Inhibition of liver X receptor-alpha-dependent hepatic steatosis by isoliquiritigenin, a licorice antioxidant flavonoid, as mediated by JNK1 inhibition

Isoliguritigenin (ILQ) a flavonoid obtained from Glycyrrhizae species has an antioxidant effect This study investigated the potential of ILQ for inhibiting liver X receptor alpha (LXR alpha) mediated lipogenesis and steatosis in hepatocytes and its underlying molecular basis Treatment with ILQ antagonized the ability of an LXR alpha agonist (10901317) to activate sterol regulatory element binding protein 1c (SREBP-1c) thereby repressing transcription of fatty acid synthase acetyl CoA carboxylase ATP-binding cassette transporter A1 and stearoyl CoA desaturase 1 ILQ treatment inhibited activating phosphorylation of JNK1 elicited by palmitate or TNF alpha JNK1 but not JNK2 increased LXR alpha phosphorylation at serine residues promoting LXR alpha activation The ability of ILQ to inhibit JNK1 downstream of ASK1-MKK7 led to the repression of T0901317-inducible LXR alpha and SREBP 1c activation In mice fed a high-fat diet ILQ treatment inhibited hepatic steatosis as shown by a decrease in fat accumulation and repression of lipogenic genes The results of blood biochemistry and histopathology confirmed attenuation of high fat diet induced liver injury by ILQ Moreover ILQ inhibited oxidative stress as indicated by decreases in throbai bituilc acid-reactive substance formation iNOS and COX2 induction and nitrotyrosinylation Our results demonstrate that ILQ has the ability to repress LXR alpha dependent hepatic steatosis through JNK1 inhibition and protect hepatocytes from oxidative injury inflicted by fat accumulation (C) 2010 Elsevier Inc All rights reservedThis work was supported by a National Research Foundation of Korea grant funded by the government of Korea (MEST) (No 20090063233