Tissue-specific Functions in the Fatty Acid-binding Protein Family

Storch, Judith; Thumser, Alfred E.

doi:10.1074/jbc.r110.135210

Cited by 287 publications

(237 citation statements)

References 56 publications

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“…The fundamental biochemical property of FakB that explains its role in exogenous FA incorporation is its ability to exchange a bound ligand (FA or acyl-PO 4 ) for a ligand embedded in a phospholipid bilayer. This type of exchange reaction is catalyzed by eukaryotic FA binding proteins (19)(20)(21). FakA phosphorylates FakB(FA) and the resulting FakB(acyl-PO 4 ) exchanges its bound acyl-PO 4 for a membrane FA, and the cycle repeats (Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of a two-component fatty acid kinase responsible for host fatty acid incorporation by Staphylococcus aureus

Parsons

Broussard

Bose

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

142

230

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Extracellular fatty acid incorporation into the phospholipids of Staphylococcus aureus occurs via fatty acid phosphorylation. We show that fatty acid kinase (Fak) is composed of two dissociable protein subunits encoded by separate genes. FakA provides the ATP binding domain and interacts with two distinct FakB proteins to produce acyl-phosphate. The FakBs are fatty acid binding proteins that exchange bound fatty acid/acyl-phosphate with fatty acid/acyl-phosphate presented in detergent micelles or liposomes. The ΔfakA and ΔfakB1 ΔfakB2 strains were unable to incorporate extracellular fatty acids into phospholipid. FakB1 selectively bound saturated fatty acids whereas FakB2 preferred unsaturated fatty acids. Affymetrix array showed a global perturbation in the expression of virulence genes in the ΔfakA strain. The severe deficiency in α-hemolysin protein secretion in ΔfakA and ΔfakB1 ΔfakB2 mutants coupled with quantitative mRNA measurements showed that fatty acid kinase activity was required to support virulence factor transcription. These data reveal the function of two conserved gene families, their essential role in the incorporation of host fatty acids by Gram-positive pathogens, and connects fatty acid kinase to the regulation of virulence factor transcription in S. aureus.T he pathway for the uptake and incorporation of host fatty acids (FA) by bacterial pathogens is important to understanding their physiology and determining if type II fatty acid synthesis (FASII) inhibitors will be useful antibacterial therapeutics. FASII is an energy-intensive process, and the advantage of being able to use host FA for membrane assembly obviously allows ATP to be diverted to the synthesis of other macromolecules. Gram-positive pathogens are capable of incorporating extracellular FA into their phospholipids. In species related to Streptococcus agalactiae, extracellular FA can completely replace endogenously synthesized FA, rendering the FASII inhibitors ineffective growth inhibitors if sufficient FA are present (1, 2). In contrast, FASII inhibitors exemplified by the enoyl-acyl carrier protein (ACP) reductase therapeutic AFN-1252 are effective against Staphylococcus aureus, even when extracellular FA are abundant (2, 3). A major impediment to our understanding of this diversity is that the pathway and enzymes responsible for the incorporation of extracellular FA is not established in the Firmicutes. A recent analysis of a ΔplsX knockout strain of S. aureus ruled out a role for either acyl-CoAs or acyl-ACP as intermediates in host FA metabolism and instead provided evidence for the existence of a new enzyme that phosphorylates FA, called FA kinase (Fak) (4) (Fig. 1A). Host FA are phosphorylated by Fak, and the acyl-PO 4 formed is either used by the PlsY glycerol-3-phosphate acyltransferase or converted to acyl-ACP by PlsX. The acyl-ACP may be either elongated by FASII or used by PlsC. Despite the strong evidence for their existence, the genes/proteins that encode this novel enzyme in FA metabolism were previously unidentif...

