Ming Gu1, Yu Zhang1,2, Chuhe Liu1, Dongshan Wang1, Li Feng1, Shengjie Fan1,3, Baican Yang1, Qingchun Tong3, Guang Ji4, Cheng Huang1. 1. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China. 2. School of Life Science and Technology, Shanghai Tech University, Shanghai, China. 3. Brown Foundation Institute of Molecular Medicine and Program in Neuroscience, Graduate School of Biological Sciences, University of Texas McGovern Medical School, Houston, TX, USA. 4. Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Abstract
BACKGROUND AND PURPOSE: Morin is a natural occurring flavonoid in many dietary plants and has a wide range of beneficial effects on metabolism; however, the mechanism underlying its action remains elusive. EXPERIMENTAL APPROACH: A reporter assay and the time-resolved FRET assay were used to identify morin as a dual antagonist of liver X receptor (LXR)-α and -β. Morin (100 mg. 100 g-1 diet) was administered to high-fat diet-induced obese or LXRβ-/- mice. The pharmacological effects and mechanism of action of morin were evaluated by Western blot and RT-PCR analyses. KEY RESULTS: From the in vitro assays, morin was shown to be a dual antagonist of LXRα and LXRβ. In vivo, morin blunted the development of liver hepatic steatosis, reduced body weight gains, lowered triglyceride levels and improved glucose and insulin tolerance in mice fed a high-fat diet. Mechanistically, morin inhibited 3T3-L1 adipocyte differentiation and lipid formation in human hepatic HepG2 cells and suppressed the mRNA expression of genes downstream of LXR. Consistently, the effects of morin on metabolic disorders were attenuated in LXRβ-/- mice. CONCLUSION AND IMPLICATIONS: Our data reveal that morin is a dual antagonist of LXRα and LXRβ and suggest that morin may alleviate hepatic steatosis and other associated metabolic disorders via the suppression of LXR signalling and, therefore, shows promise as a novel therapy or nutraceutical for nonalcoholic fatty liver disease.
BACKGROUND AND PURPOSE: Morin is a natural occurring flavonoid in many dietary plants and has a wide range of beneficial effects on metabolism; however, the mechanism underlying its action remains elusive. EXPERIMENTAL APPROACH: A reporter assay and the time-resolved FRET assay were used to identify morin as a dual antagonist of liver X receptor (LXR)-α and -β. Morin (100 mg. 100 g-1 diet) was administered to high-fat diet-induced obese or LXRβ-/- mice. The pharmacological effects and mechanism of action of morin were evaluated by Western blot and RT-PCR analyses. KEY RESULTS: From the in vitro assays, morin was shown to be a dual antagonist of LXRα and LXRβ. In vivo, morin blunted the development of liver hepatic steatosis, reduced body weight gains, lowered triglyceride levels and improved glucose and insulin tolerance in mice fed a high-fat diet. Mechanistically, morin inhibited 3T3-L1 adipocyte differentiation and lipid formation in human hepatic HepG2 cells and suppressed the mRNA expression of genes downstream of LXR. Consistently, the effects of morin on metabolic disorders were attenuated in LXRβ-/- mice. CONCLUSION AND IMPLICATIONS: Our data reveal that morin is a dual antagonist of LXRα and LXRβ and suggest that morin may alleviate hepatic steatosis and other associated metabolic disorders via the suppression of LXR signalling and, therefore, shows promise as a novel therapy or nutraceutical for nonalcoholic fatty liver disease.
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