GSK2033 is a potent LXR antagonist, with IC50 values of 310nM and 83nM for LXRα and LXRβ, respectively[1]. GSK2033 reduces the fraction of monounsaturated lipids and increases the chain length of free fatty acids (FFAs) and ceramides, resulting in an improvement in lipid organization[2]. GSK2033 has been widely used to enhance the anti-tumor immune response of T cells in glioma[3].
In vitro, GSK2033 treatment (2µM) for 18 hours inhibited the phagocytic activity and bactericidal ability of bone marrow-derived macrophages (BMDM) mediated by growth differentiation factor 3 (GDF3)[4]. Treatment with 1µM GSK2033 for 2 hours suppressed the expression of CCL3 in THP-1 cells induced by 27-hydroxycholesterol, reduced the production of CXCL8, and promoted the secretion of TNF-α[5].
In vivo, GSK2033 treatment via intraperitoneal injection (30mg/kg) for 28 consecutive days stimulated increased expression of Fasn and Srebp1c in the liver of diet-induced obese mice[6]. Daily intragastric administration of GSK2033 at a dose of 10mg/kg for 3 months attenuated the cognitive improvement induced by TO901317 in a mouse model of Alzheimer's disease and increased the protein level of Caveolin-1 in brain tissues[7]. A single intracerebroventricular injection of GSK2033 at a dose of 0.3mg/kg blocked the antidepressant-like effect of GW3965 in lipopolysaccharide-treated mice within 30 hours[8].
References:[1] Patel R, Magomedova L, Tsai R, et al. Separating the anti-inflammatory and diabetogenic effects of glucocorticoids through LXR β antagonism[J]. Endocrinology, 2017, 158(4): 1034-1047.
[2] Helder R W J, Boiten W A, van Dijk R, et al. The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models[J]. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 2020, 1865(2): 158546.
[3] Bi C, Lan S, Sun Z, et al. cRGD-Functionalized macrophage extracellular vesicles loaded with GSK2033 enhance T cell antitumor immunity in GBM by disrupting the LXR/ABCA1-Mediated Myelin lipid transfer axis[J]. Journal of Nanobiotechnology, 2026, 24(1): 247.
[4] Wang P, Mu X, Zhao H, et al. Administration of GDF3 into septic mice improves survival via enhancing LXRα-mediated macrophage phagocytosis[J]. Frontiers in immunology, 2021, 12: 647070.
[5] Kim B Y, Son Y, Cho H, et al. 27-Hydroxycholesterol induces macrophage gene expression via LXR-dependent and-independent mechanisms[J]. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 2021, 25(2): 111-118.
[6] Griffett K, Burris T P. Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease[J]. Biochemical and Biophysical Research Communications, 2016, 479(3): 424-428.
[7] Yingmao L U O, Xiaolin T A N, Xiong Z, et al. Effect of liver X receptor agonist TO901317 on cognitive function in APP/PS1 double transgenic mice with Alzheimer’s disease and the underlying mechanism[J]. Journal of Central South University Medical Sciences, 2022, 47(10): 1324.
[8] Xu X, Xiao X, Yan Y, et al. Activation of liver X receptors prevents emotional and cognitive dysfunction by suppressing microglial M1-polarization and restoring synaptic plasticity in the hippocampus of mice[J]. Brain, Behavior, and Immunity, 2021, 94: 111-124.