Phytosteroid 28-homobrassinolide targets cholesterol and glucose homeostasis implicating ABCA1 and SREBP role in regulation

Oxysterols are natural ligands of certain nuclear receptors known as liver X receptors (LXR). LXRs are regulators of fatty acid, Cholesterol, and glucose homeostasis. Dietary phyto-oxysterol 28-homobrassinolide (28-HB) has been demonstrated to transactivate rat LXR α and β. In this study we assessed the potential of 28-HB to effect such changes in - (1) human HepG2 Cancer cell line, (2) isolated perfused goat liver, and (3) high-fat diet-fed C57BL/6J mice. Serum and perfusate marker levels along with Hexokinase activity were determined through Enzyme assays. Fat deposition was studied by Oil Red O staining, ATP-binding cassette transporter (ABCA1), and sterol regulatory element-binding transcription factor 2 (SREBP2) protein expression by Western blot and their mRNA expression through Real-Time PCR. In HepG2 cells, 28-HB (5-20 μM) treatment indicated a 2-fold increase in glucose utilization and ABCA1 and SREBP2 protein expression within 12 h. Tissue glucose and Cholesterol levels decreased in 28-HB perfused goat liver within 2 h, whereas Cholesterol level increased 54% in the perfusate (p < 0.05) and tissue Hexokinase activity increased 23% (p < 0.05). Glucokinase, ABCA1, and SREBF1 gene expression increased 2.6, 5.37, and 2.85 fold respectively in the perfused tissue after 4 h. High-fat diet-fed C57BL/6J mice when treated with 28-HB (1-20 µg/day) for 6 weeks exhibited a marked decrease in aortic fat deposit and serum marker levels. Our study suggests that 28-HB modulates Cholesterol and glucose homeostasis in animal cells through activation of LXR involving ABCA1 and SREBP-1 and 2 augmentations.

28-homobrassinolide; Brassinosteroid; HepG2; Liver X receptor; Oxysterol; Perfusion.