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

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.

Keywords: 22S-hydroxycholesterol (PubChem CID: 168038); GW4064 (PubChem CID: 9893571); Geranylgeranylpyrophosphate (PubChem CID: 44134732); Liver X receptor α (LXRα); Nonalcoholic fatty liver disease (NAFLD); Receptor interacting protein 140 (RIP140); Reverse cholesterol transport; Rifampicin (PubChem CID: 5381226); Sterol-response element binding protein 1c (SREBP1c); T0901317 (PubChem CID: 447912); meso-Dihydroguaiaretic acid (PubChem CID: 476856).