Identification of a New Fatty Acid Synthesis-Transport Machinery at the Peroxisomal Membrane

Hillebrand, Merle; Gersting, Søren W.; Lotz-Havla, Amelie S.; Schäfer, Annika; Rosewich, Hendrik; Valerius, Oliver; Muntau, Ania C.; Gärtner, Jutta

doi:10.1074/jbc.m111.272732

Cited by 32 publications

(31 citation statements)

References 44 publications

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“…FAS is involved in generating ether-linked glycerophosphocholines that may be endogenous ligands for the nuclear receptor PPARγ in adipocytes, and FAS is enriched in adipocyte peroxisome fractions (Lodhi et al, 2012). FAS interacts with PMP70, a peroxisomal membrane protein involved in fatty acyl CoA transport into peroxisomes (Hillebrand et al, 2012), directly linking FAS to peroxisome lipid metabolism. Collectively, these results suggest that FAS channels fatty acids to peroxisomes for ether lipid synthesis.…”

Section: Discussionmentioning

confidence: 99%

Peroxisomal Lipid Synthesis Regulates Inflammation by Sustaining Neutrophil Membrane Phospholipid Composition and Viability

Lodhi

Wei

et al. 2015

Cell Metabolism

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SUMMARY Fatty acid synthase (FAS) is altered in metabolic disorders and cancer. Conventional FAS null mice die in utero so effects of whole body inhibition of lipogenesis following development are unknown. Inducible global knockout of FAS (iFASKO) in mice was lethal due to a disrupted intestinal barrier and leukopenia. Conditional loss of FAS was associated with the selective suppression of granulopoiesis without disrupting granulocytic differentiation. Transplantation of iFASKO bone marrow into wild type mice followed by Cre induction resulted in selective neutrophil depletion but not death. Impaired lipogenesis increased ER stress and apoptosis in neutrophils by preferentially decreasing peroxisome-derived membrane phospholipids containing ether bonds. Inducible global knockout of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, also produced neutropenia. FAS knockdown in neutrophil-like HL-60 cells caused cell loss that was partially rescued by ether lipids. Inhibiting ether lipid synthesis selectively constrains neutrophil development, revealing an unrecognized pathway in immunometabolism.

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Section: Discussionmentioning

confidence: 99%

Peroxisomal Lipid Synthesis Regulates Inflammation by Sustaining Neutrophil Membrane Phospholipid Composition and Viability

Lodhi

Wei

et al. 2015

Cell Metabolism

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“…It is also possible that in addition to activating VLCFA, organelle-localized FATPs function to transport VLCFA across organellar membranes for downstream metabolic pathways. Recent studies have identified FATP4 to be a component of a new fatty acid synthesis-transport machinery at the peroxisomal membrane where peroxisomal ABC transporters interact with proteins functioning in fatty acid synthesis and activation, facilitating fatty acid metabolism in peroxisomes [44]. …”

Section: Mechanisms Of Fatty Acid Transport To Epidermismentioning

confidence: 99%

Fatty acid transporters in skin development, function and disease

Lin¹,

Khnykin²

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Fatty acids in the epidermis can be incorporated into complex lipids or exist in a free form, and they are crucial to proper functions of the epidermis and its appendages, such as sebaceous glands. Epidermal fatty acids can be synthesized de novo by keratinocytes or taken up from extracutaneous sources in a process that likely involves protein transporters. Several proteins that are expressed in the epidermis have been proposed to facilitate the uptake of long-chain fatty acids (LCFA) in mammalian cells, including fatty acid translocase/CD36, fatty acid binding protein, and fatty acid transport protein (FATP)/very long-chain acyl-CoA synthetase. In this review, we will discuss the mechanisms by which these candidate transporters facilitate the uptake of fatty acids. We will then discuss the clinical implications of defects in these transporters and relevant animal models, including the FATP4 animal models and ichthyosis prematurity syndrome, a congenital ichthyosis caused by FATP4 deficiency. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier.

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“…Consistent with this possibility, humans and mice with mutations in ABCD1 have decreased levels of ethanolamine plasmalogens, coupled with accumulation of very long chain fatty acids in brain white matter (Khan et al, 2008). ABCD1 was recently shown to interact with several lipogenic enzymes, including ATP citrate lyase (ACLY), acetyl CoA carboxylase (ACC), and fatty acid synthase (FAS) (Hillebrand et al, 2012). FAS is a large multifunctional enzyme that primarily synthesizes palmitate (C16:0) using malonyl CoA as a two carbon source (Lodhi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Peroxisomes: A Nexus for Lipid Metabolism and Cellular Signaling

2014

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Peroxisomes are often dismissed as the cellular hoi polloi, relegated to cleaning up reactive oxygen chemical debris discarded by other organelles. However, their functions extend far beyond hydrogen peroxide metabolism. Peroxisomes are intimately associated with lipid droplets and mitochondria, and their ability to carry out fatty acid oxidation and lipid synthesis, especially the production of ether lipids, may be critical for generating cellular signals required for normal physiology. Here we review the biology of peroxisomes and their potential relevance to human disorders including cancer, obesity-related diabetes, and degenerative neurologic disease.

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Identification of a New Fatty Acid Synthesis-Transport Machinery at the Peroxisomal Membrane

Cited by 32 publications

References 44 publications

Peroxisomal Lipid Synthesis Regulates Inflammation by Sustaining Neutrophil Membrane Phospholipid Composition and Viability

Peroxisomal Lipid Synthesis Regulates Inflammation by Sustaining Neutrophil Membrane Phospholipid Composition and Viability

Fatty acid transporters in skin development, function and disease

Peroxisomes: A Nexus for Lipid Metabolism and Cellular Signaling

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