Not all lipids are the same

Just like not all proteins are the same, there is a staggering variety of lipids in nature and not all lipids are functionally equivalent. Rather, different lipids (or the same lipid in different places) play a variety of roles in cell signaling, structure, and energy storage, such as the function of 16:0/18:1-GPC in activating PPARĮ (and not just 16:0/18:1-GPC, but FAS-derived 16:0/18:1-GPC specifically). While the variety of functions of such a diverse class of

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biomolecules shouldn’t come as a big surprise, the importance of lipids in signaling has only gained attention in the past fifteen years. As an illustration of this, the phrases “lipid signaling”

and “signaling lipid” appeared 584 times in articles in the PubMed database over the past fifteen years (as of 6/20/2013), and prior to that only 44 times since the first usage of “lipid signaling” in the literature in 1988.

The increasing interest in signaling lipids partly results from improvements in mass spectrometry, allowing for rapid identification of low-abundance lipid molecules. It also represents a recognition that the abundance of distinct lipid species may reflect a

corresponding variety in functions. To me, this recognition ties in with the third point in emphasizing just how much we still do not know about cell biology, even in research fields that have been studied for decades, such as lipids and housekeeping genes. Thanks to the enormous increase in our knowledge of biology over the past century, a textbook in molecular biology may make it seem as if most cell biology has already been worked out.

The challenge lies in seeing the gaps in our knowledge.

The most important classes of larger biomolecules in living organisms are proteins, nucleic acids, lipids and polysaccharides. It would be easy to dismiss any of the latter classes as simply “fats” and “sugars” meant for storing and transporting energy, yet the sheer number of unique lipid species and polysaccharide modifications suggest that there is much we do not yet know. Developments in mass spectrometry have improved our ability to fill these gaps in knowledge.

Establishing lipid-protein relationships for signaling lipids will be crucial, as the existence of protein targets facilitate pharmacological and genetic manipulation for research or therapeutic purposes. For all the lipid species of yet unknown function, there will be

known and novel proteins involved in their synthesis, transport, and catabolism. Identification of signaling lipids may provide novel pathways that can be targeted to treat human disease,

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and knowledge of these proteins would provide feasible pharmacological targets to treat metabolic disease.

117 REFERENCES

1. Vance, D.E. and J.E. Vance, Biochemistry of lipids, lipoproteins and membranes. 5th ed. 2008, Amsterdam ; Boston: Elsevier. xii, 631 p., 8 p. of plates.

2. Plate, C.A., et al., Studies on the mechanism of fatty acid synthesis. XXI. The role of fructose 1,6-diphosphate in the stimulation of the fatty acid synthetase from pigeon liver. J Biol Chem, 1968. 243(20): p. 5439-45.

3. Qureshi, A.A., et al., Separation of two active forms (holo-a and holo-b) of pigeon liver fatty acid synthetase and their interconversion by phosphorylation and dephosphorylation. Biochem Biophys Res Commun, 1975. 66(1): p. 344-51.

4. Semenkovich, C.F., Regulation of fatty acid synthase (FAS). Prog Lipid Res, 1997.

36(1): p. 43-53.

5. Menendez, J.A., et al., Fatty acid synthase: association with insulin resistance, type 2 diabetes, and cancer. Clin Chem, 2009. 55(3): p. 425-38.

6. Sul, H.S. and D. Wang, Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu Rev Nutr, 1998. 18: p. 331-51.

7. Alberts, B., Molecular biology of the cell. 4th ed. 2002, New York: Garland Science.

xxxiv, 1548 p.

8. Ferguson, R.E., et al., Housekeeping proteins: a preliminary study illustrating some limitations as useful references in protein expression studies. Proteomics, 2005. 5(2):

p. 566-71.

9. Chakravarthy, M.V., et al., Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell, 2009. 138(3): p. 476-88.

10. Chakravarthy, M.V., et al., "New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab, 2005. 1(5): p. 309-22.

11. Chakravarthy, M.V., et al., Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. J Clin Invest, 2007. 117(9): p. 2539-52.

12. Funai, K., et al., Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling. J Clin Invest, 2013. 123(3): p. 1229-40.

13. Jensen-Urstad, A.P., et al., Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARalpha. J Lipid Res, 2013. 54(7): p. 1848-59.

