Role of Brain Liver X Receptor in Parkinson's Disease: Hidden Treasure and Emerging Opportunities

Abstract

Parkinson's disease (PD) is a neurodegenerative disease due to the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). The liver X receptor (LXR) is involved in different neurodegenerative diseases. Therefore, the objective of the present review was to clarify the possible role of LXR in PD neuropathology. LXRs are the most common nuclear receptors of transcription factors that regulate cholesterol metabolism and have pleiotropic effects, including anti-inflammatory effects and reducing intracellular cholesterol accumulation. LXRs are highly expressed in the adult brain and act as endogenous sensors for intracellular cholesterol. LXRs have neuroprotective effects against the development of neuroinflammation in different neurodegenerative diseases by inhibiting the expression of pro-inflammatory cytokines. LXRs play an essential role in mitigating PD neuropathology by reducing the expression of inflammatory signaling pathways, neuroinflammation, oxidative stress, mitochondrial dysfunction, and enhancement of BDNF signaling.In conclusion, LXRs, through regulating brain cholesterol homeostasis, may be effectual in PD. Also, inhibition of node-like receptor pyrin 3 (NLRP3) inflammasome and nuclear factor kappa B (NF-κB) by LXRs could effectively prevent neuroinflammation in PD. Taken together, LXRs play a crucial role in PD neuropathology by inhibiting neuroinflammation and associated degeneration of DNs.

Keywords: Liver X receptor; Neurodegenerative diseases; Parkinson’s disease.

Fig. 1

The potential effect of liver X receptor (LXRs) agonists: LXR agonists advance vascular smooth muscle cells by increasing the expression of alpha-smooth muscle actin (α-SMA) and decreasing the expression of angiotensin 1 receptor (AT1R). LXR agonists encourage the functional capacity of endothelial cells by increasing the expression of ATP-binding cassette A1 (ABCA1) and STEAROYL-CoA desaturase-1 (SCD-1) and reducing the expression of adhesion molecule and pro-inflammatory cytokines. In macrophages, LXR agonists upsurge expression of ABCA1 and mer tyrosine kinase receptor with reduced expression of IL-6, cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase 9 (MMP-9)

Fig. 2

Potential functional role of LXRs: LXR agonists could be a promising therapeutic target in cancer, prostatic carcinoma, Goodpasture disease (GBM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and irritable bowel disease (IBD). LXR agonists produce their effects by pleiotropic effects including anti-inflammatory effects, reduced intracellular cholesterol accumulation, immune regulation, anti-proliferative effects, anti-tumor effects, and prevention of the development of endoplasmic reticulum stress

Fig. 3

Brain cholesterol homeostasis: Astrocytes synthesize cholesterol which is transported with the assistance of ApoE via ATP-binding cassette (ABCA1) to neurons. Cholesterol in the neurons is metabolized to 24S-hydroxycholesterol (24S-OH), which is transported to astrocyte and inhibit cholesterol biosynthesis. Some of 24S-OH are regulated by the liver X receptor (LXR) and excreted via ABCA1 to synthesize cholesterol in the neurons. However, the other part of 24S-OH is eliminated from the systemic circulation

Fig. 4

Role of LXRs in neurodegenerative diseases

Fig. 5

Role of LXRs in Parkinson’s disease neuropathology