Inhibition of liver X receptor-α-dependent hepatic steatosis by isoliquiritigenin, a licorice antioxidant flavonoid, as mediated by JNK1 inhibition.
Isoliquiritigenin (ILQ), a flavonoid obtained from Glycyrrhizae species, has an antioxidant effect. This study investigated the potential of ILQ for inhibiting liver X receptor-α (LXRα)-mediated lipogenesis and steatosis in hepatocytes and its underlying molecular basis. Treatment with ILQ antagonized the ability of an LXRα agonist (T0901317) 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 TNFα. JNK1, but not JNK2, increased LXRα phosphorylation at serine residues, promoting LXRα activation. The ability of ILQ to inhibit JNK1 downstream of ASK1-MKK7 led to the repression of T0901317-inducible LXRα 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 thiobarbituric acid-reactive substance formation, iNOS and COX2 induction, and nitrotyrosinylation. Our results demonstrate that ILQ has the ability to repress LXRα-dependent hepatic steatosis through JNK1 inhibition and protect hepatocytes from oxidative injury inflicted by fat accumulation.
Kim
Young Mi
YM
Innovative Drug Research Center for Metabolic and Inflammatory Diseases, College of Pharmacy, Seoul National University, Seoul, Korea.
Kim
Tae Hyun
TH
Kim
Young Woo
YW
Yang
Yoon Mee
YM
Ryu
Da Hye
DH
Hwang
Se Jin
SJ
Lee
Jong Rok
JR
Kim
Sang Chan
SC
Kim
Sang Geon
SG
D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D047188:Chalcones / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control*; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D006035:Glycyrrhiza / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects
D000975:Antioxidants; D047188:Chalcones; D005419:Flavonoids; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047428:Protein Kinase Inhibitors; C040920:isoliquiritigenin; D048055:Mitogen-Activated Protein Kinase 8