14. Wei, X., et al., Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin 2. Cell Host Microbe, 2012. 11(2): p. 140-52.

118 Appendix A

Jensen-Urstad APL, Semenkovich CF. “Fatty acid synthase and liver triglyceride

metabolism: housekeeper or messenger?” Biochimica et Biophysica Acta. 2012. 1821(5):747-53.

Review

Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger?☆

Anne P.L. Jensen-Urstad, Clay F. Semenkovich⁎

Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,

Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA

a b s t r a c t a r t i c l e i n f o

Article history:

Received 7 June 2011

Received in revised form 26 September 2011 Accepted 27 September 2011

Fatty acid synthase (FAS) catalyzes the de novo synthesis of fatty acids. In the liver, FAS has long been cate-gorized as a housekeeping protein, producing fat for storage of energy when nutrients are present in excess.

Most previous studies of FAS regulation have focused on the control of gene expression. However, recent findings suggest that hepatic FAS may also be involved in signaling processes that include activation of peroxi-some proliferator-activated receptorα (PPARα). Moreover, reports of rapid alterations in FAS activity as well asfindings of post-translational modifications of the FAS protein support the notion that dynamic events in ad-dition to transcription impact FAS regulation. These results indicate that FAS enzyme activity can impact liver physiology through signaling as well as energy storage and that its regulation may be complex. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

© 2011 Elsevier B.V. All rights reserved.

1. Introduction

The liver is involved in the uptake, synthesis, storage, secretion, and catabolism of fatty acids and triglycerides. Fatty acid synthase (FAS), the enzyme catalyzing de novo synthesis of fatty acids, is tradi-tionally thought of as a housekeeping protein, producing fatty acids that can be used for energy storage, membrane assembly and repair, and secretion in the form of lipoprotein triglycerides. However, the contribution by FAS to secreted triglycerides appears to be negligible compared to other sources of fat under common dietary conditions.

An unexpected role for FAS as a signaling enzyme emerged with the finding that FAS can affect fatty acid oxidation through PPARα, the main mediator of the fasting response in the liver.

The possibility that FAS may be involved in promoting fat catabo-lism in addition to its known function of synthesizing fat raises new questions regarding the regulation of FAS. Are there multiple pools of FAS with distinct functions, allowing separate control of mediated signaling and mediated energy storage? How is FAS-PPARα signaling regulated in response to nutritional and hormonal stimuli, and how is it possible for FAS to be activated or inhibited rapid-ly? FAS has been thought to be regulated mostly at the transcriptional level, which might preclude an immediate response by FAS to changes in nutritional or hormonal stimuli since FAS mRNA is fairly stable. A role for FAS in signaling suggests the presence of rapid, post-translational mechanisms of FAS regulation. This review will address

physiological functions of hepatic FAS, its regulation by nutrients and hormones, and mechanisms of regulation.

FAS may be a therapeutic target for treating fatty liver and dyslipi-demia [1]. Both are common features of the metabolic syndrome [2,3], which affects ~ 1 in 4 Americans[4]. Both are also independent risk factors for coronary artery disease [5–7], the most common cause of death worldwide. Identification of regulatory proteins and pathways distinguishing housekeeping FAS from signaling FAS could potentially lead to novel therapeutics that selectively target FAS function.

1.1. Hepatic triglyceride metabolism

Under nutrient-replete conditions, the primary fuel of the liver is glucose rather than fat. Fatty acids are not subjected toβ-oxidation and instead are incorporated into triglycerides for storage in lipid droplets or secretion in very low-density lipoproteins (VLDL). Dietary fat in the form of chylomicron remnants is taken up by the liver; de novo synthesis of fatty acids by FAS may make a modest contribution to storing energy as fat when nutrients are present in excess.

During fasting, lipolysis in peripheral tissues (primarily adipose tissue) increases the levels of plasma free fatty acids (FFAs), which are taken up by the liver. Activation of the transcription factor peroxi-some proliferator-activated receptorα (PPARα) mediates the adaptive response to fasting by promoting the transcription of genes involved in the uptake and catabolism of fatty acids[8–11]. Fatty acids derived from peripheral tissues or intrahepatic lipid droplets are catabolized through β-oxidation to produce ketone bodies, which are used as fuel when glu-cose is scarce.