28-Homobrassinolide: a novel oxysterol transactivating LXR gene expression

Abstract

Cholesterol is the template for steroid hormone biosynthesis. Cholesterol homeostasis is regulated by Cyt-P450 oxygenated cholesterols acting as ligands on LXR-α and LXR-β transcription factors that are now emerging as drug targets. Heterodimerization of LXRs with retinoic acid receptor is considered a prerequisite for target gene activation. Dietary plant oxysterol 28-homobrassinolide (28-HB) is a proven antihyperglycemic and a pro-steroidogenic agent in the rat. Whether 28-HB has a role in LXR gene expression was therefore investigated using oral gavage (15 days) of 28-HB (333 µg/kg b w) to normal and diabetic rat. PCR amplified LXR-α and β mRNA transcripts from treated rat liver and testis exhibited quantitative differences in their expression. Conformational differences in 28-HB docking to LXR-α and β binding domains were also noted through in silico studies, LXR-β adopting lesser specificity. We report that 28-HB transactivates LXR genes in the rat tissues.

28-HOMOCASTASTERONE: A NOVEL DIETARY PHYTO KETO OXYSTEROL MODULATING TESTICULAR STEROID METABOLISM AND LxR mRNA EXPRESSION IN DIABETIC RAT

“…The remarkable ability to increase testosterone level by 28-HC in the present study reflects the significant biological potency associated with this compound. However, Premalatha et al failed to specified which isoform of LxRs gene and protein upregulated by 28-HB, thus given the observed effects on diabetic rat testicular tissues [5,17,18]. On the other hand Fatim-Zorah et al reported that LxR-α isoform regulates sertoli cell cholesterol metabolism, whereas LxR-β regulates leyding cell cholesterol metabolism and testosterone biosynthesis [2].…”

“…Earlier studies with plant oxysterol 28-homobrasslinoloide (28-HB) an aldo steroid induces testosterone production, 3β-HSD, 17β-HSD, LxR-α and β gene expression in normal and diabetic rat testis, proposed that phyto oxysterol modulating rat testicular steroid metabolism through LxRs activation. This study Premalatha et al failed to specified which isomer of LxRs upregulated by 28-HB, that given the observed effect on diabetic rat testicular tissues [5]. However, 28-HB and 28-HC are active plant hormones comes under the brasslinolide family aldo-keto isomers, both isomers retained anti-glycemic property in diabetic male rat [6].…”

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

“…Interestingly, the oral administration of 10 resulted in the inhibition of the intestinal cholesterol adsorption without increasing plasma triglyceride levels, in contrast to what observed with non-steroidal ligands. 19,30 To our knowledge, the study of phytosterols as LXR agonists is limited to the mentioned compound 10, to the plant hormone 28-homobrassinolide (11), 31 and to 24(S)-saringosterol (12), a minor component isolated from marine seaweeds which showed to act as a selective LXRβ agonist. 32…”

“…To our knowledge, the study of phytosterols as LXR agonists is limited to the mentioned compound 10 , to the plant hormone 28-homobrassinolide ( 11 ), and to 24­( S )-saringosterol ( 12 ), a minor component isolated from marine seaweeds which showed to act as a selective LXRβ agonist …”

“…Interestingly, the oral administration of 10 resulted in the inhibition of the intestinal cholesterol adsorption without increasing plasma triglyceride levels, in contrast to what observed with nonsteroidal ligands. 19,30 To our knowledge, the study of phytosterols as LXR agonists is limited to the mentioned compound 10, to the plant hormone 28-homobrassinolide (11), 31 and to 24(S)-saringosterol (12), a minor component isolated from marine seaweeds which showed to act as a selective LXRβ agonist. 32 Therefore, intrigued by the ability of some phytosterols to interfere with cholesterol homeostasis by acting as analogs of endogenous oxysterols, 33 we engaged ourselves in a vast research project aimed at synthesizing stigmasterol and ergosterol derivatives characterized by the presence of oxygenated functions, structural features known to be crucial for LXR activation, at all the possible side-chain positions.…”