Fucosterol Is a Selective Liver X Receptor Modulator That Regulates the Expression of Key Genes in Cholesterol Homeostasis in Macrophages, Hepatocytes, and Intestinal Cells

Abstract

Fucosterol, a sterol that is abundant in marine algae, has hypocholesterolemic activity, but the mechanism underlying its effect is not clearly understood. Because data suggest that fucosterol can increase plasma high-density lipoprotein concentrations, we investigated whether it could activate liver X receptors (LXRs), critical transcription factors in reverse cholesterol transport. Fucosterol dose-dependently stimulated the transcriptional activity of both LXR-α and -β in a reporter gene assay, responses that were attenuated by the LXR antagonist As(2)O(3). Fucosterol also activated co-activator recruitment in cell-free time-resolved fluorescence resonance energy transfer analysis. In THP-1-derived macrophages, it induced the transcriptional activation of ABCA1, ABCG1, and ApoE, key genes in reverse cholesterol transport, and thereby significantly increased the efflux of cholesterol. Fucosterol also regulated intestinal NPC1L1 and ABCA1 in Caco-2 cells. Notably, fucosterol did not induce cellular triglyceride accumulation in HepG2 cells, primarily because of its upregulation of Insig-2a, which delays nuclear translocation of SREBP-1c, a key hepatic lipogenic transcription factor. These results suggest that fucosterol is a dual-LXR agonist that regulates the expression of key genes in cholesterol homeostasis in multiple cell lines without inducing hepatic triglyceride accumulation.

Plant sterols: Friend or foe in CNS disorders?

“…In this study, fucosterol, sitostanol, and campestanol potently activated LXRa and LXRb at concentrations ranging from 10nM to 10 mM. By using a luciferase reporter assay (100-200 lM) and a TR-FRET assay (1 nm-100 lM), Hoang and colleagues confirmed the LXR-agonizing capacity of fucosterol [149]. Although fucosterol appears a strong LXR activator, it remains speculative whether concentrations of fucosterol in this range can be reached via nutritional supplementation.…”

“…However, synthetic LXR agonists show severe side-effects such as hepatic hypertriglyceridemia, resulting in liver steatosis [147]. By using cell-free and cell-based assays, multiple studies defined that plant sterols, such as sitosterol, fucosterol, stigmasterol, schottenol, 24(S)-saringosterol, and spinasterol, bind and activate LXRa and/or LXRb [46,53,[148][149][150][151]. Interestingly, in contrast to synthetic LXR agonists such as T0901317 and GW3965 [152][153][154], phytosterols do not induce hypertriglyceridemia and hepatic steatosis [152][153][154][155][156][157][158].…”

Age, APOE and sex: Triad of risk of Alzheimer’s disease

“…LXR agonists have also been shown to increase the activities of mitochondrial mediated antioxidant enzymes, such as SOD and glutathione (71). …”

“…Support for the early role of mitochondrial bioenergetics in the progression of AD is strengthened by evidence that young ɛ4 carriers show reductions in cytochrome-c oxidase (COX) activity, a measure of oxidative metabolism, in brain tissue from the posterior cingulate, even in the absence of fibrillar amyloid (95). Likewise, AD patients with the ɛ4 allele show higher levels of hydroxyl radicals than AD patients without an E4 allele and reduced levels of glutathione peroxidase, an enzyme with antioxidant capacity that is produced in mitochondria (71, 96). These differences may partially be explained in that mass spectrometry analysis have revealed the methionine-108 region of apoE is considerably more reactive toward free radical labeling in ɛ4 (97).…”

Kaempferol reduces hepatic triglyceride accumulation by inhibiting Akt

“…The ApoA1‐dependent efflux of 22‐NBD‐cholesterol was analyzed using a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA, USA) and Cell Quest Pro software (BD Biosciences, USA). The ApoA1‐dependent efflux of 22‐NBD‐cholesterol was calculated as described previously (Hoang et al, ). Each efflux assay was performed in triplicate.…”