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Cell-Specific Discrimination of Desmosterol and Desmosterol Mimetics Confers Selective Regulation of LXR and SREBP in Macrophages

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Cell-Specific Discrimination of Desmosterol and Desmosterol Mimetics Confers Selective Regulation of LXR and SREBP in Macrophages Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages Evan D. Musea,b,1, Shan Yuc,1, Chantle R. Edillora,2, Jenhan Taoa,2, Nathanael J. Spanna, Ty D. Troutmana, Jason S. Seidmana, Adam Henkec, Jason T. Rolandc, Katherine A. Ozekia, Bonne M. Thompsond, Jeffrey G. McDonaldd, John Bahadoranie, Sotirios Tsimikase, Tamar R. Grossmanf, Matthew S. Tremblayc,3, and Christopher K. Glassa,e,3,4 aDepartment of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093; bDivision of Cardiovascular Diseases, Scripps Clinic, Scripps Translational Science Institute, La Jolla, CA 92037; cCalifornia Institute for Biomedical Research, La Jolla, CA 92037; dCenter for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390; eDepartment of Medicine, University of California, San Diego, La Jolla, CA 92093; and fIonis Pharmaceuticals, Carlsbad, CA 92010 Contributed by Christopher K. Glass, March 14, 2018 (sent for review August 23, 2017; reviewed by Steven J. Bensinger and Carlos Fernandez-Hernando) Activation of liver X receptors (LXRs) with synthetic agonists promotes in macrophages, the liver X receptors (LXRs) represent logical reverse cholesterol transport and protects against atherosclerosis targets for pharmacologic intervention in atherosclerosis (9–11). in mouse models. Most synthetic LXR agonists also cause marked LXR activation is known to promote cholesterol efflux in macro- hypertriglyceridemia by inducing the expression of sterol regulatory phages by activation of ATP-binding cassette transporter A1 and element-binding protein (SREBP)1c and downstream genes that drive G1 (ABCA1/ABCG1) (12, 13) while also repressing the proin- fatty acid biosynthesis. Recent studies demonstrated that desmosterol, flammatory products of NF-κB signaling (14). Stimulation of cho- an intermediate in the cholesterol biosynthetic pathway that sup- lesterol efflux in macrophages and other cell types contributes to presses SREBP processing by binding to SCAP, also binds and activates overall functions of LXRs in mediating reverse cholesterol transport LXRs and is the most abundant LXR ligand in macrophage foam cells. from peripheral cells to the liver for biliary secretion (15, 16). Here we explore the potential of increasing endogenous desmosterol Consistent with these homeostatic functions, deletion of LXRs production or mimicking its activity as a means of inducing LXR activity either at the whole-body level or within the hematopoietic while simultaneously suppressing SREBP1c-induced hypertriglyceride- mia. Unexpectedly, while desmosterol strongly activated LXR target Significance genes and suppressed SREBP pathways in mouse and human macro- phages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators The beneficial effects of LXR-pathway activation have long been of LXRs have biochemical and transcriptional properties predicted of appreciated, but clinical application of synthetic LXR ligands has desmosterol mimetics and selectively regulate LXR function in macro- been limited by coactivation of SREBP1c and consequent hyper- phages in vitro and in vivo. These studies thereby reveal cell-specific triglyceridemia. Natural LXR ligands such as desmosterol do not discrimination of endogenous and synthetic regulators of LXRs and promote hypertriglyceridemia because of coordinate down- SREBPs, providing a molecular basis for dissociation of LXR functions in regulation of the SREBP pathway. Here we demonstrate that macrophages from those in the liver that lead to hypertriglyceridemia. synthetic desmosterol mimetics activate LXR in macrophages both in vitro and in vivo while suppressing SREBP target genes. macrophage | LXR | hepatocyte | cholesterol | SREBP Unexpectedly, desmosterol and synthetic desmosterol mimetics have almost no effect on LXR activity in hepatocytes in com- parison with conventional synthetic LXR ligands. These findings lthough improvements in the prevention and treatment of reveal cell-specific differences in LXR responses to natural and Acardiovascular disease (CVD) over the last decade have synthetic ligands in macrophages and liver cells that provide a contributed to a significant reduction in the burden of CVD, it still conceptually new basis for future drug development. accounts for nearly a third of all deaths in the United States and worldwide each year (1). In fact, more people die each year sec- Author contributions: E.D.M., S.Y., C.R.E., N.J.S., T.D.T., J.S.S., A.H., J.T.R., K.A.O., J.G.M., ondary to CVD than any other cause, with coronary heart disease S.T., T.R.G., M.S.T., and C.K.G. designed research; E.D.M., S.Y., C.R.E., N.J.S., T.D.T., J.S.S., and stroke representing the majority of cases (2). Increased apoli- A.H., J.T.R., K.A.O., B.M.T., J.G.M., and J.B. performed research; A.H., J.T.R., J.B., S.T., and poprotein B-100–associated lipid species, namely LDL cholesterol T.R.G. contributed new reagents/analytic tools; E.D.M., S.Y., C.R.E., J.T., N.J.S., T.D.T., J.S.S., K.A.O., B.M.T., J.G.M., S.T., M.S.T., and C.K.G. analyzed data; and E.D.M., S.Y., M.S.T., and (LDL-C), remains one of the best-appreciated risk factors for C.K.G. wrote the paper. atherosclerotic heart disease. Accordingly, reduction of LDL-C Reviewers: S.J.B., University of California, Los Angeles; and C.F.