ArticleProceedings of the National Academy of Sciences of the United States of America2018
Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 111 citations in OpenAlex.
- Macrophage signaling and function are regulated by distinct sterol biochemistries.Journal of lipid research · 2026Article
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- From Storage to Signaling: Lipid Droplet Lipolysis in Cholesterol Mobilization and Foam Cell Remodeling.Current atherosclerosis reports · 2026Review
- An oral nanocombinatorial agent exhibits pleiotropic improvement in diabetic nephropathy via modulation of the SCAP/SREBPs pathway.Journal of nanobiotechnology · 2026Article
- Macrophages in human atherosclerotic plaques in the era of single-cell and spatial transcriptomics.ImmunoHorizons · 2026Review
- Nuclear Receptor-Targeted Therapies: Reprogramming Metabolism with TRβ, ERRα, and LXR Modulators.Biomolecules · 2026Review
- Serum Desmosterol Level Reflects Hepatic Inflammation Grade in Patients with Biopsy-Confirmed Metabolic Dysfunction-Associated Steatotic Liver Disease.Journal of atherosclerosis and thrombosis · 2026Article
- Role of nuclear receptors, lipid metabolism, and mitochondrial function in the pathogenesis of diabetic kidney disease.American journal of physiology. Renal physiology · 2025Review
- mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport.Molecular cell · 2025Article
- Astrocyte-neuron combined targeting for CYP46A1 gene therapy in Huntington's disease.Acta neuropathologica communications · 2025Article
- Recent Progress of Sterol Regulatory Element-binding Proteins Role in Atherosclerosis.Current atherosclerosis reports · 2025Review
- The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms.Current issues in molecular biology · 2025Review
- Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics.Signal transduction and targeted therapy · 2025Review
- Dysregulated cellular metabolism drives atherosclerotic plaque progression: a multi-cellular perspective.Frontiers in cardiovascular medicine · 2025Review
- The Liver X Receptor Promotes Immune Homeostasis via Controlled Activation of the Innate Immune System in the Liver.Biomolecules · 2024Review
- Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development.Nature communications · 2024Article
- Knockouts ofiScience · 2024Article
- Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.Nature communications · 2024Article
- DHCR24 inhibitor SH42 increases desmosterol without preventing atherosclerosis development in mice.iScience · 2024Article
- Discovery and Optimization of N-Arylated Tetracyclic Dicarboximides That Target Primary Glioma Stem-like Cells.Journal of medicinal chemistry · 2024Article
15 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.