Cellular uptake of fatty acids driven by the ER-localized acyl-CoA synthetase FATP4

Milger, Katrin; Herrmann, Thomas; Becker, Christiane; Gotthardt, Daniel; Zickwolf, Jelena; Ehehalt, Robert; Watkins, Paul A.; Stremmel, Wolfgang; Füllekrug, Joachim

doi:10.1242/jcs.03280

Cited by 202 publications

(239 citation statements)

References 68 publications

(75 reference statements)

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“…Our results with FATP4 kd adipocytes indicate that although FATP4 has a high ACSL reaction rate relative to FATP1 and ACSL1, it is localized to internal membranes and not the plasma membrane, which could be the reason why it does not contribute to either insulin-stimulated or basal fatty acid uptake. In contrast to our studies, FATP4 overexpressed in COS cells (which too was localized to the endoplasmic reticulum) did result in a net increase in LCFA influx (39). It is not clear whether these contradictory findings are the result of differences in the absolute level of FATP4 expression, differences in experimental assay conditions, or simply a difference in the cell culture system used.…”

Section: Discussioncontrasting

confidence: 99%

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

Lobo

Wiczer

Smith

et al. 2007

Journal of Lipid Research

129

116

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The role of fatty acid transport protein 1 (FATP1) and FATP4 in facilitating adipocyte fatty acid metabolism was investigated using stable FATP1 or FATP4 knockdown (kd) 3T3-L1 cell lines derived from retrovirus-delivered short hairpin RNA (shRNA). Decreased expression of FATP1 or FATP4 did not affect preadipocyte differentiation or the expression of FATP1 (in FATP4 kd), FATP4 (in FATP1 kd), fatty acid translocase, acyl-coenzyme A synthetase 1, and adipocyte fatty acid binding protein but did lead to increased levels of peroxisome proliferator-activated receptor g and CCAAT/enhancer binding protein a. Both FATP1 and FATP4 kd adipocytes exhibited reduced triacylglycerol deposition and corresponding reductions in diacylglycerol and monoacylglycerol levels compared with control cells. FATP1 kd adipocytes displayed an ?25% reduction in basal 3 H-labeled fatty acid uptake and a complete loss of insulin-stimulated 3 H-labeled fatty acid uptake compared with control adipocytes. In contrast, FATP4 kd adipocytes as well as HEK-293 cells overexpressing FATP4 did not display any changes in fatty acid influx. FATP4 kd cells exhibited increased basal lipolysis, whereas FATP1 kd cells exhibited no change in lipolytic capacity. Consistent with reduced triacylglycerol accumulation, FATP1 and FATP4 kd adipocytes exhibited enhanced 2-deoxyglucose uptake compared with control adipocytes. These findings define unique and distinct roles for FATP1 and FATP4 in adipose fatty acid metabolism.

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Section: Discussioncontrasting

confidence: 99%

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

Lobo

Wiczer

Smith

et al. 2007

Journal of Lipid Research

129

116

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“…Altering these critical residues inhibits ACS activity (43,44) and blocks uptake of Bodipy B 12 -FA (Ref. 42 and personal observations). The ⌬Fatp4 cDNA was placed under the control of the involucrin promoter and microinjected to make several lines of transgenic mice, three of which were shown to express the transgene well by Northern analysis (Fig.…”

Section: Molecular Analysis Of Ceramide Fatty Acid Composition-mentioning

confidence: 98%

“…Expression of a Mutated FATP4 Does Not Rescue the Skin Phenotype-FATP4 has a conserved ACS domain, and the ACS activity of FATP4 is thought to drive fatty acid uptake (4, 38 -41), as demonstrated most recently by transfections of WT and ACS mutant FATP4 into cells (42). To investigate the role of ACS activity in FATP4 in vivo, and to determine whether FATP4 might exhibit any function in the absence of ACS activity, we generated a Fatp4 cDNA (⌬Fatp4) carrying two amino acid substitutions, S247G and T249G.…”

Section: Molecular Analysis Of Ceramide Fatty Acid Composition-mentioning

confidence: 99%

Keratinocyte-specific Expression of Fatty Acid Transport Protein 4 Rescues the Wrinkle-free Phenotype in Slc27a4/Fatp4 Mutant Mice

