Fig. 1

Direct regulation mechanism of microglial LDs.Homeostasis of microglial lipid droplets is regulated through four core direct pathways. In the fatty acid uptake process, the fatty acid transporter CD36 on the cell surface recognizes and binds extracellular free fatty acids (FFA), internalizing them via endocytosis to provide substrates for lipid droplet (LD) synthesis. In the triglyceride (TG) regulatory pathway, internalized FFAs are catalyzed by acyl-CoA synthetase (ACSL) to generate fatty acyl-CoA, which is then esterified with glycerol-3-phosphate to synthesize TGs stored in the LD core. The LD-coating protein PLIN2 anchors to the LD monolayer phospholipid membrane via its N-terminal domain, forming a physical barrier, while its C-terminal structure binds to comparative gene identification-58 (CGI-58), inhibiting the formation of the adipose-triglyceride lipase (ATGL)-CGI-58 complex and thereby suppressing lipolysis initiation. When energy mobilization is required, ATGL, hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL) sequentially catalyze the hydrolysis of TGs into diacylglycerol (DAG), monoacylglycerol (MAG), and ultimately release FFAs and glycerol (Gly). The autophagy-lysosome pathway selectively degrades LDs: the autophagosome membrane protein microtubule-associated protein 1 light chain 3 (LC3) binds to the LC3-interacting region on the LD surface protein PLIN2, driving the encapsulation of LDs by autophagosomes. Subsequently, autophagosomes fuse with lysosomes, and lysosomal acid lipase (LAL) is activated in the acidic environment to hydrolyze TGs into FFAs and glycerol. In the cholesterol transport process, intracellular free cholesterol is reverse-transported out of the cell via the transporters ATP-binding cassette transporter A1 (ABCA1) and ABCG1, binding to apolipoprotein A-I (ApoA-I) to form nascent high-density lipoprotein (HDL) or to mature HDL particles, respectively, thereby completing cholesterol efflux.(TG, Triglyceride; CE, Cholesterol ester; PLIN2, Perilipin 2; CGI-58, Comparative gene identification-58; LC3, Microtubule-associated protein 1 light chain 3; LAL, Lysosomal acid lipase; ATGL, Adipose-triglyceride lipase; HSL, Hormone-sensitive lipase; MGL, Monoacylglycerol lipase; DAG, Diacylglycerol; MAG, Monoacylglycerol; Gly, Glycerol; FFA, Free fatty acids; ACSL, Acyl-CoA synthetase; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; ApoA-I, Apolipoprotein A-I; HDL, High-density lipoprotein; CD36, Cluster of differentiation 36). This Figure is original. Created with MedPeer (medpeer.cn)