit treatment improved steatosis as revealed by HE staining of liver tissues and enhanced AMPK and LKB1 phosphorylation levels. Moreover, activation of Sirt1 was higher, while the liver fatty acid synthase (FAS) level was lower. Azan staining of liver sections revealed a reduction in fibrogenesis following L-Cit treatment. Further, the liver levels of TGF-β, Smad2/3, and α-SMA, fibrogenesis-related proteins and genes, were lower in the L-Cit-treated group.
From the results of analysis of the epididymal fat and the liver, L-Cit inhibits body weight gain and hepatic fat accumulation by activating lipid metabolism and promoting fatty acid β-oxidation in SHRSP5/Dmcr rats.
体重增加是一个全球性的社会问题。当体重增加时，肝脏脂肪堆积也会增加，进而导致脂肪肝疾病。因此，开发新的治疗方法并阐明其机制很有必要。L-瓜氨酸（L-Cit）是一种主要存在于西瓜中的游离氨基酸。目前尚无关于其对改善肝脂肪变性和纤维化作用的报道。本研究的目的是阐明L-Cit对高脂高胆固醇喂养的SHRSP5/Dmcr大鼠体重增加和肝脏脂肪堆积的抑制作用及其机制。
对六周龄雄性SHRSP5/Dmcr大鼠通过灌胃给予L-Cit或水（对照组），持续九周。给药期间记录体重和食物摄入量，并在实验结束时处死大鼠。之后，收集并分析血液以及与脂质代谢相关的器官和组织。
L-Cit治疗可减轻体重增加以及降低肝脏总胆固醇（TC）和甘油三酯（TG）水平，还有血清天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平。L-Cit可增强附睾脂肪中腺苷酸活化蛋白激酶（AMPK）、肝脏激酶B1（LKB1）、蛋白激酶A（PKA）和激素敏感性脂肪酶（HSL）的蛋白磷酸化水平。肝脏组织苏木精-伊红（HE）染色显示，L-Cit治疗改善了脂肪变性，并增强了AMPK和LKB1的磷酸化水平。此外去乙酰化酶1（Sirt1）的激活程度更高，而肝脏脂肪酸合酶（FAS）水平更低。肝脏切片的偶氮染色显示L-Cit治疗后纤维化减少。此外，L-Cit治疗组中肝脏转化生长因子-β（TGF-β）、Smad2/3和α-平滑肌肌动蛋白（α-SMA）（纤维化相关蛋白和基因）水平较低。
根据附睾脂肪和肝脏的分析结果，L-Cit通过激活脂质代谢和促进SHRSP5/Dmcr大鼠脂肪酸β-氧化来抑制体重增加和肝脏脂肪堆积。