Moulson

Lin

White

et al. 2007

Journal of Biological Chemistry

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FATP4 (fatty acid transport protein 4; also known as SLC27A4) is the most widely expressed member of a family of six long chain fatty acid transporters. FATP4 is highly expressed in enterocytes and has therefore been proposed to be a major importer of dietary fatty acids. Two independent mutations in Fatp4 cause mice to be born with thick, tight, shiny, "wrinklefree" skin and a defective skin barrier; they die within hours of birth from dehydration and restricted movements. In contrast, induced keratinocyte-specific deficiency of FATP4 in adult mice causes only mild skin abnormalities. Therefore, whether the loss of FATP4 from skin or a systemic gestational metabolic defect causes the severe skin defects and neonatal lethality remain important unanswered questions. To investigate the basis for the phenotype, we first generated wild-type tetraploid/mutant diploid aggregates that should lead to rescue of any abnormalities caused by loss of FATP4 from the placenta. However, the skin phenotype was not ameliorated. We then generated transgenic mice expressing exogenous FATP4 either widely or specifically in suprabasal keratinocytes, and we bred the transgenes onto the Fatp4 ؊/؊ background. Both modes of FATP4 expression led to rescue of the neonatally lethal skin defects, and the resulting mice were viable and fertile. Keratinocyte expression of an FATP4 variant with mutations in the acyl-CoA synthetase domain did not provide any degree of rescue. We conclude that expression of FATP4 with an intact acyl-CoA synthetase domain in suprabasal keratinocytes is necessary for normal skin development and that FATP4 functions in establishing the cornified envelope. Fatty acid transport proteins (FATPs)2 compose a family of transmembrane proteins that facilitate cellular long chain fatty acid uptake (1-3). The most widely expressed member of this family is FATP4 (4, 5), which is encoded by Slc27a4 (solute carrier family 27 member 4 gene). The most robust expression of FATP4 is in intestinal epithelial cells (5), but its broad expression pattern is suggestive of functions in many organs.Surprisingly, the "wrinkle-free" phenotype we discovered in mice with a spontaneous mutation in Slc27a4 (Slc27a4 wrfr ) and the identical phenotype of mice with a targeted Slc27a4 mutation (Slc27a4) indicate critical roles for FATP4 in skin and hair development (6, 7). For these mutations, which both affect exon 3, homozygotes are born with tight, thick, shiny skin and a defective skin barrier; they die shortly after birth because of restricted movements and dehydration. These defects are reminiscent of human restrictive dermopathy, but this disease has recently been linked to mutations in zinc metalloproteinase STE24 (8 -10). Interestingly, deletion of Slc27a4 exons 2 and 3 (the first two coding exons; Slc27a4 tm1Asta ) results in embryonic lethality prior to embryonic day 9.5 (11). The reason for the striking difference in phenotypes remains unknown, but it may involve a partially functional truncated protein in the first two mutants or early ...

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“…For example, overexpressing ACSL and FATP isoforms increases FA uptake despite the fact that ACSL1 [15,23], ACSL4 [24], ACSL5 [25], and FATP4 [15] are located only on intracellular organelles in the cells examined. (FATP4 is present on the apical side of enterocytes but it was not located to a specific membrane [26]).…”

Section: Role Of Acyl-coa Synthetases In Modulating Fa Uptakementioning

confidence: 99%

“…Not only can several ACSL isoforms be present in different subcellular locations within a single cell, but a single ACSL isoform may vary in its subcellular location. For example, ACSL1 has been reported to be located on the plasma membrane [12] and in GLUT4 vesicles [13] in adipocytes, and on the ER in hepatocytes [14] and mitochondria in epithelial cells [15]. Cell-specific differences in location could arise by differential splicing or proteinprotein interactions, both of which may contribute to tissue-specific functions.…”

mentioning

confidence: 99%

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

2007

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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...

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Cellular uptake of fatty acids driven by the ER-localized acyl-CoA synthetase FATP4

Cited by 202 publications

References 68 publications

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

Keratinocyte-specific Expression of Fatty Acid Transport Protein 4 Rescues the Wrinkle-free Phenotype in Slc27a4/Fatp4 Mutant Mice

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

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