Natural selective pressure throughout evolution of the Eukarya has generated a staggering array of control mechanisms that maintain energy homeostasis, such as allosteric regulation of glycolysis, nutritional control of gene expression, and the nutritional control of triglyceride hydrolysis and oxidation. The latter process of triglyceride hydrolysis and oxidation provides a major source of energy for most eukaryotes, and, as such, triglycerides are deposited in a phylogenetically conserved, ubiquitous organelle called the lipid droplet. The lipid droplet plays an important role in storage of cellular triglycerides and has the capacity to expand and contract dependent on caloric intake and energy demand.
One unresolved issue in lipid droplet biology is determining the mechanisms for lipid droplet biogenesis. There is substantive new evidence that lipid droplets are formed from the endoplasmic reticulum (1). More recently, our research group discovered a two-gene family of endoplasmic reticulum membrane proteins having six transmembrane domains that we named fat-storage-inducing transmembrane (FITM1/FIT1 and FITM2/FIT2) protein. FIT proteins are phylogenetically conserved from yeast to human. Genetic evidence from overexpression and knockdown studies in mammalian cells indicates that FIT proteins play an important role in the generation of lipid droplets (2–4).
FIT2 is the anciently conserved FIT family member. Indeed, human FIT2 can complement several phenotypes found in an S. cerevisiae strain deleted for FIT2, SCS3, indicating conservation of function (5). How might FIT proteins mediate lipid droplet formation? Structural information on the FIT family is lacking, making it difficult to infer function based on sequence alone. Biochemical evidence indicates that FIT proteins do not mediate fatty-acid or glycerolipid biosynthesis but rather partition newly synthesized triglycerides into lipid droplets (2). Part of the biochemical mechanism appears to require direct binding of triglyceride (6), raising the possibility that FIT proteins might play a role in solubilizing membrane triglyceride to nucleate a de novo forming droplet within the endoplasmic reticulum membrane.
FIT1 and FIT2 have distinct tissue distributions in mice and humans – with FIT1 primarily expressed in skeletal muscle and in lower levels in heart and with FIT2 ubiquitously expressed at low levels in tissues but highly expressed in adipocytes of white and brown origin. The disparate tissue distributions of FIT1 and FIT2 and the observation that FIT1 produces small lipid droplets characteristic of skeletal muscle lipid droplets and that FIT2 produces large lipid droplets more akin to adipocyte lipid droplets indicate that each might have a unique physiological role in metabolism. Skeletal-muscle-specific overexpression of FIT2 in mice resulted in a marked increase in intramyocellular triglycerides but paradoxically a decrease in fatty-acid oxidation and expression of PPARalpha target genes and an increase in the utilization of glucose and branched-chain amino acids (4). These findings suggest that FIT2 produces lipid droplets that are not coupled to mitochondria fatty acid beta-oxidation.
FIT1 is more abundant than FIT2 in skeletal muscle. What might its physiological role be in lipid metabolism? It recently has been shown (7) that PGC1alpha, a major exercise-induced regulator of mitochondria biogenesis and function, can induce expression of FIT1 in primary human skeletal myocytes. Given this finding, it is tempting to speculate that FIT1 plays a causative role in the exercise-induced intramycocellular accumulation of triglycerides noted in the athletes paradox (8).
The current view of the pathophysiology of the lipid droplet in adipocytes is that increased capacity or expandability of the adipocyte lipid droplet is beneficial to maintaining glucose and insulin sensitivity. For example, PPARgamma activators improve glucose and insulin sensitivity but increase body weight, in part due to adipocyte differentiation and expansion (9). In light of these findings, it might be significant that mouse and human FIT2 are direct targets of PPARgamma (10), suggesting that enhancing FIT2 expression would be beneficial to improve metabolic parameters in obese, insulin-resistant people. These ideas await testing using mouse FIT1- and FIT2-deficiency models as well as the identification of human mutations in these interesting, anciently conserved fat-storing genes.
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David L. Silver (firstname.lastname@example.org) is an associate professor in the cardiovascular and metabolic disorders program at the Duke-National University of Singapore Graduate School of Medicine in Singapore.