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• W2912778549 abstract "The storage and degradation of long-chain FA underpin eukaryotic energy metabolism. The two extremes of dysregulated energy metabolism, obesity and cachexia, are linked to major noninfectious chronic disorders, including diabetes, cardiovascular disease, and cancer. Thus, for the past 60 years, scientists and clinicians have worked to understand FAs and triacylglycerol (TAG) in terms of their pathways of synthesis, regulation, and physiological effects in liver, skeletal muscle, heart, and adipose tissue. Although we have long been aware that cellular compartments, including the cytosol, are packed tightly with proteins, textbook descriptions of biochemical pathways suggest that substrates and products of sequential enzyme steps wander around randomly before encountering the next enzymatic active site. Textbook drawings are similarly deceptive in showing sequential enzymes isolated from the myriad of other soluble and membrane-associated proteins and lipids. These misleading portrayals are particularly problematic for the initial steps in lipid metabolism, long-chain acyl-CoA synthetase (ACSL) and glycerol-3-phosphate acyltransferase (GPAT). As products of ACSL and as substrates for GPAT, long-chain acyl-CoAs are not uniformly available within the cytosol. In theory, sequestration of acyl-CoAs should not be possible: acyl-CoAs are water-soluble and amphipathic, and should therefore be able to move freely within the cytosol and within membrane monolayers. However, genetic information, biochemical data, and studies of knockout mice challenge this idea. The initiation of glycerolipid biosynthesis begins with ACSL-mediated thioesterification of FAs to produce long-chain acyl-CoAs. GPAT then esterifies these acyl-CoAs to form lysophosphatidic acid (LPA). Subsequent esterification steps and the action of phosphatidic acid (PA) phosphohydrolase result in the synthesis of TAG. The PA and diacylglycerol (DAG) intermediates in this pathway are also precursors of all the glycerophospholipids. Although this series of five biochemical steps was fully elucidated by 1960 (1.Kennedy E.P. Biosynthesis of complex lipids.Fed. Proc. 1961; 20: 934-940PubMed Google Scholar, 2.Kornberg A. Pricer Jr., W.E. Enzymatic synthesis of the conenzyme A derivatives of long-chain fatty acids.J. Biol. Chem. 1953; 204: 329-343Abstract Full Text PDF PubMed Google Scholar), we have since learned that each step in the pathway of TAG synthesis is catalyzed by at least two, and as many as 13 independent proteins, each encoded by a separate gene (Fig. 1) (3.Coleman R.A. Mashek D.G. Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling.Chem. Rev. 2011; 111: 6359-6386Crossref PubMed Scopus (170) Google Scholar). Why are so many isoenzymes required to catalyze each step? Does each isoform have a different function or are the isoforms redundant? If each isoform has a different function, what mechanism ensures this? Differences in tissue expression may underlie some specific biochemical or metabolic phenotypes. The current data suggest an underlying complexity of lipid metabolism that strongly indicates that lipids are channeled within cells, both functionally and mechanistically. Enzymes that control metabolic pathways are frequently regulated by multiple mechanisms. We propose that a complex network of interacting proteins constitutes an unexplored mechanism for FA regulatory channeling. Data from studies of GPAT and ACSL isoforms have led us to conclude that assemblies of interacting proteins must facilitate the channeling of FAs and acyl-CoAs into specific downstream pathways. Long-chain FAs must be converted to acyl-CoAs by one of 13 long-chain ACSL isoforms before they can enter most synthetic or degradative pathways (Fig. 1). In highly oxidative tissues, such as skeletal muscle, brown adipose, and heart, ACSL1 is the major isoform and is primarily located on the outer mitochondrial membrane (OMM) (4.Cooper D.E. Young P.A. Klett E.L. Coleman R.A. Physiological consequences of compartmentalized acyl-CoA metabolism.J. Biol. Chem. 2015; 290: 20023-20031Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar) where it interacts with CPT1 (5.Lee K. Kerner J. Hoppel C.L. Mitochondrial carnitine palmitoyltransferase 1a (CPT1a) is part of an outer membrane fatty acid transfer complex.J. Biol. Chem. 2011; 286: 25655-25662Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar) and directs FAs toward mitochondrial β-oxidation (6.Ellis J.M. Li L.O. Wu P.C. Koves T.R. Ilkayeva O. Stevens R.D. Watkins S.M. Muoio D.M. Coleman R.A. Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis.Cell Metab. 2010; 12: 53-64Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 7.Ellis J.M. Mentock S.M. Depetrillo M.A. Koves T.R. Sen S. Watkins S.M. Muoio D.M. Cline G.W. Taegtmeyer H. Shulman G.I. et al.Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs fatty acid oxidation and induces cardiac hypertrophy.Mol. Cell. Biol. 2011; 31: 1252-1262Crossref PubMed Scopus (135) Google Scholar, 8.Li L.O. Grevengoed T.J. Paul D.S. Ilkayeva O. Koves T.R. Pascual F. Newgard C.B. Muoio D.M. Coleman R.A. Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.Diabetes. 2015; 64: 23-35Crossref PubMed Scopus (73) Google Scholar). Mice lacking ACSL1 in skeletal muscle are able to run only half as far as controls despite having muscle content of long-chain acyl-CoA that is twice as high, indicating that acyl-CoAs synthesized by other ACSL isoforms are unavailable for β-oxidation. Similarly, in adipose tissue devoid of ACSL1, FA oxidation is markedly impaired while TAG synthesis remains unaffected (6.Ellis J.M. Li L.O. Wu P.C. Koves T.R. Ilkayeva O. Stevens R.D. Watkins S.M. Muoio D.M. Coleman R.A. Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis.Cell Metab. 2010; 12: 53-64Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). These studies strongly suggest that acyl-CoAs are compartmentalized within the cytosol. In adipose tissue, skeletal muscle, and heart, ACSL1 is primarily located on the OMM and channels FAs specifically into the mitochondria for β-oxidation (6.Ellis J.M. Li L.O. Wu P.C. Koves T.R. Ilkayeva O. Stevens R.D. Watkins S.M. Muoio D.M. Coleman R.A. Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis.Cell Metab. 2010; 12: 53-64Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 7.Ellis J.M. Mentock S.M. Depetrillo M.A. Koves T.R. Sen S. Watkins S.M. Muoio D.M. Cline G.W. Taegtmeyer H. Shulman G.I. et al.Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs fatty acid oxidation and induces cardiac hypertrophy.Mol. Cell. Biol. 2011; 31: 1252-1262Crossref PubMed Scopus (135) Google Scholar, 8.Li L.O. Grevengoed T.J. Paul D.S. Ilkayeva O. Koves T.R. Pascual F. Newgard C.B. Muoio D.M. Coleman R.A. Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.Diabetes. 2015; 64: 23-35Crossref PubMed Scopus (73) Google Scholar, 9.Grevengoed T.J. Cooper D.E. Young P.A. Ellis J.M. Coleman R.A. Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation.FASEB J. 2015; 29: 4641-4653Crossref PubMed Scopus (28) Google Scholar). In liver, however, the ACSL1 located on the OMM appears to direct FAs toward β-oxidation, but the fate of the acyl-CoAs synthesized by the remaining 50% of ACSL1 protein on the ER remained unclear (10.Li L.O. Ellis J.M. Paich H.A. Wang S. Gong N. Altshuller G. Thresher R.J. Koves T.R. Watkins S.M. Muoio D.M. et al.Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition.J. Biol. Chem. 2009; 284: 27816-27826Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). Differential FA partitioning is likely to require ACSL1 to interact with other specific proteins. In order to understand which protein interactions were unique to ACSL1 in its two locations, we used the unbiased protein interaction discovery technique, BioID (11.Roux K.J. Kim D.I. Raida M. Burke B. A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells.J. Cell Biol. 2012; 196: 801-810Crossref PubMed Scopus (1234) Google Scholar). This method detects interacting proteins, including those that may have weak or transient interactions with the bait protein. As a fusion protein with the Escherichia coli biotin ligase, BirA*, ACSL1 was targeted to either the ER or the OMM of Hepa1-6 (mouse hepatoma) cells (12.Young P.A. Senkal C.E. Suchanek A.L. Grevengoed T.J. Lin D.D. Zhao L. Crunk A.E. Klett E.L. Fullekrug J. Obeid L.M. et al.Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways.J. Biol. Chem. 2018; 293: 16724-16740Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Proteomic analysis identified 98 proteins that specifically interacted with ACSL1 at the ER, 55 at the OMM and 43 proteins common to both subcellular locations. Cohorts of peroxisomal and lipid droplet proteins, tethering proteins, and vesicle proteins uncovered a dynamic role for ACSL1 in organelle and lipid droplet interactions. Using primary mouse hepatocytes from both male and female mice, we confirmed by coimmunoprecipitation that ACSL1 interacts with specific networks of proteins that enable its acyl-CoA product to be directed into the mitochondria for β-oxidation or into niche pathways at the ER related to ceramide and branched-chain FA metabolism (12.Young P.A. Senkal C.E. Suchanek A.L. Grevengoed T.J. Lin D.D. Zhao L. Crunk A.E. Klett E.L. Fullekrug J. Obeid L.M. et al.Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways.J. Biol. Chem. 2018; 293: 16724-16740Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Proteins that interacted with ACSL1 targeted to the OMM included a group of proteins believed to tether lipid droplets to the OMM; these include SNAP23, Stx7, and VAMP2, -4, and -5 (12.Young P.A. Senkal C.E. Suchanek A.L. Grevengoed T.J. Lin D.D. Zhao L. Crunk A.E. Klett E.L. Fullekrug J. Obeid L.M. et al.Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways.J. Biol. Chem. 2018; 293: 16724-16740Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). These results confirmed that the intracellular location of ACSL1 allows it to interact with independent networks of proteins. Primary hepatocytes can be used to investigate weak or transient interactions because they respond well to physiological stimuli. Thus, specific interactions of ACSL1 with SNAP23 and VAMP4 were abrogated in the presence of 25 mM of glucose (12.Young P.A. Senkal C.E. Suchanek A.L. Grevengoed T.J. Lin D.D. Zhao L. Crunk A.E. Klett E.L. Fullekrug J. Obeid L.M. et al.Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways.J. Biol. Chem. 2018; 293: 16724-16740Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar), suggesting that the link between ACSL1 and FAs released from lipid droplets depends on the cell's nutrient status (Fig. 2). Supporting this interpretation, incubation in the absence of glucose enhanced FA oxidation, whereas incubation with glucose enhanced incorporation of FA into complex lipids (12.Young P.A. Senkal C.E. Suchanek A.L. Grevengoed T.J. Lin D.D. Zhao L. Crunk A.E. Klett E.L. Fullekrug J. Obeid L.M. et al.Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways.J. Biol. Chem. 2018; 293: 16724-16740Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). In contrast to the modulation of SNAP23 and VAMP4 interactions, the interaction of ACSL1 with the OMM protein, CPT1, did not change. These data show that the transient interactions are specific and relevant to the disposition of acyl-CoAs during fasting and feeding. Of the three liver GPAT isoenzymes, only GPAT1 is an integral member of the pathway that converts excess dietary carbohydrate into TAG, a principal source of diet-related hepatic steatosis (13.Lambert J.E. Ramos-Roman M.A. Browning J.D. Parks E.J. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.Gastroenterology. 2014; 146: 726-735Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar). GPAT1 is a target of the insulin- and nutrient-activated transcription factors, SREBP-1c and ChREBP (14.Shimano H. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes.Prog. Lipid Res. 2001; 40: 439-452Crossref PubMed Scopus (575) Google Scholar, 15.Shimano H. SREBPs: physiology and pathophysiology of the SREBP family.FEBS J. 2009; 276: 616-621Crossref PubMed Scopus (150) Google Scholar, 16.Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3757) Google Scholar, 17.Linden A.G. Li S. Choi H.Y. Fang F. Fukasawa M. Uyeda K. Hammer R.E. Horton J.D. Engelking L.J. Liang G. Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice.J. Lipid Res. 2018; 59: 475-487Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 18.Ericsson J. Jackson S.M. Kim J.B. Spiegelman B.M. Edwards P.A. Identification of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor 1-and sterol regulatory element-binding protein-responsive gene.J. Biol. Chem. 1997; 272: 7298-7305Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 19.Huo M. Zang H.L. Zhang D.J. Wang B. Wu J. Zhang X.Y. Chen L.H. Li J. Yang J.C. Guan Y.F. Role of increased activity of carbohydrate response element binding protein in excessive lipid accumulation in the liver of type 2 diabetic db/db mouse.Beijing Da Xue Xue Bao Yi Xue Ban. 2009; 41 ([Article in Chinese]): 307-312PubMed Google Scholar). In the presence of high dietary carbohydrate and insulin, these transcription factors upregulate the export of mitochondrial citrate (20.Giudetti A.M. Stanca E. Siculella L. Gnoni G.V. Damiano F. Nutritional and hormonal regulation of citrate and carnitine/acylcarnitine transporters: two mitochondrial carriers Involved in fatty acid metabolism.Int. J. Mol. Sci. 2016; 17: E817Crossref PubMed Scopus (28) Google Scholar) and the enzymes that use citrate for de novo lipogenesis (DNL) (Fig. 3) (16.Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3757) Google Scholar). Although both GPAT1 and -4 use exogenously derived palmitate, only GPAT1 initiates TAG synthesis from FA synthesized de novo from acetate (21.Wendel A.A. Cooper D.E. Ilkayeva O.R. Muoio D.M. Coleman R.A. Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation.J. Biol. Chem. 2013; 288: 27299-27306Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar), thereby linking nutrient excess to hepatic DNL and TAG synthesis (3.Coleman R.A. Mashek D.G. Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling.Chem. Rev. 2011; 111: 6359-6386Crossref PubMed Scopus (170) Google Scholar). When GPAT1 is absent, acetate incorporation into TAG is almost totally blocked, and its incorporation into phospholipids is diminished by 60–80% (21.Wendel A.A. Cooper D.E. Ilkayeva O.R. Muoio D.M. Coleman R.A. Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation.J. Biol. Chem. 2013; 288: 27299-27306Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Because FAS releases free palmitate, a specific ACSL must activate this FA and direct it to GPAT1, which, unlike GPAT3/4, has a twofold preference for saturated FAs (3.Coleman R.A. Mashek D.G. Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling.Chem. Rev. 2011; 111: 6359-6386Crossref PubMed Scopus (170) Google Scholar). Although none of the 13 ACSLs (22.Watkins P.A. Maiguel D. Jia Z. Pevsner J. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome.J. Lipid Res. 2007; 48: 2736-2750Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar) is a known target of SREBP-1c or ChREBP, both ACSL3 and ACSL5 are upregulated by refeeding a high carbohydrate diet after a 24 h fast (unpublished observations), suggesting that these isoforms might link DNL FAs to TAG synthesis. Although the “handoff” of LPA to a specific AGPAT or to a further downstream DAG acyltransferase (DGAT) isoenzyme would seem reasonable, no AGPAT, PAPase/lipin, or DGAT isoforms are known to be upregulated by SREBP-1c. In the absence of GPAT1, newly synthesized FAs are oxidized in the mitochondria, demonstrating the importance of the DNL-GPAT1 liaison in avoiding a futile cycle by preventing the immediate degradation of newly synthesized FAs (Fig. 1) (23.Hammond L.E. Neschen S. Romanelli A.J. Cline G.W. Ilkayeva O.R. Shulman G.I. Muoio D.M. Coleman R.A. Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs.J. Biol. Chem. 2005; 280: 25629-25636Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Because each of the GPAT isoforms uses the same substrates, the most likely mechanism by which long-chain acyl-CoAs can be channeled into specific downstream pathways is via close interactions between the pathway enzymes to traffic newly synthesized FAs into TAG synthesis. Thus, GPAT1 and at least some of the enzymes indicated in yellow and green (Fig. 3) must interact, even though their locations are in separate cellular areas (cytosol, OMM, and ER) (3.Coleman R.A. Mashek D.G. Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling.Chem. Rev. 2011; 111: 6359-6386Crossref PubMed Scopus (170) Google Scholar). Furthermore, because TAG synthesis occurs primarily at the ER (24.Poppelreuther M. Sander S. Minden F. Dietz M.S. Exner T. Du C. Zhang I. Ehehalt F. Knuppel L. Domschke S. et al.The metabolic capacity of lipid droplet localized acyl-CoA synthetase 3 is not sufficient to support local triglyceride synthesis independent of the endoplasmic reticulum in A431 cells.Biochim. Biophys. Acta. Mol. Cell Biol. Lipids. 2018; 1863: 614-624Crossref PubMed Scopus (16) Google Scholar), it also follows that additional downstream enzymes may be integrated with this pathway. Thus, excess oxidation of DNL FAs in the absence of GPAT1 protects against diet-induced insulin resistance (25.Neschen S. Morino K. Hammond L.E. Zhang D. Liu Z.X. Romanelli A.J. Cline G.W. Pongratz R.L. Zhang X.M. Choi C.S. et al.Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knock out mice.Cell Metab. 2005; 2: 55-65Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar), decreases hepatic steatosis and VLDL secretion in chow-fed and high fat-fed mice (26.Hammond L.E. Gallagher P.A. Wang S. Hiller S. Kluckman K.D. Posey-Marcos E.L. Maeda N. Coleman R.A. Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition.Mol. Cell. Biol. 2002; 22: 8204-8214Crossref PubMed Scopus (161) Google Scholar), and reverses preexisting hepatic steatosis in ob/ob mice (27.Wendel A.A. Li L.O. Li Y. Cline G.W. Shulman G.I. Coleman R.A. Glycerol-3-phosphate acyltransferase 1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance or obesity.Diabetes. 2010; 59: 1321-1329Crossref PubMed Scopus (44) Google Scholar). During fasting, when insulin is low, GPAT1 mRNA, protein, and activity decrease, so that FAs that enter the liver from lipolyzed adipose TAG are either oxidized or esterified, presumably by GPAT3 and -4. Despite its importance in initiating TAG synthesis, little is known about the acute regulation of GPAT1 or other enzymes in the TAG synthetic pathway. AMP-activated kinase inhibits (28.Muoio D.M. Seefeld K. Witters L.A. Coleman R.A. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target.Biochem. J. 1999; 338: 783-791Crossref PubMed Scopus (345) Google Scholar) and casein kinase-II stimulates (29.Onorato T.M. Chakraborty S. Haldar D. Phosphorylation of rat liver mitochondrial glycerol-3-phosphate acyltransferase by casein kinase 2.J. Biol. Chem. 2005; 280: 19527-19534Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar) hepatic GPAT1 activity, but no functional consequences are known. Does inhibiting or inducing lipolysis with insulin, glucose deprivation, or AMPK activation alter the ability of GPAT1 to use de novo synthesized FAs, cause impaired insulin signaling, or modify the binding of specific proteins to GPAT1? Supporting the idea that the different GPATs are not functionally equivalent and that cytosolic FA pools do not mix is the fact that markedly different phenotypes are observed in Gpat1-, Gpat3-, and Gpat4-null mice (21.Wendel A.A. Cooper D.E. Ilkayeva O.R. Muoio D.M. Coleman R.A. Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation.J. Biol. Chem. 2013; 288: 27299-27306Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 23.Hammond L.E. Neschen S. Romanelli A.J. Cline G.W. Ilkayeva O.R. Shulman G.I. Muoio D.M. Coleman R.A. Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs.J. Biol. Chem. 2005; 280: 25629-25636Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 26.Hammond L.E. Gallagher P.A. Wang S. Hiller S. Kluckman K.D. Posey-Marcos E.L. Maeda N. Coleman R.A. Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition.Mol. Cell. Biol. 2002; 22: 8204-8214Crossref PubMed Scopus (161) Google Scholar, 30.Vergnes L. Beigneux A.P. Davis R.G. Watkins S.M. Young S.G. Reue K. Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity.J. Lipid Res. 2006; 47: 745-754Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 31.Beigneux A.P. Vergnes L. Qiao X. Quatela S. Davis R. Watkins S.M. Coleman R.A. Walzem R.L. Philips M. Reue K. et al.Agpat6–a novel lipid biosynthetic gene required for triacylglycerol production in mammary epithelium.J. Lipid Res. 2006; 47: 734-744Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 32.Cao J. Li J.L. Li D. Tobin J.F. Gimeno R.E. Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase, a key enzyme in de novo triacylglycerol synthesis.Proc. Natl. Acad. Sci. USA. 2006; 103: 19695-19700Crossref PubMed Scopus (166) Google Scholar, 33.Cooper D.E. Grevengoed T.J. Klett E.L. Coleman R.A. Glycerol-3-phosphate acyltransferase isoform-4 (GPAT4) limits oxidation of exogenous fatty acids in brown adipocytes.J. Biol. Chem. 2015; 290: 15112-15120Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). Each of these studies was carried out in whole-body knockout models, so information from isolated hepatocytes may be more relevant than the liver phenotype itself. Although GPAT3 and -4 have been less well studied, GPAT4 may contribute primarily to phospholipid synthesis (34.Nagle C.A. Vergnes L. Dejong H. Wang S. Lewin T.M. Reue K. Coleman R.A. Identification of a novel sn-glycerol-3-phosphate acyltransferase isoform, GPAT4, as the enzyme deficient in Agpat6−/− mice.J. Lipid Res. 2008; 49: 823-831Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 35.Chen Y.Q. Kuo M.S. Li S. Bui H.H. Peake D.A. Sanders P.E. Thibodeaux S.J. Chu S. Qian Y.W. Zhao Y. et al.AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase (GPAT).J. Biol. Chem. 2008; 283: 10048-10057Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Differences are also observed in hepatic signaling via mTORC2; both GPAT1 and GPAT4, but not GPAT3, initiate the synthesis of DAG and PA, the intermediates that inhibit mTORC2 phosphorylation of Akt and impair insulin signaling (36.Zhang C. Cooper D.E. Grevengoed T.J. Li L.O. Klett E.L. Eaton J.M. Harris T.E. Coleman R.A. Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor.Am. J. Physiol. Endocrinol. Metab. 2014; 307: E305-E315Crossref PubMed Scopus (24) Google Scholar, 37.Zhang C. Wendel A.A. Keogh M.R. Harris T.E. Chen J. Coleman R.A. Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling.Proc. Natl. Acad. Sci. USA. 2012; 109: 1667-1672Crossref PubMed Scopus (79) Google Scholar). Differential signaling is consistent with the presence of compartmentalized lipid intermediates. To reconcile the experimental data, we propose that the ACSLs and GPATs are part of compartmentalized pathways that are organized by multi-enzyme assemblies; the metabolites would be channeled to enzymes in a sequential manner without equilibrating with the cytosolic aqueous phase or nearby membrane monolayers. Channeling involves what Paul Srere defined as a metabolon, a supramolecular complex of sequential metabolic enzymes and cellular structural elements (38.Srere P.A. Complexes of sequential metabolic enzymes.Annu. Rev. Biochem. 1987; 56: 89-124Crossref PubMed Scopus (806) Google Scholar, 39.Ovádi J. Srere P.A. Macromolecular compartmentation and channeling.Int. Rev. Cytol. 2000; 192: 255-280Crossref PubMed Google Scholar). In addition to intracellular organelles, the cytosol also appears to be structurally organized, as observed in centrifuged Neurospora and Euglena in which cell contents were layered with a final top “cytosolic” layer, surprisingly devoid of macromolecules (40.Kempner E.S. Miller J.H. The molecular biology of Euglena gracilis. IV. Cellular stratification by centrifuging.Exp. Cell Res. 1968; 51: 141-149Crossref PubMed Scopus (34) Google Scholar, 41.Zalokar M. Cytochemistry of centrifuged hyphae of Neurospora.Exp. Cell Res. 1960; 19: 114-132Crossref PubMed Scopus (37) Google Scholar). Substrates might be channeled within metabolons by movement along protein surfaces, by tunneling within associated proteins (42.Hyde C.C. Ahmed S.A. Padlan E.A. Miles E.W. Davies D.R. Three-dimensional structure of the tryptophan synthase alpha 2 beta 2 multienzyme complex from Salmonella typhimurium.J. Biol. Chem. 1988; 263: 17857-17871Abstract Full Text PDF PubMed Google Scholar), or by probabilistic channeling within a large group of clustered proteins (Fig. 4). The clustered proteins might interact directly or via scaffolding to regional structural or membrane proteins. It has been proposed that surface movements could occur via electrostatic interactions with the substrate (43.Sweetlove L.J. Fernie A.R. The role of dynamic enzyme assemblies and substrate channelling in metabolic regulation.Nat. Commun. 