| Summary: | Abstract Background 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. Methods 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. Results 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. Conclusions 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.
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