Evolutionarily conserved gene family important for fat storage

Abstract

The ability to store fat in the form of cytoplasmic triglyceride droplets is conserved from Saccharomyces cerevisiae to humans. Although much is known regarding the composition and catabolism of lipid droplets, the molecular components necessary for the biogenesis of lipid droplets have remained obscure. Here we report the characterization of a conserved gene family important for lipid droplet formation named fat-inducing transcript (FIT). FIT1 and FIT2 are endoplasmic reticulum resident membrane proteins that induce lipid droplet accumulation in cell culture and when expressed in mouse liver. shRNA silencing of FIT2 in 3T3-LI adipocytes prevents accumulation of lipid droplets, and depletion of FIT2 in zebrafish blocks diet-induced accumulation of lipid droplets in the intestine and liver, highlighting an important role for FIT2 in lipid droplet formation in vivo. Together these studies identify and characterize a conserved gene family that is important in the fundamental process of storing fat.adipocytes ͉ diabetes ͉ FIT ͉ obesity ͉ triglyceride T he ability to store energy in the form of triglyceride (TG) is conserved from Saccharomyces cerevisiae to humans. TGs are stored in the cytoplasm surrounded by a monolayer of phospholipid in distinct structures or organelles given numerous names, such as lipid particles, oil bodies, adiposomes, eicosasomes, and, more commonly, lipid droplets (1). Under normal physiological conditions, lipid droplets are involved in maintaining energy balance at the cellular and whole-organism levels. Yet under conditions of extreme lipid droplet acquisition, as in obesity, the risk for acquiring common debilitating diseases such as type 2 diabetes and cardiovascular diseases is increased (2).Despite their central role in energy homeostasis, only recently have the composition and functions of many of the components of lipid droplets from S. cerevisiae, Drosophila, and mammalian cells been revealed. In general, lipid droplets are composed of a core of neutral lipids, primarily TGs, surrounded by a monolayer of phospholipids and lipid droplet-associated proteins (3-7). In mammalian cells, the catabolism of lipid droplets is a highly regulated process involving hormonal signals, droplet-associated proteins, and lipases (8-10). Although much has been learned about the components and catabolism of lipid droplets, the molecular mechanism of lipid droplet biogenesis has remained unknown. The prevailing view is that lipid droplets are formed at the endoplasmic reticulum (ER) because the ER is the site of TG biosynthesis, and lipid droplets are often observed in close association with the cytoplasmic face of the ER (11-13). A widely accepted model of lipid droplet biogenesis involves the formation of a core or lens of newly synthesized TG between the leaflets of the ER membrane that buds off with the cytoplasmic leaflet of the ER surrounding the neutral lipid core and acquires exchangeable cytosolic lipid droplet-associated proteins (14). However, this view was recently challenged by observatio...

Not Just Fat: The Structure and Function of the Lipid Droplet

“…This result suggests that ADRP not only protects lipid esters from lipases, but it is also intimately related to the process of LD formation. It is intriguing that the ER membrane proteins FIT1 and FIT2 also appear to facilitate LD formation without enhancing TG synthesis or inhibiting lipolysis (Kadereit et al 2008). PAT proteins, as well as FIT1 and FIT2, are likely to constitute an active molecular mechanism making LDs from lipid ester in the membrane.…”

Keeping FIT, storing fat: Lipid droplet biogenesis

“…Mammals have a muscle-specific FIT protein (FIT1) that seems to be absent in worms; 22 it may be that the sole FIT protein in worms performs the functions of FIT1 and FIT2 in mammals. It has recently been found that the expression of the FIT1 gene is altered in patients with facioscapulohumeral muscular dystrophy (FSHD, discussed in 27 ).…”

“…21 These proteins, called fat storageinducing transmembrane (FIT) proteins, are conserved and were first identified because, when over produced in mammalian cells, cause a dramatic increase in neutral lipid and LD production. 22 Humans have 2 of these proteins, FIT1, which is expressed in muscle, and FIT2, found in all tissues. 22 The yeast S. cerevisiae has 2 FIT2 homologs and lacks a homolog of FIT1.…”

“…22 Humans have 2 of these proteins, FIT1, which is expressed in muscle, and FIT2, found in all tissues. 22 The yeast S. cerevisiae has 2 FIT2 homologs and lacks a homolog of FIT1. We found that in a yeast mutant lacking both FIT proteins, LDs fail to bud from the ER and often become wrapped by the ER membrane (Fig.…”

NTE1-encoded Phosphatidylcholine Phospholipase B Regulates Transcription of Phospholipid Biosynthetic Genes

“…The SCS3 gene was first identified as required for inositol prototrophy in the presence of choline, and it was reported that its inactivation triggered neither a reduction in the level of INO1 mRNA nor a decrease in the enzymatic activity of Ino1p (48). Recently, it was characterized as the yeast orthologue of a conserved gene family involved in lipid droplet formation (49). As for many other inositol auxotroph mutants analyzed here, the overexpression of NTE1 allowed scs3⌬ cells to grow in the absence of exogenous inositol (Fig.…”