Sterol Intermediates from Cholesterol Biosynthetic Pathway as Liver X Receptor Ligands

Abstract

The liver X receptors (LXRs) are ligand-activated transcription factors that regulate the expression of genes controlling lipid metabolism. Oxysterols bind LXRs with high affinity in vitro and are implicated as ligands for the receptor. We showed previously that accumulation of selected dietary sterols, in particular stigmasterol, is associated with activation of LXR in vivo. In the course of the defining of structural features of stigmasterol that confer LXR agonist activity, we determined that the presence of an unsaturated bond in the side chain of the sterol was necessary and sufficient for activity, with the C-24 unsaturated cholesterol precursor sterols desmosterol and zymosterol exerting the largest effects. Desmosterol failed to increase expression of the LXR target gene, ABCA1, in LXR␣/␤-deficient mouse fibroblasts, but was fully active in cells lacking cholesterol 24-, 25-, and 27-hydroxylase; thus, the effect of desmosterol was LXR-dependent and did not require conversion to a side chain oxysterol. Desmosterol bound to purified LXR␣ and LXR␤ in vitro and supported the recruitment of steroid receptor coactivator 1. Desmosterol also inhibited processing of the sterol response element-binding protein-2 and reduced expression of hydroxymethylglutaryl-CoA reductase. These observations are consistent with specific intermediates in the cholesterol biosynthetic pathway regulating lipid homeostasis through both the LXR and sterol response element-binding protein pathways.The liver X receptors (LXR␣ and LXR␤) 4 are ligand-dependent transcription factors belonging to the nuclear hormone receptor superfamily (1). Although the two transcription factors are encoded by separate genes, LXR␣ and LXR␤ share 78% similarity within the ligand-binding domains (2). LXR␤ (NR1H2) is ubiquitously expressed, whereas LXR␣ (NR1H3) has a more restricted distribution with the highest expression observed in the liver, adipose tissue, intestine, kidney, and macrophages (3). LXRs regulate multiple genes involved in lipid metabolism, including those involved in sterol transport (4, 5) and fatty acid biosynthesis (6 -8). More recently, LXRs have been found to play a role in the regulation of glucose metabolism (9, 10), immunity, and cellular responses to various environmental stresses (11)(12)(13)(14).To function as a transcription factor, LXR must heterodimerize with retinoid X receptor (RXRs) and then bind to LXR-response elements in target genes. The LXR-response elements consist of two direct hexanucleotide repeats separated by four nucleotides (DR4 element) (3). The binding of LXR or RXR ligands results in a conformational change in the heterodimer and recruitment of nuclear receptor coactivators such as steroid receptor coactivator-1 (SRC-1), resulting in the activation of gene transcription (16). Several compounds have been identified that are potent LXR agonists, including various oxysterols (17, 18). Position-specific monooxidation of the sterol side chain leads to high affinity binding and activation of LXR (19). Analysis of...

Desmosterol in human nonalcoholic steatohepatitis

“…Thus, its levels could relate either to direct effects of desmosterol or reflect changes in other components of the cholesterol synthesis pathway. Desmosterol strongly activates LXR target genes in vivo 35,36 and in a mouse model deficient for the gene coding the desmosterol reductase enzyme (DHCR24), which catalyzes the conversion of desmosterol into cholesterol. 37,38 Our gene expression results support the view that desmosterol may have a specific role in activating, e.g., LXR target genes, as compared to cholestenol and lathosterol (Supporting Table 5).…”

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

“…Thus, the infantile consumption of sitosterol is estimated at around 1,000 mg/ day if an infant ingests 1,000 ml of breast milk per day; this amount of sitosterol intake is close to that of an adult but greater in terms of proportion with body weight. The accumulation of non-cholesterol sterols contributes to the very low cholesterol biosynthesis in cases with sitosterolaemia (Yang et al 2006), leading us to speculate that severe hypercholesterolaemia observed in infantile sitosterolaemia during breastfeeding reflects the reduced catabolism of LDL or excretion of cholesterol into the bile, rather than an increase in cholesterol biosynthesis. Compared with the dietary intake of cholesterol by adults, infants ingest about 3 to 4 times the amount of cholesterol per kg body weight through breast milk (Ohta et al 2002;Ohlsson 2010), or the high content of saturated fatty acids in breast milk (Ohlsson 2010), which may explain the extreme hypercholesterolaemia of infants with sitosterolaemia.…”

Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol

“…36 The natural ligands for LXR include sterols made in the mevalonate pathway, including the oxysterol 24(S),25-epoxycholesterol 37 and the cholesterol biosynthetic precursor desmosterol. 38 Given that APD treatment results in the accumulation of a diverse array of intermediates/products of the mevalonate pathway (Supplementary Figure 5), it is possible that these may include activators of LXR. Alternatively, the APDs may themselves act as LXR agonists.…”