Insulin Causes Fatty Acid Transport Protein Translocation and Enhanced Fatty Acid Uptake in Adipocytes

Stahl, Andreas; Evans, James G.; Pattel, Shraddha; Hirsch, David J.; Lodish, Harvey F.

doi:10.1016/s1534-5807(02)00143-0

Cited by 216 publications

(264 citation statements)

References 30 publications

(11 reference statements)

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“…We (Fig. 3) and others (5) have shown that in 3T3-L1 adipocytes, insulin can stimulate the translocation of FATP1 from intracellular membranes to the plasma membrane. However, as opposed to GLUT4, only a small fraction (estimated to be ,10%) of total FATP1 translocated.…”

Section: Discussionsupporting

confidence: 55%

“…Although diffusion may play a fundamental role in the transbilayer movement of LCFA, molecular and genetic evidence from loss-or gain-of-function studies have identified a number of proteins facilitating some component of the fatty acid influx process (4)(5)(6)(7)(8). Proteins implicated in fatty acid uptake are fatty acid translocase (CD36), acyl-CoA synthetases [fatty acid transport protein (FATP) and acyl-coenzyme A synthetase (ACSL) family members], plasma membrane fatty acid binding protein, and caveolin-1.…”

mentioning

confidence: 99%

“…FATP1 is a 63 kDa protein localized primarily to highdensity membranes and to a lesser extent in the plasma and low-density membrane fractions of murine adipocytes and 3T3-L1 cells (5). FATP1 (as well as ACSL1) was identified using an expression clone strategy designed to identify proteins that enhanced LCFA uptake (11).…”

mentioning

confidence: 99%

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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

125

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: Discussionsupporting

confidence: 55%

mentioning

confidence: 99%

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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

125

116

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“…On the other hand, FATP1 dimerization may depend on the presence of chaperones in the endoplasmic reticulum or Golgi. FATP1 is co-translationally inserted into membranes and likely traffics from the endoplasmic reticulum to the Golgi to intracellular vesicles (25) prior to its appearance at the plasma membrane. It is unclear at what point FATP1 dimerization occurs.…”

Section: Discussionmentioning

confidence: 99%

Oligomerization of the Murine Fatty Acid Transport Protein 1

Richards

Listenberger

Kelly

et al. 2003

Journal of Biological Chemistry

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The 63-kDa murine fatty acid transport protein 1 (FATP1) was cloned on the basis of its ability to augment fatty acid import when overexpressed in mammalian cells. The membrane topology of this integral plasma membrane protein does not resemble that of polytopic membrane transporters for other substrates. Western blot analysis of 3T3-L1 adipocytes that natively express FATP1 demonstrate a prominent 130-kDa species as well as the expected 63-kDa FATP1, suggesting that this protein may participate in a cell surface transport protein complex. To test whether FATP1 is capable of oligomerization, we expressed functional FATP1 molecules with different amino-or carboxyl-terminal epitope tags in fibroblasts. These epitope-tagged proteins also form apparent higher molecular weight species. We show that, when expressed in the same cells, differentially tagged FATP1 proteins co-immunoprecipitate. The region between amino acid residues 191 and 475 is sufficient for association of differentially tagged truncated FATP1 constructs. When wild type FATP1 and the non-functional s250a FATP1 mutant are co-expressed in COS7 cells, mutant FATP1 has dominant inhibitory function in fatty acid uptake assays. Taken together, these results are consistent with a model in which FATP1 homodimeric complexes play an important role in cellular fatty acid import.

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“…Interestingly, insulin causes FATP1 and FATP4 to translocate from the ER to the plasma membrane, a process that could enable insulin to enhance FA uptake [20]. The location of FATP5 on the basal plasma membrane of hepatocytes [21] and FATP6 on the plasma membrane of monkey cardiac myocytes [22] suggest that a plasma membrane location is required to mediate FA uptake, since hepatocytes from mice lacking FATP5 have 50% lower rates of FA uptake and overexpressing FATP6 in HEK293 cells enhances FA uptake [21,22].…”

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

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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Insulin Causes Fatty Acid Transport Protein Translocation and Enhanced Fatty Acid Uptake in Adipocytes

Cited by 216 publications

References 30 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

Oligomerization of the Murine Fatty Acid Transport Protein 1

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

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