Targeted Deletion of Fatty Acid Transport Protein-4 Results in Early Embryonic Lethality

Gimeno, Ruth E.; Hirsch, David J.; Punreddy, Sandhya; Sun, Ying; Ortegon, Angelica M.; Wu, Hui; Daniels, Tom; Stricker–Krongrad, Alain; Lodish, Harvey F.; Stahl, Andreas

doi:10.1074/jbc.m309759200

Cited by 126 publications

(99 citation statements)

References 39 publications

(45 reference statements)

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“…The fact that a positive relationship exists between FATP-4 protein and LCFA uptake by enterocytes in FATP4 1/2 mice is consistent with this assumption (22).…”

Section: Discussionsupporting

confidence: 75%

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

Petit

Arnould́

Martin³

et al. 2007

Journal of Lipid Research

117

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The effects of chronic fat overconsumption on intestinal physiology and lipid metabolism remain elusive. It is unknown whether a fat-mediated adaptation to lipid absorption takes place. To address this issue, mice fed a high-fat diet (40%, w/w) were refed or not a control diet (3%, w/w) for 3 additive weeks. Despite daily lipid intake 7.7-fold higher than in controls, fecal lipid output remained unchanged in mice fed the triglyceride (TG)-rich diet. In situ isolated jejunal loops revealed greater [1-14 C]linoleic acid uptake without TG accumulation in mucosa, suggesting an increase in lipid absorption capacity. Induction both in intestinal mitotic index and in the expression of genes involved in fatty acid uptake, trafficking, and lipoprotein synthesis was found in high-fat diet mice. These changes were lipid-mediated, in that they were fully abolished in mice refed the control diet. A lipid load test performed in the presence or absence of the LPL inhibitor tyloxapol showed a sustained blood TG clearance in fat-fed mice likely attributable to intestinal modulation of LPL regulators (apolipoproteins C-II and C-III). These data demonstrate that a chronic high-fat diet greatly affects intestinal physiology and body lipid use in the mouse.-Petit, V., L. Arnould, P. Martin, M-C. Monnot, T. Pineau, P. Besnard, and I. Niot. Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse. J. Lipid Res.

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“…The fact that a positive relationship exists between FATP-4 protein and LCFA uptake by enterocytes in FATP4 1/2 mice is consistent with this assumption (22).…”

Section: Discussionsupporting

confidence: 75%

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

Petit

Arnould́

Martin³

et al. 2007

Journal of Lipid Research

117

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“…More recently, blocking of FATP4 function has been targeted as an alternative treatment to pancreatic lipase inhibitors for inhibition of fat absorption. Using targeted deletion, Gimeno et al [38] demonstrated that the loss of one allele of FATP4 in mice reduced fatty acid uptake but did not alter fat absorption on either a normal-fat diet or a high-fat diet. Deletion of both FATP4 alleles, however, resulted in embryonic lethality.…”

Section: Gene Expressionmentioning

confidence: 99%

β-Glucan extracts inhibit the in vitro intestinal uptake of long-chain fatty acids and cholesterol and down-regulate genes involved in lipogenesis and lipid transport in rats☆

Drozdowski

Reimer

Temelli

et al. 2010

The Journal of Nutritional Biochemistry

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Background-Dietary fiber reduces the intestinal absorption of nutrients and the blood concentrations of cholesterol and triglycerides.Aim-We wished to test the hypothesis that high-viscosity (HV) and low-viscosity preparations of barley and oat β-glucan modify the expression of selected genes of lipid-binding proteins in the intestinal mucosa and reduce the intestinal in vitro uptake of lipids.Methods-Five different β-glucan extracts were separately added to test solutions at concentrations of 0.1-0.5% (wt/wt), and the in vitro intestinal uptake of lipids into the intestine of rats was assessed. An intestinal cell line was used to determine the effect of β-glucan extracts on the expression of intestinal genes involved in lipid metabolism and fatty acid transport.Results-All extracts reduced the uptake of 18:2 when the effective resistance of the unstirred water layer was high. When the unstirred layer resistance was low, the HV oat β-glucan extract reduced jejunal 18:2 uptake, while most extracts reduced ileal 18:2 uptake. Ileal 18:0 uptake was reduced by the HV barley extract, while both jejunal and ileal cholesterol uptakes were reduced by the medium-purity HV barley extract. The inhibitory effect of HV barley β-glucan on 18:0 and 18:2 uptake was more pronounced at higher fatty acid concentrations. The expression of genes involved in fatty acid synthesis and cholesterol metabolism was down-regulated with the HV β-glucan extracts. β-Glucan extracts also reduced intestinal fatty-acid-binding protein and fatty acid transport protein 4 mRNA.Conclusions-The reduced intestinal fatty acid uptake observed with β-glucan is associated with inhibition of genes regulating intestinal uptake and synthesis of lipids. The inhibitory effect of β-glucan on intestinal lipid uptake raises the possibility of their selective use to reduce their intestinal absorption.☆ Laurie A. Drozdowski and Raylene A. Reimer contributed equally to this publication.

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“…For example, ACSL6 preferentially activates very-long-chain polyunsaturated FAs, and when ACSL6 is overexpressed in PC12 neurons, it enhances the uptake and metabolism of docosahexaenoic acid relative to oleic acid [44]. In the several mouse models that lack FATP4 (Table 3), mice are variably characterized by altered epidermal FA composition accompanied by a neonatally lethal restrictive dermopathy [45], altered skin development, impaired hair growth and abnormal lipid metabolism [46], and early embryonic lethality [47]. 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].…”

Section: Role Of Acyl-coa Synthetases In Fa Channelingmentioning

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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Targeted Deletion of Fatty Acid Transport Protein-4 Results in Early Embryonic Lethality

Cited by 126 publications

References 39 publications

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

β-Glucan extracts inhibit the in vitro intestinal uptake of long-chain fatty acids and cholesterol and down-regulate genes involved in lipogenesis and lipid transport in rats☆

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

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