Fatty Acid Transport Protein 4 Is the Principal Very Long Chain Fatty Acyl-CoA Synthetase in Skin Fibroblasts

Jia, Zhenzhen; Moulson, Casey L.; Pei, Zhengtong; Miner, Jeffrey H.; Watkins, Paul A.

doi:10.1074/jbc.m700568200

Cited by 102 publications

(103 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The decreased amount of very-long-chain FAs in tissues from FATP4 knockouts supports data from ACS activity assays showing that FATP4 prefers very-long-chain FAs over long chain FAs [45]. Supporting this interpretation are data from fibroblasts from FATP4 null mice in which the rate of 24:0 degradation and incorporation into phospholipids, TAG and cholesterol esters were diminished [1]. In contrast, compared to wild type controls, livers from FATP5 null mice contain 60% less TAG, a greater decrease in saturated and polyunsaturated FAs in TAG relative to monounsaturated FA, and 37% lower unesterified FA [21].…”

Section: Role Of Acyl-coa Synthetases In Fa Channelingsupporting

confidence: 71%

“…[6, 48] ER, nuclear fraction, plasma membrane (3T3-L1 adipocytes) [12]; GLUT4 vesicle (rat adipocytes) [13]; mitochondria (PtK2 epithelial cells) [15]; ER, MAM, cytosol (rat liver) [79]; lipid droplet fraction (3T3-L1 adipocytes) [80] Triacsin C [35,81] NP_001986 ACSL3 Brain, gonads [48,82] Lipid droplet fraction (3T3-L1 adipocytes [80]; HuH7 cells [83]; CHO cells [84]; epithelial A431 cells [85]; HepG2 cells [86] Triacsin [26]; plasma membrane (mouse adipocytes) [20]; ER (multiple cell lines) [15]; mitochondria, nuclei, MAM, peroxisomes (skin fibroblasts) [1] n-dodecyl-D-maltopyranoside, …”

Section: Unanswered Questionsmentioning

confidence: 99%

“…The ACS family is comprised of at least 25 members [1]. Although overlap exists, ACS family members are broadly classified by their substrate specificities for FAs of varying chain length.…”

Section: A Family Of Acyl-coa Synthetases Activates Intracellular Lonmentioning

confidence: 99%

See 2 more Smart Citations

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

2007

View full text Add to dashboard Cite

Thirteen homologous proteins comprise the long-chain acyl-CoA synthetase (ACSL), fatty acid transport protein (FATP), and bubblegum (ACSBG) subfamilies that activate long-chain and verylong-chain fatty acids to form acyl-CoAs. Gain-and loss-of-function studies show marked differences in the ability of these enzymes to channel fatty acids into different pathways of complex lipid synthesis. Further, the ability of the ACSLs and FATPs to enhance cellular FA uptake does not always require these proteins to be present on the plasma membrane; instead, FA uptake can be increased by enhancing its conversion to acyl-CoA and its metabolism in downstream pathways. Since altered fatty acid metabolism is a hallmark of numerous metabolic diseases and pathological conditions, the ACSL, FATP and ACSBG isoforms are likely to play important roles in disease etiology. A family of acyl-CoA synthetases activates intracellular long-chain fatty acidsBefore a fatty acid (FA) from an exogenous or endogenous source can enter any metabolic pathway with the exception of eicosanoid metabolism, it must first be activated to form an acyl-CoA. This activation step is catalyzed by acyl-CoA synthetase (ACS) via a two-step reaction: 1) the formation of an intermediate fatty acyl-AMP with the release of pyrophosphate, and 2) the formation of a fatty acyl-CoA with the release of AMP.The ACS family is comprised of at least 25 members [1]. Although overlap exists, ACS family members are broadly classified by their substrate specificities for FAs of varying chain length. This review will focus on the three subfamilies of ACS enzymes that activate long-chain and/ or very-long-chain saturated and unsaturated FAs, long-chain ACSs (ACSL), very-long-chain ACSs (FATP), and bubblegum (ACSBG) isoforms [2].The ACSL, FATP and ACSBG families include multiple isoforms, each encoded by a separate gene (Tables 1, 2). Additionally, splice variants of ACSL isoforms have been identified in both humans and rodents [3]. ACS enzymes share significant amino acid sequence similarity, particularly in two highly conserved regions, a putative ATP-AMP signature motif for ATP binding and a motif for FA binding [4]. Despite these similarities, purified ACSL and FATP isoforms and their splice variants show distinct enzyme kinetics, differences in sensitivity to inhibitors ( Role of acyl-CoA synthetases in FA channelingThe existence of 13 ACSL, FATP and ACSBG isoforms that all activate long-chain FA has suggested that each has an independent role in channeling FA within cells. Unique roles for ACS isoforms were first identified in studies of Saccharomyces cerevisiae mutants that lacked the ACS isoforms Faa1 and Faa4, and were unable to use exogenously provided fatty acids [31]. Similarly, complementation studies of ACS-deficient E. coli showed that each of the 5 rat ACSL isoforms differs in its ability to channel FA into specific pathways like phospholipid synthesis and β-oxidation [32]. The ACSL and FATP isoforms also differ in their ability to complement FA uptake and a...

show abstract

Section: Role Of Acyl-coa Synthetases In Fa Channelingsupporting

confidence: 71%

Section: Unanswered Questionsmentioning

confidence: 99%

See 1 more Smart Citation

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

2007

View full text Add to dashboard Cite

show abstract

“…Within mammalian systems, several members of this family (FATP1, FATP2, FATP4 and FATP6) have been shown to participate in the transport of exogenous fatty acids into the cell [2][3][4][5][6][7][8][9][10][11]. Additionally, some also condense either very long chain fatty acids (FATP1, FATP2, FATP3 and FATP4) or bile acids (FATP5) with CoA for downstream metabolism [8,[12][13][14][15][16][17][18]. The first FATP (now designated FATP1) was identified using expression cloning from a cDNA library prepared from murine 3T3-L1 adipocytes, directly demonstrating the physiological role of this protein in the net accumulation of fatty acids across a biological membrane [9].…”

