ReviewFatty acid flux in adipocytes: The in's and out's of fat cell lipid trafficking☆
Introduction
The adipocyte has evolved as a specialized cell type for the storage and release of fatty acids. Adipocytes are unique in that they can accommodate without deleterious effects the massive storage of triacylglycerol (TAG) during energy abundance and releases free fatty acids into the plasma for the use by other tissues during times of energy need. This process of fatty acid uptake and storage balanced by lipolysis is a highly regulated process that takes cues from nutritional and efferent signals to store and supply energy as the body dictates. The adipocyte has a unique cellular organization as well, with greater than 90% of the cell volume being TAG. These results in limited cytosolic space and a contiguous ER, nuclear, plasma membrane interface. This geometry may accommodate the transport of hydrophobic molecules, such as fatty acids and fatty acyl-CoA's to and from the membrane during uptake and lipolysis. The insolubility of fatty acids may also be accommodated by intracellular carriers such as the fatty acid binding proteins and acyl-CoA binding proteins. The exact location and mechanism of trafficking these hydrophobic molecules is under debate but is an important factor when discussing adipocyte storage and lipolysis of TAG.
Section snippets
Fatty acid uptake
Long-chain fatty acids (LCFA) transported across the plasma membrane of adipocytes are derived from circulating plasma LCFA's generated by lipoprotein lipase catalyzed hydrolysis of triglycerides in chylomicra or in very low-density lipoproteins (Bernlohr and Simpson, 1996). Although most circulating LCFAs are bound to serum albumin, there is a relatively small fraction of unbound long-chain fatty acid (LCFAu) that is the moiety transported across membranes. The mechanism by which LCFAu are
Putative fatty acid transporters
Four proteins have been implicated by a variety of methods as functionally linked to fatty acid transport (Fig. 1):
- 1.
Plasma membrane fatty acid binding protein (FABPpm);
- 2.
Fatty acid translocase (FAT/CD36);
- 3.
Caveolin-1;
- 4.
Fatty acyl-CoA synthetases (FATP and ACSL).
Fatty acyl-CoA synthetases
Fatty acid transport proteins (FATP) and long-chain acyl-CoA synthetases (ACSL) are two different classes of membrane bound enzymes catalyzing the ATP-dependent esterification of long-chain (ACSL) and very long-chain (FATP) fatty acids to their acyl-CoA derivatives (Hall et al., 2003, Hall et al., 2005). Proteins belonging to both classes of proteins have common ATP/AMP binding and fatty acid signature motifs. In mammals, six isoforms of FATP (FATP1-6) and five isoforms of ACSL (ACSL1, 3, 4, 5
Conclusions
Transport of LCFA across the adipocyte plasma membrane is a highly complex process. There is compelling evidence for the role of two different but not mutually exclusive processes: diffusion and protein-mediated uptake. It is likely that under cellular physiological conditions, LCFA influx observed may represent a balance between both processes.
Despite evidence for the role of putative fatty acid transporters in LCFA uptake, their molecular mechanism is still not very well understood. This, in
Regulation of lipolysis
Adipocyte lipolysis encompasses the hydrolysis of triacylglycerol (TAG) and release of fatty acids for use as an energy source by other tissues such as the heart and skeletal muscle. The regulation of adipocyte lipolysis is an intricate balance of signaling cascades to release fatty acids during times of energy need. This process is highly regulated and as evidenced in obesity when mis-regulated can lead to insulin resistance. The present data suggests that regulation of lipolysis occurs mainly
Lipases
Complete hydrolysis of TAG results in three molecules of fatty acid and one molecule of glycerol. Three lipases have been implicated as the major enzymes of adipocyte lipolysis, adipose triglyceride lipase, also known as desnutrin (ATGL), hormone sensitive lipase (HSL) and monoacylglycerol lipase (MGL). The present data indicates that ATGL is the main triacylglycerol lipase, HSL is the main diacylglycerol (DAG) lipase and MGL is the main monoacylglycerol (MAG) lipase (Fig. 2). Many other TAG
Lipid droplet and lipid binding proteins
