Review
Fatty acid flux in adipocytes: The in's and out's of fat cell lipid trafficking

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Abstract

The trafficking of fatty acids into and out of adipocytes is regulated by a complex series of proteins and enzymes and is under control by a variety of hormonal and metabolic factors. The biochemical basis of fatty acid influx, despite its widespread appreciation, remains enigmatic with regard to the biophysical and biochemical properties that facilitate long-chain fatty acid uptake. Fatty acid efflux is initiated by hormonally controlled lipolysis of the droplet stores and produces fatty acids that must transit from their site of production to the plasma membrane and subsequently out of the cells. This review will focus on the “in's and out's” of fatty acid trafficking and summarize the current concepts in the field.

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

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