Liver X receptor beta deficiency attenuates autoimmune-associated neuroinflammation in a T cell-dependent manner

Bogie, Jeroen F. J.; Vanmierlo, Tim; Vanmol, Jasmine; Timmermans, Silke; Mailleux, Jo; Nelissen, Katherine; Wijnands, Erwin; Wouters, Kristiaan; Stinissen, Piet; Gustafsson, Jan Åke; Steffensen, Knut R.; Mulder, Monique; Zelcer, Noam; Hendriks, Jerome J. A.

doi:10.1016/j.jaut.2021.102723

Cited by 11 publications

(5 citation statements)

References 39 publications

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“…In drug‐target MR analysis, ABCA1 was also been identified as a potential druggable protein. Several drugs activating ABCA1 via transcription factors have been investigated to treat autoimmune disease, including peroxisome proliferator‐activated receptor alpha (PPARA) agonists 54,55 and liver X receptor (LXR) agonists 56 …”

Section: Discussionmentioning

confidence: 99%

Lipoprotein lipids and apolipoproteins in primary immune thrombocytopenia: Results from a clinical characteristics and causal relationship verification, potential drug target identification by Mendelian randomization analyses

Ou,

Zhan,

Shao

et al. 2023

Br J Haematol

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SummaryPrimary immune thrombocytopenia (ITP) is an acquired autoimmune disease. Cellular and systemic lipid metabolism plays a significant role in the regulation of immune cell activities. However, the role of lipoprotein lipids and apolipoproteins in ITP remains elusive. The automatic biochemistry analyser was used to measure the levels of serum total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein A‐I (apoA‐I), apoB, apoE and lipoprotein a [LP(a)]. Genetic variants strongly associated with circulating lipoprotein lipids and apolipoproteins (LDL‐C, apoB, TG, HDL‐C and apoA‐I) were extracted to perform Mendelian randomization (MR) analyses. Finally, drug‐target MR and passive ITP mice model was used to investigate the potential druggable targets of ITP. Levels of HDL‐C, apoA‐I, decreased and LP(a) increased in ITP patients compared with healthy controls. Low HDL‐C was causally associated with ITP susceptibility. Through drug‐target MR and animal modelling, ABCA1 was identified as a potential target to design drugs for ITP. Our study found that lipid metabolism is related to ITP. The causative association between HDL‐C and the risk of ITP was also established. The study provided new evidence of the aetiology of ITP. ABCA1 might be a potential drug target for ITP.

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Section: Discussionmentioning

confidence: 99%

Lipoprotein lipids and apolipoproteins in primary immune thrombocytopenia: Results from a clinical characteristics and causal relationship verification, potential drug target identification by Mendelian randomization analyses

Ou,

Zhan,

Shao

et al. 2023

Br J Haematol

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“…Studies of cell-type-specific LXR knockouts are already underway, and we have made some exciting findings: loss of LXRβ in astrocytes leads to anxiety-like behaviors [ 97 ], and LXRβ deficiency affects the inflammatory features of microglia in vitro. However, these changes do not underlie the reduced EAE disease severity in whole-body LXRβ knockout mice [ 24 ]. We look forward to more experimental findings in this regard.…”

Section: Discussionmentioning

confidence: 99%

“…In the adult mouse CNS, LXRs are expressed in microglia [ 24 ], astrocytes [ 25 ] and oligodendrocytes [ 26 ]. LXRs are not detected in neurons of the adult mouse brain.…”

