간조직 지질대사에서 진귤과피 활성성분의 기능

Abstract

Plants of the genus citrus are primarily valued for their edible fruit, but they also have traditional medicinal value. Although a number of previous studies have investigated their pharmacological activities of extracts isolated from the peel of citrus fruits, little is known about pharmacologically active compounds and related action mechanism underlying each pathological condition. The present study aimed to investigate the effect of extract isolated from the peel of citrus sunki hort.ex Tanaka, one of Jeju-native citrus fruits, on the hepatic lipid metabolism. Additionally, we performed compositional analysis to find out any leading compounds that is active in regulating lipid metabolism in liver cells. Finally, action mechanism of each compound to suppress hepatic lipid accumulation was also investigated. Treatment of HepG2 liver cells with the extract of fermented citrus sunki peel (FSE) suppressed free fatty acid (FFA)-induced lipid accumulation. In vivo studies using high fat diet rats also found that FSE can suppress the increased levels of a number of pathological indicators including AST, ALT, ??-GT, triglyceride within plasma, weight of liver and spleen, and the degree of hepatic fat accumulation that were induced by high fat diet. From the compositional analysis, five rich compounds were characterized; synephrine (alkaloid), tangeritin and nobiletin (polymethoxyflavones), rutin and hesperidin (flavonone glycoside) except other trace elements. All five compounds suppressed FFA-induced accumulation of triglyceride (TG) in the cytoplasm of HepG2 cells. The hypolipidemic activity of four compounds except tangeritin was sensitive to the inhibition of AMPK. They also decreased protein levels as well as mRNA levels of SREBP1c (a mediator of de novo lipogenesis) and stimulated the phosphorylation of AMPK, however, decreased the mRNA levels of FAS (fatty acid synthase), one of SREBP1c-regulated target gene product. Hypolipidemic activity of tangeritin was sensitive to the inhibition of PI3-kinase in HepG2 cells. Although tangeritin marginally stimulated the phosphorylation of AMPK, the inhibition of AMPK failed to suppress FFA-induced TG accumulation. Tangeritin also decreased protein levels as well as mRNA levels of SREBP1c that were increased by FFA. Taken together, 5 major compounds were totally active to suppress FFA-induced TG accumulation in the cytoplasm of HepG2 liver cells. However, action mechanism of each compound is different in part, although it shares a few signaling protein and transcription factor(s) like as AMPK and SREBP1c, respectively. The peel of citrus sunki per se. and leading compounds within the peel have a good pharmacological value to prevent or treat hepatic steatosis and more progressed liver disease like as nonalcoholic steatohepatitis (NASH).