Biology subjects

Saharan, O.

Publications and source records attributed to Saharan, O..

3 recordsLinked to original sources

bioRxiv2026

Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation

Phagocytosis, a central process in innate immunity, depends on dynamic lipid remodelling, yet how cholesterol accumulates on late phagosomes remains unresolved. Here, we identify lysosomal acid lipase (LIPA) as a key cholesterol ester (CE) hydrolase driving cholesterol mobilization during phagosomal maturation. Using integrated lipidomics, chemoproteomics, and biochemical assays, we show that LIPA exhibits acidic CE hydrolase activity enriched on late phagosomes, generating free cholesterol essential for lipid raft formation. Pharmacologically inhibiting LIPA disrupts cholesterol-rich lipid raft assembly, impairs phagosomal trafficking, and alters pathogen fate - enhancing Staphylococcus aureus persistence, while restricting Mycobacterium tuberculosis survival. These findings reveal that LIPA couples cholesterol metabolism to phagocytosis, defining a mechanistic link between lipid catabolism and antimicrobial defence. By positioning CE hydrolysis as a critical determinant of phagosomal dynamics, our work uncovers a metabolic checkpoint in innate immunity and identifies LIPA as a potential therapeutic node in infection and inflammation.

biochemistry↗

bioRxiv2025

Selective Targeting of Kinesin on Lipid Droplets in the Liver Reduces Serum Lipids

The liver controls plasma lipids by secreting lipid-rich very low density lipoproteins (VLDL) into blood. Inside hepatocytes in the liver, Lipid Droplets (LDs) are transported to the smooth Endoplasmic Reticulum (sER) by kinesin-1 motors, and then catabolized in the sER to supply lipids for VLDL assembly. LDs are the only cellular organelle bounded by a phospholipid monolayer, and are thus distinct from all other (bilayer-bounded) organelles. It is therefore plausible that a given protein can bind to the LD membrane using mechanisms that are completely different from all other organelles. Indeed, here we find that kinesin-1 uses its tail domain to bind LDs, but alternative mechanisms to bind other organelles. A peptide corresponding to kinesins tail domain therefore competes with, and removes kinesin-1 selectively from LDs with minimal effect on other organelles. Delivery of lipids for VLDL assembly is consequently reduced, causing a remarkable reduction of [~]50% of secreted lipids (triglycerides and cholesterol) in cell culture. We further develop Orally fed Egg-liposomes as a method to deliver kinesin tail domain peptide to the liver of Zebrafish. The peptide reverses diet-induced hyperlipidaemia in Zebrafish larvae and brings the larvae back to a normolipidaemic state, thus confirming the effectiveness of our method in a physiologically relevant in-vivo situation. Strikingly, the peptide causes no unwanted accumulation of lipids in the liver, no toxicity and no developmental or behavioural defects in Zebrafish. Using a peptide to displace proteins (e.g. kinesin) selectively from LDs provides a conceptually novel and radically different approach against hyperlipidaemia. This monolayer-versus-bilayer strategy can be potentially extended to target other LD-bound proteins that function as key regulators of Lipid metabolism.

cell biology↗

bioRxiv2024

Chemical Proteomics Identifies Protein Ligands for Monoacylglycerol Lipids

Signaling lipids are hormone-like small biomolecules that regulate many critical facets of physiology in mammals, including humans. Given their biomedical importance, the past few decades have seen a tremendous increase in our mechanistic understanding of the physiological processes regulated by a handful of such signaling lipids (e.g.: endocannabinoids, lysophospholipids, prostaglandins). However, a significant number of signaling lipid classes still remain poorly characterized, despite their direct associations to human pathophysiology and disease. Over the past decade, the advent of chemical proteomics technologies coupled with the development of multifunctional lipid probes has rapidly expanded our knowledge in terms of the protein ligands and biological pathways that the different signaling lipids interact with and modulate respectively. While the signaling pathways regulated by the endocannabinoid 2-arachidonoyl-glycerol in mammals are extensively characterized, the same cannot be said for the other members of the monoacylglycerol (MAG) family of signaling lipids. To understand this, here, we report the synthesis of a bifunctional MAG probe, containing a photoreactive group and a biorthogonal handle. Using established chemical proteomics approaches, we profile this bifunctional MAG probe in mouse brain and mammalian cell lysates, and leveraging probe competition experiments identify hitherto unknown protein ligands for MAG lipids. Finally, we biochemically validate the neuronal calcium sensor Hippocalcin as a putative MAG protein ligand, and show for the first time, that MAG may have a role to play in calcium sensing and downstream signaling in the mammalian brain.

biochemistry↗