2018; 9: 2136Crossref PubMed Scopus (189) Google Scholar), which would be possible with acyl-CoAs, but perhaps not with their downstream glycerolipid intermediates. More likely is the idea of clustered scaffolded proteins like glycogen granules that contain metabolic enzymes and regulatory kinases and phosphatases (44.Roach P.J. Depaoli-Roach A.A. Hurley T.D. Tagliabracci V.S. Glycogen and its metabolism: some new developments and old themes.Biochem. J. 2012; 441: 763-787Crossref PubMed Scopus (400) Google Scholar). The textbook concept of enzyme pathways underlies traditional analyses of enzyme kinetics. Thus, isolated proteins are evaluated for substrate affinity, substrate preference, and Vmax. This is particularly problematic with enzymes that metabolize lipids. In such cases, Kornberg's “Commandment IV”, “Do not waste clean thinking on dirty enzymes,” (Ref. 45; p. 3614) must give way to his subsequent thought that for some analyses, the marked dilution of proteins in solution must be restored to the more normal crowded molecular state (“Commandment VII”) (45.Kornberg A. Ten commandments: lessons from the enzymology of DNA replication.J. Bacteriol. 2000; 182: 3613-3618Crossref PubMed Scopus (77) Google Scholar). Molecular dilution is even more of a problem for membrane-associated enzymes in which substrates are likely to be highly concentrated within the membrane mono- or bilayer. For example, the acyl-CoA “concentration” within a cell is a meaningless number unless one considers the amount near the GPAT1 active site at the membrane-cytosol interface. Even cations and molecules such as Na, K, ATP, amino acids, and glucose are probably not distributed uniformly within the cytosol (38.Srere P.A. Complexes of sequential metabolic enzymes.Annu. Rev. Biochem. 1987; 56: 89-124Crossref PubMed Scopus (806) Google Scholar). As multi-enzyme assemblies, pathway efficiency should be enhanced because substrates and intermediates are not diluted into the bulk phase, but instead, remain near potential subsequent proteins where they can interact productively with active sites. This process allows for better regulation of the steady state flux and ensures associations that can enhance the stability of intermediates and avoid interference by other cellular constituents. The interactome can increase reaction rates by increasing local substrate concentrations and by restricting intermediates from entering competing reactions. Moreover, this concept does not preclude “leakiness” that permits substrates to enter branch-point pathways. We propose that protein interactomes constitute novel and unexplored regulatory mechanisms that facilitate FA and acyl-CoA channeling and metabolism. The interactions of multi-enzyme assemblies might be direct via surface binding or via structural proteins that form a scaffold for multiple members of the pathway interactome. These interactions might be transient, as observed with purinosomes that form in the cytosol to enhance purine synthesis (46.Pedley A.M. Benkovic S.J. A new view into the regulation of purine metabolism: the purinosome.Trends Biochem. Sci. 2017; 42: 141-154Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar) or with the insulin signaling pathway that forms and disassembles depending on the interaction of insulin with its receptor (47.Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms.J. Endocrinol. 2014; 220: T1-T23Crossref PubMed Scopus (9) Google Scholar). In addition to the described interactomes for ACSL1 and GPAT1, we predict that other pathways that metabolize lipids will prove to exist in similar physiologically regulated protein interactomes. The author is grateful to Dr. Florencia Pascual for her insightful comments. acyl-CoA synthetase diacylglycerol diacylglycerol acyltransferase de novo lipogenesis glycerol-3-phosphate acyltransferase lysophosphatidic acid outer mitochondrial membrane phosphatidic acid triacylglycerol" @default.
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• W2912778549 title "It takes a village: channeling fatty acid metabolism and triacylglycerol formation via protein interactomes" @default.
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