-H., Yale University School through the use of statins or recently developed antibodies di- of Medicine. rected against proprotein convertase subtilisin/kexin type 9 repre- The authors declare no conflict of interest. sents one of the mainstays of preventive therapy (3, 4). However, This open access article is distributed under Creative Commons Attribution-NonCommercial- myocardial infarction and stroke still occur in a subset of indi- NoDerivatives License 4.0 (CC BY-NC-ND). viduals despite cholesterol lowering, and therapies directed at Data deposition: Sequencing data supporting these studies have been deposited in the additional targets are of potential clinical benefit. Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession Macrophages are key cellular players in the initiation and pro- no. GSE90615). gression of atherosclerosis through their roles in uptake of modified See Commentary on page 5051. lipoproteins in the artery wall, production of inflammatory mediators, 1E.D.M. and S.Y. contributed equally to this work. and secretion of metalloproteases that contribute to plaque instability 2C.R.E. and J.T. contributed equally to this work. (5–8). A subset of macrophages within atherosclerotic lesions are 3M.S.T. and C.K.G. contributed equally to this work. characterized by massive accumulation of cholesterol esters in lipid 4To whom correspondence should be addressed. Email: [email protected]. droplets, resulting in a “foam cell” phenotype indicative of a failure This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of normal cholesterol homeostasis. Given their central role in in- 1073/pnas.1714518115/-/DCSupplemental. tegrating both cholesterol homeostasis and inflammatory signaling Published online April 9, 2018. E4680–E4689 | PNAS | vol. 115 | no. 20 www.pnas.org/cgi/doi/10.1073/pnas.1714518115 Downloaded by guest on September 28, 2021 compartment results in accelerated atherosclerosis in mouse ABSEE COMMENTARY models (17, 18). Conversely, administration of potent synthetic Dhcr24 mRNA Expression 1.5 LXR agonists, such as GW3965, inhibits the development of ) ssion atherosclerosis in these models (19–21). However, most synthetic 6B4 DHCR24 3 1.0 xpre agonists of LXR have also been found to strongly activate sterol to regulatory element-binding protein (SREBP)1c and downstream 0.5 HO HO genes involved in fatty acid biosynthesis, including fatty acid (Norm. * * * * synthase (FAS), that subsequently lead to increased serum Desmosterol Cholesterol Relative E 0.0 ASO: SCR 805 830 832 847 cholesterol and triglyceride levels (22, 23). Thus, while activating P9 DHCR24 LXR has positive effects in the prevention of atherosclerosis in MM C Dhcr24 Abca1 Abcg5 Abcg8 terms of enhancing reverse cholesterol transport and suppression 1.5 1.5 1.5 1.5 of proinflammatory pathways, the negative aspect of hyper- ) 1.0 1.0 1.0 1.0 triglyceridemia and fatty liver—a product of SREBP activation— 36B4 has prevented synthetic LXR agonists from being clinically 0.5 0.5 0.5 0.5 useful therapeutics. Empiric efforts to develop “dissociated” ** ** 0.0 0.0 0.0 0.0 LXR agonists that retain the ability to activate LXRs but do not ASO: SCR 805 873 SCR 805 873 SCR 805 873 SCR 805 873 induce hypertriglyceridemia have been partially successful (24– Hmgcr 27), but underlying mechanisms are poorly understood. 2.5 Fasn 1.5 Scd2 2.0 1.5 Idol LXR activity is normally induced under conditions of choles- 2.0 1.5 1.5 1.0 1.0 terol excess in a manner that is reciprocal to coordinate inhibi- 1.0 1.0 0.5 0.5 tion of the processing of the SREBP transcription factors. LXRs 0.5 do not sense cholesterol directly but are instead positively reg- 0.5 Relative Expression (Norm. Relative Expression to 0.0 0.0 0.0 0.0 ulated by oxysterols and intermediates in the cholesterol bio- ASO: SCR 805 873 SCR 805 873 SCR 805 873 SCR 805 873 synthetic pathway (28–30). In contrast to most synthetic LXR agonists, natural LXR agonists also suppress processing of the D SCR ASO805 ASO873 E Esterified SREBP proteins (31). In the case of oxysterols, such as 25- 20 Free hydroxycholesterol, inhibition is mediated through interactions *** ** with the insulin-induced gene (INSIG) proteins that prevent DHCR24 ng/mg 10 trafficking of SREBPs to the Golgi for proteolytic activation Desm Liver (32). The cholesterol biosynthetic intermediate desmosterol was 0 5 first noted to be an endogenous LXR-activating ligand in studies *** Actin 4 of plant sterols and sterol intermediates in the cholesterol bio- M 3 ** synthetic pathway (30).
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