Ursolic Acid, a Novel Liver X Receptor α (LXRα) Antagonist Inhibiting Ligand-Induced Nonalcoholic Fatty Liver and Drug-Induced Lipogenesis

• Published in: Journal of agricultural and food chemistry Vol. 66; no. 44; pp. 11647 - 11662
• Main Authors: Lin, Yen-Ning, Wang, Charles C. N, Chang, Hsiao-Yun, Chu, Fang-Yi, Hsu, Yu-An, Cheng, Wai-Kok, Ma, Wei-Chih, Chen, Chao-Jung, Wan, Lei, Lim, Yun-Ping
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07.11.2018
• Subjects: agonists; AMP-activated protein kinase; animal models; Animals; antagonists; atherosclerosis; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; cholesterol; computer simulation; excretion; fatty liver; genes; homeostasis; Humans; Hydrocarbons, Fluorinated - administration & dosage; Hydrocarbons, Fluorinated - chemistry; hyperlipidemia; intestines; leucine zipper; Ligands; lipid content; lipogenesis; Lipogenesis - drug effects; liver; Liver - drug effects; Liver - metabolism; Liver X Receptors - antagonists & inhibitors; Liver X Receptors - chemistry; Liver X Receptors - genetics; Liver X Receptors - metabolism; Male; messenger RNA; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; phosphorylation; pregnanes; promoter regions; protein synthesis; steroid receptors; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Sulfonamides - administration & dosage; Sulfonamides - chemistry; therapeutics; transcriptional activation; Triterpenes - administration & dosage; Triterpenes - chemistry; Ursolic Acid; nonalcoholic fatty liver disease; pregnane X receptor; liver X receptor α; ursolic acid
• ISSN: 0021-8561; 1520-5118; 1520-5118
• DOI: 10.1021/acs.jafc.8b04116

Nonalcoholic fatty liver disease (NAFLD) is a very common liver disease, and its incidence has significantly increased worldwide. The liver X receptor α (LXRα) is a multifunctional nuclear receptor that controls lipid homeostasis. Inhibition of LXRα transactivation may be beneficial for NAFLD and hyperlipidemia treatment. Ursolic acid (UA) is a plant triterpenoid with many beneficial effects; however, the mechanism of its action on LXRα remains elusive. We evaluated the effects of UA on T0901317 (T090)-induced LXRα activation and steatosis. UA significantly decreased the LXR response element and sterol regulatory element-binding protein-1c (SREBP-1c) gene promoter activities, mRNA, protein expression of LXRα target genes, and hepatic cellular lipid content in a T090-induced mouse model. A molecular docking study indicated that UA bound competitively with T090 at the LXRα ligand binding domain. UA stimulated AMP-activated protein kinase (AMPK) phosphorylation in hepatic cells and increased corepressor, small heterodimer partner-interacting leucine zipper protein (SMILE) but decreased coactivator, steroid receptor coactivator-1 (SRC-1) recruitment to the SREBP-1c promoter region. In contrast, UA induced SRC-1 binding but decreased SMILE binding to reverse cholesterol transport-related gene promoters in intestinal cells, increasing lipid excretion from intestinal cells. Additionally, UA reduced valproate-induced LXRα mediated and rifampin-induced pregnane X receptor mediated lipogenesis, offering potential treatments for drug-induced hepatic steatosis. Thus, UA displays liver specificity and can be selectively repressed while RCT stimulation by LXRα is preserved and enhanced. This is a novel therapeutic option to treat NAFLD and may be helpful in developing LXR agonists to prevent atherosclerosis.