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Section: Discussionmentioning

confidence: 99%

Identification of a two-component fatty acid kinase responsible for host fatty acid incorporation by Staphylococcus aureus

Parsons

Broussard

Bose

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

142

230

View full text Add to dashboard Cite

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“…Studies with FABP -/-mice showed that these mice exhibited diminished hepatic β-oxidation that was not caused by an impaired oxidative capacity (Atshaves et al, 2010,Newberry et al, 2003. This result lead to the hypothesis, that hepatic FABP acts as a transporter of FFA to the site of β-oxidation (Storch and Thumser, 2010). Additionally, FABP deficient mice show reduced FA uptake and decreased hepatic TG levels when fed a HFD (Newberry et al, 2003,Newberry et al, 2006.…”

Section: Iii52 Fatty Acid (Fa) Import and Transportmentioning

confidence: 93%

The Role of PI3K p110gamma in chronic liver injury

Dostert¹,

Saugspier²,

Dorn³

et al. 2012

Z Gastroenterol

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“…FABPs all contain a 10-stranded antiparallel β-barrel structure. The ligand-binding pocket is located inside the β-barrel and is framed on one side by an N-terminal helix-turn-helix motif that is thought to act as the major portal for long-chain fatty acid entry and exit (13). The expression of different FABPs is distributed through various tissues in a highly specific manner with different levels and functions.…”

Section: Si-h-fabp Reduces Pa-induced Oxidative Stress In Podocytesmentioning

confidence: 99%

“…Total RNA was extracted from cultured cells using TRIzol ® reagent (Invitrogen; Thermo Fisher Scientific, Inc.). Single-stranded complementary (c)DNA was generated from DNaseI-treated RNA samples using Moloney murine leukemiavirus reverse transcriptase and oligo(dT) [12][13][14][15][16][17][18] (Toyobo Life Science, Osaka, Japan). A total of 1 µl cDNA samples were used for conventional PCR amplifications.…”

Section: H-fabp Small Interfering (Si)rna Transfectionmentioning

confidence: 99%

Overexpression of heart-type fatty acid binding protein enhances fatty acid-induced podocyteï¿½injury

et al. 2017

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Abstract. Deregulated lipid metabolism is a characteristic of metabolic diseases including type 2 diabetes and obesity, and likely contributes to podocyte injury and end-stage kidney disease. Heart-type fatty acid binding protein (H-FABP) was reported to be associated with lipid metabolism. The present study investigated whether H-FABP contributes to podocyte homeostasis. Podocytes were transfected by lentiviral vector to construct a cell line which stably overexpressed H-FABP. Small interfering RNA capable of effectively silencing H-FABP was introduced into podocytes to construct a cell line with H-FABP knockdown. Certain groups were treated with palmitic acid (PA) and the fat metabolism, as well as inflammatory and oxidative stress markers were measured. PA accelerated lipid metabolism derangement, inflammatory reaction and oxidative stress in podocytes. Overexpression of H-FABP enhanced the PA-induced disequilibrium in podocytes. The mRNA and protein expression levels of acyl-coenzyme A oxidase 3 and monocyte chemotactic protein 1, and the protein expression levels of 8-hydroxy-2'-deoxyguanosine and 4-hydroxynonenal were upregulated in the H-FABP overexpression group, while the mRNA and protein expression of peroxisome proliferator activated receptor α was downregulated. Knockdown of H-FABP inhibited the PA-induced injury and lipid metabolism derangement, as well as the inflammatory reaction and oxidative stress in podocytes. These results indicated that overexpression of H-FABP enhances fatty acid-induced podocyte injury, while H-FABP inhibition may represent a potential therapeutic strategy for the prevention of lipid metabolism-associated podocyte injury.

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Tissue-specific Functions in the Fatty Acid-binding Protein Family

Cited by 287 publications

References 56 publications

Identification of a two-component fatty acid kinase responsible for host fatty acid incorporation by Staphylococcus aureus

Identification of a two-component fatty acid kinase responsible for host fatty acid incorporation by Staphylococcus aureus

The Role of PI3K p110gamma in chronic liver injury

Overexpression of heart-type fatty acid binding protein enhances fatty acid-induced podocyteï¿½injury

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