SPTLC1 Binds ABCA1 To Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter

Tamehiro, Norimasa; Zhou, Suiping; Okuhira, Keiichiro; Benita, Yair; Brown, Cari E; Zhuang, Debbie Z.; Latz, Eicke; Hornemann, Thorsten; Eckardstein, Arnold von; Xavier, Ramnik J.; Freeman, Mason W.; Fitzgerald, Michael L.

doi:10.1021/bi800182t

Cited by 45 publications

(40 citation statements)

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“…Interestingly, at 15 months, the wild-type SPTLC1 overexpressing mice had twice the sperm count compared with the wild type. These findings are consistent with the fact that SPTLC1 is a negative regulator of ABCA1 (Tamehiro et al, 2008) and that ABCA1 overexpressing mice have aspermatogenesis (Selva et al, 2004).…”

Section: Aging Mutant Sptlc1supporting

confidence: 89%

Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Eichler¹,

Hornemann²,

McCampbell³

et al. 2009

J. Neurosci.

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Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1 C133W ) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1 C133W , but not in the wild-type, double-transgenic tgSPTLC1 WT ϩ C133W or SPTLC1 ϩ/Ϫ mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.

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Section: Aging Mutant Sptlc1supporting

confidence: 89%

Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Eichler¹,

Hornemann²,

McCampbell³

et al. 2009

J. Neurosci.

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“…How SPT activity and sphingolipids may act to promote the progression of atherosclerosis is unclear, but the data do suggest analysis of factors that regulate SPT activity should provide mechanistic insight into the link between de novo sphingolipid synthesis and atherosclerosis. In this regard we have found that SPTLC1 can interact with the ABCA1 transporter and inhibit its ability to transfer cholesterol to apoA-I, a mechanism that would be expected to promote atherosclerosis (20). Thus, along with playing a direct role in the synthesis of sphingolipids, SPTLC1 may also have evolved as an SPT subunit whose function is to regulate SPT activity in response to the cellular demand for sphingolipids and other membrane constituents such as cholesterol.…”

mentioning

confidence: 97%

Cell Polarity Factor Par3 Binds SPTLC1 and Modulates Monocyte Serine Palmitoyltransferase Activity and Chemotaxis

Tamehiro

Mujawar

Zhou

et al. 2009

Journal of Biological Chemistry

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Elevated sphingolipids have been associated with increased cardiovascular disease. Conversely, atherosclerosis is reduced in mice by blocking de novo synthesis of sphingolipids catalyzed by serine palmitoyltransferase (SPT). The SPT enzyme is composed of the SPTLC1 and -2 subunits, and here we describe a novel protein-protein interaction between SPTLC1 and the PDZ protein Par3 (partitioning defective protein 3). Mammalian SPTLC1 orthologs have a highly conserved C terminus that conforms to a type II PDZ protein interaction motif, and by screening PDZ domain protein arrays with an SPTLC1 C-terminal peptide, we found it bound the third PDZ domain of Par3. Overlay and immunoprecipitation assays confirmed this interaction and indicate Par3 is able to associate with the SPTLC1/2 holoenzyme by binding the C-terminal SPTLC1 PDZ motif. The physiologic existence of the SPTLC1/2-Par3 complex was detected in mouse liver and macrophages, and short interfering RNA inhibition of Par3 in human THP-1 monocytes significantly reduced SPT activity and de novo ceramide synthesis by nearly 40%. Given monocyte recruitment into inflamed vessels is thought to promote atherosclerosis, and because Par3 and sphingolipids have been associated with polarized cell migration, we tested whether the ability of THP-1 monocytes to migrate toward MCP-1 (monocyte chemoattractant protein 1) depended upon Par3 and SPTLC1 expression. Knockdown of Par3 significantly reduced MCP1-induced chemotaxis of THP-1 monocytes, as did knockdown of SPTLC1, and this Par3 effect depended upon SPT activity and was blunted by ceramide treatment. In conclusion, protein arrays were used to identify a novel SPTLC1-Par3 interaction that associates with increased monocyte serine palmitoyltransferase activity and chemotaxis toward inflammatory signals.Sphingolipids are a structurally diverse class of lipids that play correspondingly diverse roles in membrane structure, cell proliferation, immune function, and skin physiology (1-4). De novo sphingolipid synthesis is initiated by serine palmitoyltransferase (SPT), 2 an enzyme that condenses serine and palmitoyl-CoA forming the biosynthetic intermediate 3-ketodihydrosphingosine that is subsequently converted to ceramide, sphingomyelin, and other sphingolipids (5). SPT is a heterodimer composed of the SPTLC1 and -2 subunits (6, 7), which may form higher order multimeric structures that can include a third subunit, SPTLC3 (8, 9). Both the SPTLC2 and -3 subunits are catalytically active and contain conserved lysines that act as Schiff bases during the condensation reaction (5, 8). In contrast, SPTLC1 does not contain the conserved catalytically active lysine, but is important for stabilizing the SPTLC2 subunit and anchoring the SPT holoenyzme on the cytosolic face of the endoplasmic reticulum (10, 11).Expression and regulation of the SPTLC1/2 holoenyzme are of interest because its activity controls de novo synthesis of sphingomyelin, and increased plasma levels of this sphingolipid have been correlated with an increased incidence...