Many other proteins play significant roles in regulating lipolysis in adipocytes. Lipid droplets are increasingly recognized as dynamic organelles, regulated by the proteins that coat them. Proteomic techniques have revealed numerous proteins which associate with lipid droplets, including structural proteins, small GTPases and signaling proteins (Liu et al., 2004). One family of lipid droplet associated proteins, the perilipin family, including adipose differentiation related protein, TIP-47,
B-adrenergic receptors in humans and mice and their influence on lipolysis
The main physiological pathway for the activation of lipolysis is by catecholamines. Catacholamines interact with adrenergic receptors to give rise to intracellular signaling and functional outcomes. Adrenergic receptors are seven transmembrane G-protein coupled receptors. β-1, β-2 and β-3 adrenergic receptors are couple to Gαs which stimulate adenylyl cyclase (AC) activity while α1 and α2 adrenergic receptors are coupled to Gαi which inhibits AC activity (Lafontan and Berlan, 1993). As the
Stimulation of lipolysis
The main signaling mechanism stimulating adipocyte lipolysis is through Gαs coupled receptors activating AC as discussed above. AC converts ATP to cyclic-AMP (cAMP) that acts as a second messenger. The regulatory subunit of PKA binds cAMP and dissociates from the catalytic subunits thereby activating the kinase. PKA then phosphorylates at least two important downstream targets, HSL and perilipin. Upon phosphorylation of HSL at Ser659 and Ser660 it translocates to the lipid droplet surface and
Inhibition of lipolysis
As discussed above, inhibition of lipolysis can occur through increasing Gαi coupled receptor activation leading to inhibition of AC. Adenosine, prostaglandin E2 (PGE2) and NPY are examples of molecules that inhibit lipolysis in this manner. Stimulation of the A1-adenosine receptor, NPY-Y1 receptor and EP3 receptor results in the inhibition of lipolysis while antagonists to these receptors enhance lipolysis suggesting that they may have a role in fine tuning the lipolytic response (Kos et al.,
Natriuretic peptides
A human specific pathway to stimulate lipolysis has recently been identified. Natriuretic peptides bind to their guanylyl cyclase receptors increasing cGMP which activates protein kinase G (PKG) resulting in the phosphorylation and translocation of HSL to increase lipolysis (Lafontan et al., 2008). Confounding this mechanism is the fact that cAMP levels also rise and PKA is activated making in unclear if PKG or PKA phosphorylates HSL. In the end this is a potent stimulator of human adipocyte
Conclusions
The regulation of lipolysis is a balancing act between numerous signals and downstream effectors. This balancing act is in place to store TAG in times of excess energy while being able to rapidly mobilize this high energy substrate during times of energy need. This process is regulated by the central nervous system, hormones dictating the energy state of the body, such as insulin and glucagon, as well as autocrine/paracrine factors which allows for depot specific changes depending on the
References (118)
- et al.
Catecholamine activation of the membrane transport of long chain fatty acids in adipocytes is mediated by cyclic AMP and protein kinase
J. Biol. Chem.
(1986) - et al.
Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro
J. Biol. Chem.
(1998) - et al.
FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms
J. Biol. Chem.
(2005) - et al.
Uptake of long chain free fatty acids is selectively up-regulated in adipocytes of Zucker rats with genetic obesity and non-insulin-dependent diabetes mellitus
J. Biol. Chem.
(1997) - et al.
Adipose tissue and lipid metabolism
Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis
J. Lipid Res.
(2007)- et al.
Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis
J. Biol. Chem.
(2000) - et al.
Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes
J. Biol. Chem.
(2004) - et al.
Fatty acid flip-flop and proton transport determined by short-circuit current in planar bilayers
J. Lipid Res.
(2005) - et al.
The subcellular compartmentation of fatty acid transporters is regulated differently by insulin and by AICAR
FEBS Lett.
(2005)
FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes
J. Biol. Chem.
Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels
J. Lipid Res.
Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes
J. Biol. Chem.
CD36: implications in cardiovascular disease
Int. J. Biochem. Cell. Biol.
Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol
Biochim. Biophys. Acta
Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene
J. Biol. Chem.
Localization of adipocyte long-chain fatty acyl-CoA synthetase at the plasma membrane
J. Lipid Res.
Tumor necrosis factor alpha stimulates lipolysis in adipocytes by decreasing Gi protein concentrations
J. Biol. Chem.
Analysis of lipolytic protein trafficking and interactions in adipocytes
J. Biol. Chem.
Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway
J. Biol. Chem.
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation
Biochimie
Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis
J. Biol. Chem.
Characterization of the acyl-CoA synthetase activity of purified murine fatty acid transport protein 1
J. Biol. Chem.
Enzymatic properties of purified murine fatty acid transport protein 4 and analysis of acyl-CoA synthetase activities in tissues from FATP4 null mice
J. Biol. Chem.
FATP1 channels exogenous FA into 1,2,3-triacyl-sn-glycerol and down-regulates sphingomyelin and cholesterol metabolism in growing 293 cells
J. Lipid Res.
Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity
J. Biol. Chem.
Mouse fatty acid transport protein 4 (FATP4): characterization of the gene and functional assessment as a very long chain acyl-CoA synthetase
Gene
Characterization of the murine fatty acid transport protein gene and its insulin response sequence
J. Biol. Chem.
Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities
J. Biol. Chem.
Fat-specific protein 27 regulates storage of triacylglycerol
J. Biol. Chem.
Membrane microdomains and caveolae
Curr. Opin. Cell Biol.
Fat cell adrenergic receptors and the control of white and brown fat cell function
J. Lipid Res.
Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members
J. Lipid Res.
Control of fatty acid and glycerol release in adipose tissue lipolysis
C. R. Biol.
Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman syndrome
Cell Metab.
Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome
Am. J. Hum. Genet.
Overexpression of rat long chain acyl-coa synthetase 1 alters fatty acid metabolism in rat primary hepatocytes
J. Biol. Chem.
Chinese hamster ovary K2 cell lipid droplets appear to be metabolic organelles involved in membrane traffic
J. Biol. Chem.
Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4
J. Lipid Res.
Functional analysis of long-chain acyl-coa synthetase 1 in 3T3-L1 adipocytes
J. Biol. Chem.
The phosphorylation of serine 492 of perilipin a directs lipid droplet fragmentation and dispersion
J. Biol. Chem.
Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms
J. Biol. Chem.
Control of adipose triglyceride lipase action by serine 517 of perilipin A globally regulates protein kinase A-stimulated lipolysis in adipocytes
J. Biol. Chem.
Triacylglycerol is synthesized in a specific subclass of caveolae in primary adipocytes
J. Biol. Chem.
Isolation and partial characterization of plasma membrane fatty acid binding proteins from myocardium and adipose tissue and their relationship to analogous proteins in liver and gut
Biochem. Biophys. Res. Commun.
Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities
J. Biol. Chem.
Oligomerization of the murine fatty acid transport protein 1
J. Biol. Chem.
Prostaglandin E2 action and binding in human adipocytes: effects of sex, age, and obesity
Metabolism
Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts
Biochim. Biophys. Acta
Mapping of early signaling events in tumor necrosis factor-alpha-mediated lipolysis in human fat cells
J. Biol. Chem.
Cited by (78)
Combined exposure to deoxynivalenol facilitates lipid metabolism disorder in high-fat-diet-induced obesity mice
2023, Environment InternationalWhite adipose tissue: Distribution, molecular insights of impaired expandability, and its implication in fatty liver disease
2023, Biochimica et Biophysica Acta - Molecular Basis of DiseaseAdipocytes in obesity: A perfect reservoir for SARS-CoV-2?
2023, Medical HypothesesWe are what we eat: The role of lipids in metabolic diseases
2023, Advances in Food and Nutrition ResearchRecurrent hypoglycemia increases hepatic gluconeogenesis without affecting glycogen metabolism or systemic lipolysis in rat
2022, Metabolism: Clinical and ExperimentalCitation Excerpt :The resulting glycerol is transported across cell membrane through aquaporin (AQP) proteins [10]. The generated FFA are transported through the plasma membrane-associated fatty acid-binding protein (FABPpm, identical to GOT2), scavenger receptor CD36 and fatty acid transport proteins (FATP1, FATP2, FATP4 and FATP5) [11,12]. In addition to EGP, counterregulatory hormones prevent hypoglycemia by inhibiting glucose disposal, a process that involves the insulin-sensitive glucose transporter GLUT4.