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  • LXR-α antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver.

LXR-α antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver.

Biochemical pharmacology (2014-06-24)
Woo-Cheol Sim, Sora Park, Kang-Yo Lee, Young-Tae Je, Hu-Quan Yin, You-Jin Choi, Sang Hyun Sung, So-Jung Park, Hyun-Ju Park, Kye Jung Shin, Byung-Hoon Lee
ABSTRACT

Collaborative regulation of liver X receptor (LXR) and sterol regulatory element binding protein (SREBP)-1 are main determinants in hepatic steatosis, as shown in both animal models and human patients. Recent studies indicate that selective intervention of overly functional LXRα in the liver shows promise in treatment of fatty liver disease. In the present study, we evaluated the effects of meso-dihydroguaiaretic acid (MDGA) on LXRα activation and its ability to attenuate fatty liver in mice. MDGA inhibited activation of the LXRα ligand-binding domain by competitively binding to the pocket for agonist T0901317 and decreased the luciferase activity in LXRE-tk-Luc-transfected cells. MDGA significantly attenuated hepatic neutral lipid accumulation in T0901317- and high fat diet (HFD)-induced fatty liver. The effect of MDGA was so potent that treatment with 1mg/kg for 2 weeks completely reversed the lipid accumulation induced by HFD feeding. MDGA reduced the expression of LXRα co-activator protein RIP140 and LXRα target gene products associated with lipogenesis in HFD-fed mice. These results demonstrate that MDGA has the potential to attenuate nonalcoholic steatosis mediated by selective inhibition of LXRα in the liver in mice.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Guaiacol, natural, ≥99%, FG
Sigma-Aldrich
Guaiacol, oxidation indicator
Supelco
Guaiacol, Pharmaceutical Secondary Standard; Certified Reference Material
Guaiacol, European Pharmacopoeia (EP) Reference Standard