Fig. 2
Indirect regulation of microglial LDs. The microglial lipid droplet metabolic network is indirectly regulated by nuclear receptors, epigenetic mechanisms, membrane receptors, and long non-coding RNAs. Upon activation, the nuclear receptor PPARγ binds to the peroxisome proliferator response element, upregulating the expression of liver X receptor α. LXRα subsequently binds to the liver X receptor response element, promoting the transcription of cholesterol efflux proteins ABCA1 and ABCG1, while also upregulating the expression of lipolytic enzymes ATGL and HSL, synergistically facilitating lipid droplet breakdown and cholesterol clearance. Histone deacetylases catalyze the deacetylation of histones H3/H4, reducing chromatin accessibility and thereby suppressing the transcription of lipid metabolism genes such as ABCA1, leading to abnormal lipid droplet accumulation. Triggering receptor expressed on myeloid cells 2 binds to apolipoprotein E via its immunoglobulin-like domain, activating the downstream DAP12-Syk signaling pathway, which drives the nuclear translocation of LXRα, upregulates ABCA1/ABCG1 expression, and promotes cholesterol efflux. Simultaneously, TREM2 upregulates the expression of transforming growth factor-β1, activates Smad2/3 phosphorylation signaling, and consequently downregulates PLIN2 expression, reducing lipid droplet formation. Nuclear paraspeckle assembly transcript 1 dynamically regulates gene expression through its two isoforms: on one hand, NEAT1 recruits signal transducer and activator of transcription 3 to the promoter regions of autophagy-related genes, promoting their transcription and enhancing autophagic lipid droplet clearance; on the other hand, NEAT1 acts as a molecular sponge for miR-150-5p, relieving its inhibition of dynamin-related protein 1, enhancing mitophagy, and indirectly promoting lipid droplet metabolism. (PPARγ, Peroxisome Proliferator-Activated Receptor γ; LXRα, Liver X Receptor α; PPRE, Peroxisome Proliferator Response Element; LXRE, Liver X Receptor Response Element; ATGL, Adipose-Triglyceride Lipase; HSL, Hormone-Sensitive Lipase; HDAC, Histone Deacetylase; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; APOE, Apolipoprotein E; TREM2, Triggering Receptor Expressed on Myeloid Cells 2; DAP12, DNAX-activating protein of 12 kDa; Syk, Spleen tyrosine kinase; TGF-β1, Transforming growth factor-β1; PLIN2, Perilipin 2; NEAT1, Nuclear paraspeckle assembly transcript 1; STAT3, Signal Transducer and Activator of Transcription 3; ATG, Autophagy-related genes; DRP1, Dynamin-related protein 1.). This Figure is original. Created with MedPeer (medpeer.cn)