Enzymatic Properties of Purified Murine Fatty Acid Transport Protein 4 and Analysis of Acyl-CoA Synthetase Activities in Tissues from FATP4 Null Mice

Hall, A. Rupert; Wiczer, Brian M.; Herrmann, Thomas; Stremmel, Wolfgang; Bernlohr, David A.

doi:10.1074/jbc.m412629200

Cited by 138 publications

(118 citation statements)

References 25 publications

(33 reference statements)

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…This function appears to require the very long chain ACS activity that has been attributed to FATP4 (4) and that we have demonstrated herein to be necessary for the rescue of the Fatp4 Ϫ/Ϫ phenotype. Hall et al (41) showed a virtual absence of very long chain ACS activity in the skin of Fatp4 Ϫ/Ϫ mice, despite the fact that FATP1, FATP3, and FATP6 should still be present (52). These results point to a lack of FATP functional redundancy in suprabasal keratinocytes, as suggested previously by yeast complementation assays (39), and underscore the importance of FATP4.…”

Section: Fatp4supporting

confidence: 64%

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

View full text Add to dashboard Cite

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 ...

show abstract

Section: Fatp4supporting

confidence: 64%

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

View full text Add to dashboard Cite

show abstract

“…The lack of differences in the amount of tracer entering brain aqueous fraction, which represents products of β-oxidation (46,(67)(68)(69) (Figure 3), indicates that α-synuclein does not impact the mitochondrial pool relative to the endoplasmic reticulum pool, similar to the effect observed using 16:0 (29). Moreover, fatty acid transport protein (FATP) is associated with plasma membrane and exhibits both fatty acid transport and acyl-CoA synthetase activities (90)(91)(92) and FATP-4 is expressed in the brain (93). The potential involvement of this enzyme in acyl-CoA formation may account for the lack of differences between the groups in whole brain homogenate acyl-CoA activity and the similar incorporation coefficients for 20:4n-6 from the plasma into the total brain acyl-CoA pool.…”

Section: Discussionmentioning

confidence: 99%

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

et al. 2006

View full text Add to dashboard Cite

Because α-synuclein (Snca) has a role in brain lipid metabolism, we determined the impact that the loss of α-synuclein had on brain arachidonic acid (20:4n-6) metabolism in vivo using Snca -/-mice. We measured [1-14 C]20:4n-6 incorporation and turnover kinetics in brain phospholipids using an established steady-state kinetic model. Liver was used as a negative control and no changes were observed between groups. In Snca -/-brains, there was a marked reduction in 20:4n-6-CoA mass and in microsomal acyl-CoA synthetases (Acsl) activity toward 20:4n-6. Microsomal Acsl activity was completely restored after the addition of exogenous wt mouse or human α-synuclein, but not by A30P, E46K, and A53T forms of α-synuclein. Acsl and acyl-CoA hydrolase expression was not different between groups. The incorporation and turnover of 20:4n-6 into brain phospholipid pools was markedly reduced. The dilution coefficient lambda, which indicates 20:4n-6 recycling between the acyl-CoA pool and brain phospholipids, was increased 3.3-fold, indicating more 20:4n-6 was entering the 20:4n-6-CoA pool from the plasma relative to that being recycled from the phospholipids. This is consistent with the reduction in Acsl activity observed in the Snca -/-mice. Using titration microcalorimetry, we determined that α-synuclein bound free 20:4n-6 (K d of 3.7 μM), but did not bind 20:4n-6-CoA. These data suggest α-synuclein is involved in substrate presentation to Acsl rather than product removal. In summary, our data demonstrate that α-synuclein has a major role in brain 20:4n-6 metabolism through its modulation of endoplasmic reticulum localized acyl-CoA synthetase activity, although mutants forms of α-synuclein fail to restore this activity. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript α-Synuclein is a 140 amino acid soluble protein that is highly expressed in the central nervous system (1,2) and is abundant in presynaptic terminals of neurons (1,(3)(4)(5). α-Synuclein is also found in other regions of neurons, in astrocytes, and in oligodendroglia (6-11). Overexpression of and mutations in α-synuclein are associated with early onset Parkinson's disease (12)(13)(14)(15) and other neurodegenerative diseases (16)(17)(18)(19)(20). Despite this association with neurodegenerative diseases, the physiological function of this protein remains unclear.Several lines of evidence suggest that α-synuclein can influence brain lipid metabolism. It has structural similarities to class A2 apolipoproteins (21,22) and to fatty acid binding proteins (23), suggesting that α-synuclein may alter intracellular lipid trafficking, the regulation of lipid metabolism, and may act to stabilize lipid membranes. α-Synuclein binds to small phospholipid vesicles (22,24,25) and to brain vesicles (26). Consistent with this binding, the lack of α-synuclein decreases the resting/reserve pool of synaptic vesicles (27,28). Although the direct binding of fatty acids is controversial (23,29), recent studies indicate a strong potential for an important ...

show abstract

“…Conversely, FATP4 has a high ACSL reaction rate relative to FATP1 and ACSL1 and has a substrate preference for very long-chain (C24:0) over long-chain (C16:0) fatty acids (21). To evaluate the effect of FATP1 kd and FATP4 kd on total cellular ACSL activity, extracts were prepared and assayed for fatty acid esterification using a variety of fatty acid substrates.…”

Section: Resultsmentioning

confidence: 99%

“…FATP4 null mice displayed features of a human neonatally lethal restrictive dermopathy that has been associated with a disturbed function in the epidermal barrier (18)(19)(20). FATP4 encodes an ACSL with substrate specificity to very LCFAs that may be required for the synthesis of lipids crucial in the formation of a healthy epidermis (21,22). Polymorphisms in the human FATP4 gene locus have identified this gene as a candidate for the insulin resistance syndrome (23).…”

mentioning

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

Self Cite

128

116

View full text Add to dashboard Cite

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.

show abstract

Enzymatic Properties of Purified Murine Fatty Acid Transport Protein 4 and Analysis of Acyl-CoA Synthetase Activities in Tissues from FATP4 Null Mice

Cited by 138 publications

References 25 publications

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

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

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

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

Contact Info

Product

Resources

About