Xanthohumol Improves Diet-induced Obesity and Fatty Liver by Suppressing Sterol Regulatory Element-binding Protein (SREBP) Activation

• Published in: The Journal of biological chemistry 2015-08, Vol.290 (33), p.20565-20579
• Main Authors: Miyata, Shingo, Inoue, Jun, Shimizu, Makoto, Sato, Ryuichiro
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; CHO Cells; COPII; Cricetinae; Cricetulus; Diet; Fatty Liver - prevention & control; flavonoid; Flavonoids - pharmacology; Gene Regulation; hepatic steatosis; Humans; lipid synthesis; metabolic syndrome; Mice; Mice, Inbred C57BL; Obesity - etiology; Obesity - prevention & control; Propiophenones - pharmacology; Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors; Sterol Regulatory Element Binding Protein 1 - metabolism; sterol regulatory element-binding proteins; transcription factor; xanthohumol
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.656975

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that stimulate the expression of genes involved in fatty acid and cholesterol biosynthesis. Here, we demonstrate that a prenylated flavonoid in hops, xanthohumol (XN), is a novel SREBP inactivator that reduces the de novo synthesis of fatty acid and cholesterol. XN independently suppressed the maturation of SREBPs of insulin-induced genes in a manner different from sterols. Our results suggest that XN impairs the endoplasmic reticulum-to-Golgi translocation of the SREBP cleavage-activating protein (SCAP)-SREBP complex by binding to Sec23/24 and blocking SCAP/SREBP incorporation into common coated protein II vesicles. Furthermore, in diet-induced obese mice, dietary XN suppressed SREBP-1 target gene expression in the liver accompanied by a reduction of the mature form of hepatic SREBP-1, and it inhibited the development of obesity and hepatic steatosis. Altogether, our data suggest that XN attenuates the function of SREBP-1 by repressing its maturation and that it has the potential of becoming a nutraceutical food or pharmacological agent for improving metabolic syndrome. Background: Flavonoids are naturally occurring compounds and are known to regulate various transcription factors. Results: A prenylated flavonoid in hops, xanthohumol, improves diet-induced obesity and fatty liver by suppressing SREBP activation. Conclusion: Xanthohumol is a novel SREBP inactivator. Significance: Xanthohumol can be used as a nutraceutical food or pharmacological agent for improving metabolic syndrome.