Section: Introductionmentioning

confidence: 99%

Functional domains of the fatty acid transport proteins: Studies using protein chimeras

DiRusso

Darwis

Obermeyer

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

View full text Add to dashboard Cite

SUMMARYFatty acid transport proteins (FATP) function in fatty acid trafficking pathways, several of which have been shown to participate in the transport of exogenous fatty acids into the cell. Members of this protein family also function as acyl CoA synthetases with specificity towards very long chain fatty acids or bile acids. These proteins have two identifying sequence motifs: The ATP/AMP motif, an approximately 100 amino acid segment required for ATP binding and common to members of the adenylate-forming super family of proteins, and the FATP/VLACS motif that consists of approximately 50 amino acid residues and is restricted to members of the FATP family. This latter motif has been implicated in fatty acid transport in the yeast FATP orthologue Fat1p. In the present studies using a yeast strain containing deletions in FAT1 (encoding Fat1p) and FAA1 (encoding the major acyl CoA synthetase (Acsl) Faa1p) as an experimental platform, the phenotypic and functional properties of specific murine FATP1-FATP4 and FATP6-FATP4 protein chimeras were evaluated in order to define elements within these proteins that further distinguish the fatty acid transport and activation functions. As expected from previous work FATP1 and FATP4 were functional in the fatty acid transport pathway, while and FATP6 was not. All three isoforms were able to activate the very long chain fatty acids arachidonate (C 20:4 ) and lignocerate (C 24:0 ), but with distinguishing activities between saturated and highly unsaturated ligands. A 73 amino acid segment common to FATP1 and FATP4 and between the ATP/AMP and FATP/VLACS motifs was identified by studying the chimeras, which is hypothesized to contribute to the transport function.

show abstract

“…16 More than two dozen proteins are concentrated in MAM (see Supplemental Table S1 at http://ajp.amjpathol.org), 15,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] including proteins involved in calcium homeostasis (eg, inositol triphosphate receptor isoform 3), in lipid metabolism (eg, fatty acid co-A ligase 4 [FACL4]), in intermediate metabolism (eg, glucose-6-phosphatase), in cholesterol metabolism (eg, acyl-coenzyme A:cholesterol acyltransferase 1), and in the transfer of lipids between the ER and mitochondria. A few nonenzymatic proteins are also concentrated in MAM (see Supplemental Table S1 at http://ajp.amjpathol.org), 15,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] suggesting that it is a domain of the ER with specialized functions. Contacts between the two organelles are maintained by MAMassociated proteins, such as phosphofurin acidic cluster sorting protein 2, which controls the apposition of mitochondria with the ER and which appears to stabilize and regulate the interaction of ER and mitochondria.…”

mentioning

confidence: 99%

Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Area‐Gómez

Groof

Boldogh

et al. 2009

The American Journal of Pathology

350

305

View full text Add to dashboard Cite

Presenilin-1 (PS1) and -2 (PS2), which when mutated cause familial Alzheimer disease, have been localized to numerous compartments of the cell, including the endoplasmic reticulum, Golgi, nuclear envelope, endosomes, lysosomes, the plasma membrane, and mitochondria. Using three complementary approaches, subcellular fractionation, ␥-secretase activity assays, and immunocytochemistry, we show that presenilins are highly enriched in a subcompartment of the endoplasmic reticulum that is associated with mitochondria and that forms a physical bridge between the two organelles, called endoplasmic reticulum-mitochondria-associated membranes. A localization of PS1 and PS2 in mitochondria-associated membranes may help reconcile the disparate hypotheses regarding the pathogenesis of Alzheimer disease and may explain many seemingly unrelated features of this devastating neurodegenerative disorder. Alzheimer disease (AD) is a late onset neurodegenerative disorder characterized by progressive neuronal loss, especially in the cortex and the hippocampus. 1 The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, consisting predominantly of ␤-amyloid (A␤), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau. 1The vast majority of AD is sporadic, but mutations in amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2) have been identified in the rarer familial form, which is similar to sporadic AD but has an earlier age of onset.PS1 and PS2 are aspartyl proteases that cleave their substrates within transmembrane regions. The active forms of PS1 and PS2 are N-and C-terminal fragments, which are produced by cleavage of full-length presenilin in its "loop" domain.2 PS1 and PS2 are components of the ␥-secretase complex that processes a number of plasma-membrane proteins, including Notch, Jagged, E-cadherin, and, most relevant to AD, APP. The ␥-secretase complex also contains three other structural subunits: APH1, nicastrin (also called APH2), and presenilin enhancer protein 2.2 Following cleavage of APP by ␤-secretase, ␥-secretase cleaves the ϳ100-aa C-terminal "␤-stub" to release small amyloidogenic fragments, 40-and 42-aa in length (A␤40 and A␤42), that have been implicated in the pathogenesis of AD, as well as a ϳ60-aa APP intracellular domain.

show abstract

Fatty Acid Transport Protein 4 Is the Principal Very Long Chain Fatty Acyl-CoA Synthetase in Skin Fibroblasts

Cited by 102 publications

References 49 publications

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

Functional domains of the fatty acid transport proteins: Studies using protein chimeras

Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Contact Info

Product

Resources

About