Lipid droplets in health and disease

Lipid droplets are ubiquitous organelles that can be formed by virtually all eukaryotic cells and fulfill central roles in lipid biology. They have a unique architecture that enables them to store variable amounts of neutral lipids such as triacylglycerol and sterol esters in a central hydrophobic core compartment, which is protected from the aqueous cytosol by an outer phospholipid monolayer. This monolayer houses the lipid droplet surface proteome that comprises a large number of lipid metabolism enzymes, which mediate key steps in the biosynthesis and turnover of membrane and storage lipids [[1]]. In recent years, lipid droplet dysfunctions have started to be recognized as causes for disease, but the underlying cell biological relationships and molecular mechanisms are still largely enigmatic [[2, 3]].

This special issue of FEBS Letters entitled “Lipid droplets in health and disease” aims at providing a broad view of our current understanding of lipid droplet functions in physiological and pathological states. Sixteen review articles highlight recent key discoveries around the lipid droplet life cycle, important technological advances in the field, and insights into the cell biology underlying inherited and acquired diseases related to altered lipid storage.

Lipid droplets are formed at the endoplasmic reticulum (ER), where neutral lipids are synthesized by membrane resident enzymes. These neutral lipids are initially soluble within the ER phospholipid bilayer, but eventually phase-separate at higher concentrations into lipid lenses, which grow by addition of further neutral lipid molecules and ultimately bud to the cytosol [[4-6]]. Beside the neutral lipid synthesizing enzymes, further proteins are required in the lipid droplet biogenesis process that enable control over the lipidome, proteome, morphology, and finally metabolic dynamics of the emerging organelle. A key player in lipid droplet formation is the conserved seipin protein. Pedro Carvalho and colleagues describe recent mechanistic insights into the molecular roles of seipin and its partner proteins [[7]]. Julia Mahamid and colleagues provide a broad overview of the numerous key contributions of electron microscopy techniques to our understanding of lipid droplet form and function, ranging from initial insights into its unique phospholipid monolayer-based architecture to recent structures of key players in lipid droplet biology such as the seipin complex [[8]]. Jennifer Sapia and Stefano Vanni discuss in a Perspective article recent advancements and challenges in employing molecular dynamics simulations to contribute to our understanding of the molecular basis of lipid droplet biogenesis and protein targeting to the lipid droplet surface [[9]].

Once formed, lipid droplets can further grow either by acquiring lipids from the ER, or by fusing with other lipid droplets in a manner dependent on the CIDE proteins, which form a lipid-permeable inter-organelle bridge, reviewed in detail by Li Xu et al. [[10]]. When cells require lipids for expansion of their membrane systems or during nutrient deprivation when ATP-production relies on β-oxidation, lipid droplets are consumed by two alternative pathways: (a) a lipid droplet-specific form of autophagy termed lipophagy that results in lipid degradation by lysosomal lipases, and (b) a gradual mobilization of fatty acids from lipid droplets by cytosolic lipases in a process termed lipolysis. Access of cytosolic lipases to lipid droplets has to be tightly regulated to ensure lipid homeostasis under fluctuating metabolic conditions. In human cells, members of the conserved perilipin family have important roles in regulating lipolysis, as reviewed by Alenka Čopič and colleagues [[11]]. Mike Henne highlights the discovery of a unique lipid droplet subpopulation in baker's yeast that carries a specific set of anti-lipolytic surface proteins [[12]]. Xiaowen Duan and David Savage provide a Graphical Review on inherited forms of lipodystrophy, neutral lipid storage disease, and non-alcoholic fatty liver disease that are caused by mutations in proteins involved in lipid droplet formation, lipid droplet fusion, and lipolysis [[13]]. Hanaa Hariri and colleagues discuss the roles of lipid droplets in buffering excess lipids and mitigating lipotoxicity, as well as the cell biological consequences to prolonged lipid overload [[14]]. Michele Wölk and Maria Federova describe key advances in defining the lipidome of the neutral lipid core and phospholipid monolayer of lipid droplets [[15]]. Antonio Barbosa and Symeon Siniossoglou discuss in a Perspective article a non-canonical triacylglycerol synthesis pathway and propose an unappreciated functional relevance of this pathway in membrane lipid remodeling [[16]].

Three articles highlight contact site-based lipid droplet communication with other cellular organelles [[17-19]]. Ludovic Enkler and Anne Spang provide a detailed overview of the molecular bases and functional roles of communication between lipid droplets and mitochondria in mammals and baker's yeast [[17]]. Vera Monteiro-Cardoso and Francesca Giordano focus on tripartite lipid droplet contact sites with the ER and mitochondria and their relevance for lipid metabolism and lipid storage [[18]]. Aksel Saukko-Paavola and Robin Klemm discuss in a Perspective article the role of organelle crosstalk and the inter-organelle transfer of defined lipid populations in cellular metabolic adaptation [[19]]. Arun John Peter and Benoît Kornmann highlight a mass-tagging-based method for tracking lipid flux across organelle borders in living cells, a task that has been challenging in the past [[20]]. A Graphical Review by Eva Herker describes the implications of lipid droplets in infectious disease, focusing on how viruses exploit lipid droplets for genome replication and for the formation of infectious virions [[21]]. Albert Pol and colleagues discuss the roles of lipid droplets and lipid droplet-associated perilipins, lipases, and acyl-CoA synthases in enabling metabolic flexibility of cancer cells for disease progression [[22]].

The lipid droplet community is currently dissecting the molecular basis of the (patho-) physiological lipid droplet life cycle in a collective effort. At the same time, unexpected new roles, particularly in collaboration with partner organelles, are emerging, and the implications of lipid droplets in a broad range of pathologies are being revealed. Exciting times are clearly ahead for the lipid droplet field, and the editors of this special issue hope that this collection of articles may be an inspiration for the scientists addressing the cell biological roles of lipid droplets in health and disease.