Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages

Abstract

SignificanceThe beneficial effects of LXR-pathway activation have long been appreciated, but clinical application of synthetic LXR ligands has been limited by coactivation of SREBP1c and consequent hypertriglyceridemia. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here we demonstrate that synthetic desmosterol mimetics activate LXR in macrophages both in vitro and in vivo while suppressing SREBP target genes. Unexpectedly, desmosterol and synthetic desmosterol mimetics have almost no effect on LXR activity in hepatocytes in comparison with conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development.

Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution

“…This raises the question of whether the endogenous substrate of DHCR24, desmosterol, might be an attractive candidate, fulfilling important requirements for successful LXR activation: (1) Desmosterol has been shown to bind to LXRs in the low micromolar range (16), (2) it possesses a selective SREBP interaction potential, and (3) it inhibits inflammatory gene expression (8). Recently these processes have been demonstrated in MΦ using desmosterol and desmosterol mimetics (9).…”

“…It has recently been reported that desmosterol and desmosterol mimetics have a cell type-specific effect on LXR target gene regulation. Muse et al (9) showed that desmosterol selectively activates the LXR target gene ABCA1 (Abca1) in MΦ but not in hepatocytes. Along these lines, we tested the effects of our chemical probe SH42 in vivo in peritoneal lavage cells and liver homogenates.…”

“…Mainly through the recent work of Glass and coworkers (8,9), we identified Δ 24 -dehydrocholesterol reductase (DHCR24; also called Seladin-1) as a promising target for controlling lipid metabolism, possibly allowing its reprogramming. DHCR24 is the terminal enzyme in cholesterol biosynthesis, catalyzing the transformation of desmosterol to cholesterol ( Fig.…”

Rational application of macrophage-specific LXR agonists avoids the pitfalls of SREBP-induced lipogenesis

“…Muse et al (4) demonstrate that, unlike the often-employed synthetic LXR agonists (i.e., GW3965, T0901317), desmosterol activates genes responsible for cholesterol export (e.g., Abca1, Abcg1), while lipogenic gene expression (e.g., fatty acid synthase, Fasn) remains unaffected (Fig. 1).…”

“…Finally, Muse et al (4) tested the efficacy of these desmosterol mimetics in vivo. Injection of DMHCA and MePipHCA upregulates Abca1, but not Fasn in elicited macrophages, while failing to activate either gene in the liver.…”