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“…La ACAT2 es relativamente saturable en los humanos, por lo cual frente a una ingesta alta de colesterol no todo se esterifica (Iqbal and Hussain, 2009). El colesterol no esterificado puede seguir tres caminos: la mayor parte es devuelta al lumen intestinal, junto con otros esteroles (ej, fitoesteroles) por los transportadores ABCG5/G8 (ABC: ATP Binding Cassette) (Ikonen, 2008); otra parte es transportada a la membrana basolateral del enterocito para la biogé-nesis de las HDL de origen intestinal, proceso que realiza el transportador ABCA1 (Tamehiro et al, 2008); y una fracción menor se incorpora como tal (no esterificado) intercalándose en los fosfolípidos que forman el quilomicrón, el que además incorpora la apoproteína B48 (ApoB48) (Hassan et al, 2007;Ikonen 2008;Weinstein et al, 2010). El transporte del colesterol por ABCA1 es regulado tanto en la transcripción como en la modificación postranscripcional del transportador (Okuhira et al, 2005), con lo cual es posible aumentar o disminuir su actividad.…”

Section: Discussionunclassified

El metabolismo del colesterol: cada vez más complejo

Sanhueza¹,

Valenzuela²,

Valenzuela³

2012

Grasas y Aceites

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373circulating cholesterol and once inside the body, there should be a perfect harmony between the addition of cholesterol to various tissues, its metabolic use, the mechanisms of its tissue deposition, and the synthesis of this lipid. From this perspective, this review offers a general view of the molecular mechanisms that allow the regulation of extra and intracellular cholesterol levels. KEY-WORDS: Cholesterol -Extracellular metabolism -Intracellular metabolism -Transport. INTRODUCCIÓNDesde su descubrimiento en 1769 por el fisiólo-go Francoise Poulletier de la Salle, el colesterol ha sido motivo de numerosos estudios, investigaciones y publicaciones (Olson, 1998). Hoy sabemos más sobre su digestión, biosíntesis, sus importantes funciones bioquímicas, su regulación y su participación en el origen de numerosas enfermedades (cardio y cerebro vasculares, neurológicas, inflamatorias, etc). Sin embargo, solo en forma más reciente se han descubierto, y entendido, los intrincados mecanismos moleculares que regulan su transporte fuera y dentro de las células, los mecanismos regulatorios en los cuales interviene y las numerosas moléculas que además del colesterol intervienen en estos procesos. El propósito de esta revisión es analizar lo que hoy día sabemos sobre estos últimos aspectos. DIGESTION Y ABSORCION DEL COLESTEROLEl 90-95% del colesterol que consumimos en la dieta está esterificado, por lo cual la enzima colesterol esterasa de origen pancreático lo libera en el intestino delgado (Howles et al., 1996). Una vez incorporado a las micelas mixtas, es transferido activamente a los enterocitos a través de la proteína transportadora Niemann-Pick C1 tipo 1 (NPC1) que se ubica en la membrana apical de los enterocitos y también en la membrana canalicular de los hepa- El colesterol es una molécula importante; es necesario para la biosíntesis de hormonas esteroideas, de sales biliares y para mantener la estabilidad de las membranas biológicas en células animales. Sin embargo, su exceso es negativo y es responsable de generar enfermedades que comprometen al corazón, al cerebro o que generan algunos tipos de cáncer. Por estos motivos, los niveles de colesterol celulares deben estar finamente regulados, y para ello, participan una infinidad de mecanismos que comprometen al organismo como un todo. Estos mecanismos deben comenzar a operar en forma eficiente desde la ingesta de colesterol dietario para su incorporación al enterocito, donde están implicados transportadores de tipo ABC y NCP1, los motivos estructurales PDZ, entre otras. También debe estar adecuadamente regulado el colesterol circulante y una vez en el interior del organismo, debería establecerse una perfecta armonía entre la incorporación del colesterol a los diversos tejidos, con su utilización metabólica, la generación de reservas de colesterol en los mismos y la síntesis de este lípido. Desde esta perspectiva, la presente revisión ofrece una visión general de los mecanismos moleculares que permiten la regulación de los niveles de colesterol a nivel extra e intr...

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SPTLC1 Binds ABCA1 To Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter

Cited by 45 publications

References 40 publications

Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Cell Polarity Factor Par3 Binds SPTLC1 and Modulates Monocyte Serine Palmitoyltransferase Activity and Chemotaxis

El metabolismo del colesterol: cada vez más complejo

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