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1.
J Lipid Res ; 56(12): 2359-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26482537

RESUMO

Steatohepatitis occurs in up to 20% of patients with fatty liver disease and leads to its primary disease outcomes, including fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. Mechanisms that mediate this inflammation are of major interest. We previously showed that overload of saturated fatty acids, such as that which occurs with metabolic syndrome, induced sphingosine kinase 1 (SphK1), an enzyme that generates sphingosine-1-phosphate (S1P). While data suggest beneficial roles for S1P in some contexts, we hypothesized that it may promote hepatic inflammation in the context of obesity. Consistent with this, we observed 2-fold elevation of this enzyme in livers from humans with nonalcoholic fatty liver disease and also in mice with high saturated fat feeding, which recapitulated the human disease. Mice exhibited activation of NFκB, elevated cytokine production, and immune cell infiltration. Importantly, SphK1-null mice were protected from these outcomes. Studies in cultured cells demonstrated saturated fatty acid induction of SphK1 message, protein, and activity, and also a requirement of the enzyme for NFκB signaling and increased mRNA encoding TNFα and MCP1. Moreover, saturated fat-induced NFκB signaling and elevation of TNFα and MCP1 mRNA in HepG2 cells was blocked by targeted knockdown of S1P receptor 1, supporting a role for this lipid signaling pathway in inflammation in nonalcoholic fatty liver disease.


Assuntos
Ácidos Graxos/farmacologia , Hepatócitos/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Eukaryot Cell ; 14(5): 442-53, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25724885

RESUMO

ATP-binding cassette transporters Pdr5 and Yor1 from Saccharomyces cerevisiae control the asymmetric distribution of phospholipids across the plasma membrane as well as serving as ATP-dependent drug efflux pumps. Mutant strains lacking these transporter proteins were found to exhibit very different resistance phenotypes to two inhibitors of sphingolipid biosynthesis that act either late (aureobasidin A [AbA]) or early (myriocin [Myr]) in the pathway leading to production of these important plasma membrane lipids. These pdr5Δ yor1 strains were highly AbA resistant but extremely sensitive to Myr. We provide evidence that these phenotypic changes are likely due to modulation of the plasma membrane flippase complexes, Dnf1/Lem3 and Dnf2/Lem3. Flippases act to move phospholipids from the outer to the inner leaflet of the plasma membrane. Genetic analyses indicate that lem3Δ mutant strains are highly AbA sensitive and Myr resistant. These phenotypes are fully epistatic to those seen in pdr5Δ yor1 strains. Direct analysis of AbA-induced signaling demonstrated that loss of Pdr5 and Yor1 inhibited the AbA-triggered phosphorylation of the AGC kinase Ypk1 and its substrate Orm1. Microarray experiments found that a pdr5Δ yor1 strain induced a Pdr1-dependent induction of the entire Pdr regulon. Our data support the view that Pdr5/Yor1 negatively regulate flippase function and activity of the nuclear Pdr1 transcription factor. Together, these data argue that the interaction of the ABC transporters Pdr5 and Yor1 with the Lem3-dependent flippases regulates permeability of AbA via control of plasma membrane protein function as seen for the high-affinity tryptophan permease Tat2.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Permeabilidade da Membrana Celular/fisiologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Regulação Fúngica da Expressão Gênica , Transativadores/metabolismo
3.
Clin Lipidol ; 9(5): 553-569, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-29643939

RESUMO

Climbing obesity rates have contributed to worldwide increases in obesity-associated diseases, including the metabolic syndrome and Type 2 diabetes mellitus (T2DM). Sphingolipids, an important class of structural and signaling lipids, have emerged as key players in the development and pathogenesis of insulin resistance and T2DM. More specifically, sphingolipids have been demonstrated to play integral roles in lipotoxicity and other aspects of pathogenesis in T2DM, although the cellular mechanisms by which this occurs and by which sphingolipid metabolism is dysregulated in T2DM remain under investigation. This review summarizes current knowledge of sphingolipid metabolism and signaling in key organs and tissues affected by T2DM, including the pancreas, adipose tissue, skeletal muscle, cardiovascular system and liver, and highlights areas that ripe for future investigation.

4.
PLoS One ; 8(4): e60485, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593226

RESUMO

The oxysterol binding protein family are amphitropic proteins that bind oxysterols, sterols, and possibly phosphoinositides, in a conserved binding pocket. The Saccharomyces cerevisiae oxysterol binding protein family member Kes1 (also known as Osh4) also binds phosphoinositides on a distinct surface of the protein from the conserved binding pocket. In this study, we determine that the oxysterol binding protein family member Kes1 is required to maintain the ratio of complex sphingolipids and levels of ceramide, sphingosine-phosphate and sphingosine. This inability to maintain normal sphingolipid homeostasis resulted in misdistribution of Pma1, a protein that requires normal sphingolipid synthesis to occur to partition into membrane rafts at the Golgi for its trafficking to the plasma membrane.


Assuntos
Proteínas de Membrana/metabolismo , Receptores de Esteroides/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Esfingolipídeos/metabolismo , Membrana Celular/metabolismo , Ceramidas/metabolismo , Complexo de Golgi/metabolismo , Transporte Proteico , ATPases Translocadoras de Prótons/metabolismo
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