Biology subjects

Elhan, H.

Publications and source records attributed to Elhan, H..

3 recordsLinked to original sources

bioRxiv2026

Triglyceride/Cholesterol Ester Ratio Encodes Lipid Droplet Size and Diversity

Lipid droplet (LD) heterogeneity is a hallmark of their pathophysiological relevance. This is especially evident when cells sequester toxic cholesterol by converting it into cholesterol esters (CEs) within LDs. Since CEs can form liquid crystals (LCs), it remains unclear how such ordered structures are accommodated within the inherently dynamic environment of LDs. Here, we show that the fluidizing properties of triglycerides (TGs) help CE incorporation and influence LD growth and heterogeneity. Seipin, the key regulator of TG-LD formation and size, does not significantly impact CE-rich LD size. Instead, the CE/TG ratio, the sequence of neutral lipid deposition, and the activity of diacylglycerol acyltransferases, especially DGAT2, determine whether LDs enlarge, remain fluid, or lock into LC phases. We found that the LC phase resists LD ripening and acts as a kinetic barrier to lipid entry. Lastly, we observe that perilipins, the most abundant LD surface proteins, differentially target CE-rich LDs: Plin3 and 5 are excluded from them, whereas Plin2 and 4 are favored. These findings highlight the CE/TG ratio as a key organizing principle of lipid storage and LD function, with immediate relevance for diseases linked to sterol accumulation.

cell biology↗

bioRxiv2025

ORP5 controls the partitioning of phosphatidic acid between triacylglycerol and cardiolipin synthesis at mitochondria-ER-lipid droplet contact sites

Phosphatidic acid (PA) is a central metabolic intermediate that can fuel triacylglycerol (TAG) synthesis in lipid droplets (LDs) or cardiolipin production in mitochondria, but how cells partition PA between these competing fates has remained a fundamental unresolved question in lipid cell biology. We identify the lipid transfer protein ORP5 as a key regulator of PA partitioning at Mitochondria-Associated endoplasmic reticulum Membranes (MAM) that contact lipid droplets (LD), referred to as MAM-LD junctions. Cell imaging analysis shows that ORP5 stabilizes PA levels at MAM to promote TAG synthesis. On the other hand, loss of ORP5 causes PA accumulation on mitochondrial membranes, leading to excess cardiolipin synthesis and mitochondrial hyperfusion, while impairing triacylglycerol (TAG) synthesis and LD formation. Finally, reconstitution assays using liposomes or giant organelles further demonstrate that ORP5 can transfer PA from mitochondria to the ER via its ORD domain. Together, these findings reveal that ORP5 functions as a PA lipid transfer protein at tripartite MAM-LD contacts, where it balances LD formation with mitochondrial lipid metabolism, protecting mitochondria from cardiolipin overload.

cell biology↗

bioRxiv2023

ATG2A-mediated bridge-like lipid transport regulates lipid droplet accumulation

ATG2 proteins facilitate bulk lipid transport between membranes. ATG2 is an essential autophagy protein, but ATG2 also localizes to lipid droplets (LDs), and genetic depletion of ATG2 increases LD numbers while impairing fatty acid transport from LDs to mitochondria. How ATG2 supports LD homeostasis and whether lipid transport regulates this homeostasis remains unknown. Here we demonstrate that ATG2 is preferentially recruited to phospholipid monolayers such as those surrounding LDs rather than to phospholipid bilayers. In vitro, ATG2 can drive phospholipid transport from artificial LDs with rates that correlate with the binding affinities, such that phospholipids are moved much more efficiently when one of the ATG2-interacting structures is an artificial LD. ATG2 is thought to exhibit bridge-like" lipid transport, with lipids flowing across the protein between membranes. We mutated key amino acids within the bridge to form a transport-dead ATG2 mutant (TD-ATG2A) which we show specifically blocks bridge-like, but not shuttle-like, lipid transport in vitro. TD-ATG2A still localizes to LDs, but is unable to rescue LD accumulation in ATG2 knockout cells. Thus, ATG2 has a natural affinity for, and an enhanced activity upon LD surfaces and uses bridge-like lipid transport to support LD dynamics in cells.

cell biology↗