Section: Introductionmentioning

confidence: 99%

Liver X Receptor Regulation of Glial Cell Functions in the CNS

Song

Warner

et al. 2022

Biomedicines

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In this review, we discuss the role of liver X receptors (LXRs) in glial cells (microglia, oligodendrocytes and astrocytes) in the central nervous system (CNS). LXRs are oxysterol-activated nuclear receptors that, in adults, regulate genes involved in cholesterol homeostasis, the modulation of inflammatory responses and glutamate homeostasis. The study of LXR knockout mice has revealed that LXRβ plays a key role in maintaining the health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord and retinal ganglion cells in the eye. In the peripheral nervous system (PNS), LXRβ is responsible for the health of the spiral ganglion neurons (SGNs) in the cochlea. In addition, LXRs are essential for the homeostasis of the cerebrospinal fluid (CSF), and in LXRαβ−/− mice, the lateral ventricles are empty and lined with lipid-laden cells. As LXRαβ−/− mice age, lipid vacuoles accumulate in astrocytes surrounding blood vessels. By seven months of age, motor coordination becomes impaired, and there is a loss of motor neurons in the spinal cord of LXRβ−/− mice. During development, migration of neurons in the cortex and cerebellum is retarded in LXRβ−/− mice. Since LXRs are not expressed in dopaminergic or motor neurons in adult mice, the neuroprotective effects of LXRs appear to come from LXRs in glial cells where they are expressed. However, despite the numerous neurological deficits in LXR−/− rodents, multiple sclerosis has the clear distinction of being the only human neurodegenerative disease in which defective LXR signaling has been identified. In this review, we summarize the regulation and functions of LXRs in glial cells and analyze how targeting LXRs in glial cells might, in the future, be used to treat neurodegenerative diseases and, perhaps, disorders caused by aberrant neuronal migration during development.

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“…Not just this, LXR has also been studied to perform a neuroprotective role by lowering neuroinflammation. 26 Various neurodegenerative disorders like Amyotrophic lateral sclerosis ALS, Alzheimer’s disease (AD), and multiple sclerosis have been associated with dysregulation of cholesterol and oxysterol levels. Liver X receptor and AR have an antagonistic relation.…”

Section: Androgen Receptor and Other Receptor Interactionsmentioning

confidence: 99%

Lipid Metabolic Disorders in Neurodegenerative Diseases – Role of Androgen Receptor

Sharma,

Saini,

Dhawan

2024

The Eurasian Journal of Medicine

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The challenge of managing neurodegenerative disorders is a worldwide concern, especially in the aging population. Neurodegenerative diseases are a varied group of disorders that are characterized by progressive degeneration of the structure and function of the nerve cells. Neurodegenerative diseases are increasing at an alarming rate, and hence there is an urgent need for an in-depth analysis of various metabolic malfunctions that alter the proper functioning of a cell. Lipid metabolism is a process that involves the synthesis and simultaneous degradation of lipids and encompasses a balance that is essential to maintain the structural and functional ability of a cell. Androgen receptor (AR) plays a critical role in regulating cellular functions. Recent studies have expanded our knowledge regarding direct or indirect interactions that occur among mitochondria, peroxisome, and androgen receptors, which play a crucial role in lipid homeostasis. Unusual levels of lipids and cholesterol due to receptor excitation or inhibition are associated with multiple diseases and have been a cause of concern. The androgen receptor, along with other receptors and proteins, forms an important metabolic cascade that, if altered, may cause the accumulation of lipids and result in neurodegenerative disorders. In this review, we underscore the role of the androgen receptor in regulating lipid and cholesterol levels during neurodegenerative disorders (Alzheimers, Parkinson’s, multiple sclerosis, and Huntington’s disease).

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Liver X receptor beta deficiency attenuates autoimmune-associated neuroinflammation in a T cell-dependent manner

Cited by 11 publications

References 39 publications

Lipoprotein lipids and apolipoproteins in primary immune thrombocytopenia: Results from a clinical characteristics and causal relationship verification, potential drug target identification by Mendelian randomization analyses

Lipoprotein lipids and apolipoproteins in primary immune thrombocytopenia: Results from a clinical characteristics and causal relationship verification, potential drug target identification by Mendelian randomization analyses

Liver X Receptor Regulation of Glial Cell Functions in the CNS

Lipid Metabolic Disorders in Neurodegenerative Diseases – Role of Androgen Receptor

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