Metabolic bias: Lipid structures as determinants of their metabolic fates

Overview & Synopsis

Cellular lipids have an enormous diversity in their chemical structures, which affect the physicochemical properZes of lipids and membranes, as well as their regulatory roles on protein funcZons. Here, I review addiZonal roles of lipid structures. MulZple studies show that structural differences affect how lipids, even from the same class, are metabolically converted via disZnct pathways. I propose the name "structure-guided metabolic bias" for this phenomenon, and discuss its biological relevance. This metabolic bias seems implicated in the buildup of basic cellular lipid composiZons, as well as geneZc predisposiZon to diseases. Thus, guiding metabolic biases is an important funcZon of lipid structures, while having the characterisZc of being difficult to study by in vitro biochemical reconsZtuZons. Introduc0onCellular lipids have an enormous diversity in their chemical structures, which arises from the various combinaZons of lipid backbones, head groups, and hydrophobic tails [1]. This raises the fundamental quesZon: Why did we evolve with so many lipid species? The structural diversity is important for lipids to fulfil their mulZple funcZons as major components of membranes, energy sources, signaling molecules, and as substrates for protein post-translaZonal modificaZons. Membrane lipid structures affect biological funcZons through their impact on membrane physicochemical properZes and membrane-associated protein funcZons. It is therefore criZcal to establish structure-funcZon relaZonships for the diverse cellular lipids. In this context, efforts are made to study the roles of lipid structures by reconsZtuZng membranerelated biological processes in vitro using various syntheZc lipids [2,3]. Being able to recapitulate in vitro the differences in lipid funcZons depending on their species would be the most convincing way to demonstrate the roles of lipid structures, in line with the quote of Richard Feynman "What I cannot create, I do not understand". However, it is unknown if all roles of lipid structures fall in the categories menZoned above (physicochemical properZes, membrane-associated protein funcZons), and therefore some funcZons of lipid structures might be impossible to recapitulate in vitro. In this review, I will present some studies demonstraZng that lipid structures affect their metabolic fates, leading to the concept of "structure-guided metabolic bias". This implies that in some cases, structural features per se do not directly affect lipid funcZons in a way that can be biochemically or biophysically reconsZtuted, but rather influence their roles in cells by dictaZng which addiZonal structural features are added (or removed) via metabolism.