Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart

We have examined the effects of streptozotocin (STZ)-induced diabetes (moderate and severe) on fatty acid transport and fatty acid transporter (FAT/CD36) and plasma membrane-bound fatty acid binding protein (FABPpm) expression, at the mRNA and protein level, as well as their plasmalemmal localization. These studies have shown that, with STZ-induced diabetes, 1) fatty acid transport across the plasma membrane is increased in heart, skeletal muscle, and adipose tissue and is reduced in liver; 2) changes in fatty acid transport are generally not associated with changes in fatty acid transporter mRNAs, except in the heart; 3) increases in fatty acid transport in heart and skeletal muscle occurred with concomitant increases in plasma membrane FAT/CD36, whereas in contrast, the increase and decrease in fatty acid transport in adipose tissue and liver, respectively, were accompanied by concomitant increments and reductions in plasma membrane FABPpm; and finally, 4) the increases in plasma membrane transporters (FAT/CD36 in heart and skeletal muscle; FABPpm in adipose tissue) were attributable to their increased expression, whereas in liver, the reduced plasma membrane FABPpm appeared to be due to its relocation within the cell in the face of slightly increased expression. Taken together, STZ-induced changes in fatty acid uptake demonstrate a complex and tissue-specific pattern, involving different fatty acid transporters in different tissues, in combination with different underlying mechanisms to alter their surface abundance.

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Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2015.08.055 ◽

2015 ◽

Vol 465 (3) ◽

pp. 534-541 ◽

Cited By ~ 5

Author(s):

Nipun Saini ◽

Paul N. Black ◽

David Montefusco ◽

Concetta C. DiRusso

Keyword(s):

Fatty Acid ◽

Lipid Accumulation ◽

Transport Protein ◽

Fatty Acid Transport ◽

Acid Transport ◽

Fatty Acid Transport Protein

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Rv3723/LucA coordinates fatty acid and cholesterol uptake inMycobacterium tuberculosis

10.1101/121780 ◽

2017 ◽

Author(s):

Evgeniya V. Nazarova ◽

Christine R. Montague ◽

Thuy La ◽

Kaley M. Wilburn ◽

Neelima Sukumar ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Pathogenic Bacteria ◽

Bacterial Virulence ◽

Fatty Acid Transport ◽

Acid Transport ◽

Uncharacterized Protein ◽

Fatty Acid Transporter ◽

Important Fatty Acid

AbstractPathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts andMycobacterium tuberculosis(Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infection in mammals. While the uptake of cholesterol by Mtb is mediated by the Mce4 transporter, the route(s) of uptake of fatty acids remain unknown. Here, we demonstrate that an uncharacterized protein LucA, integrates the assimilation of both cholesterol and fatty acids in Mtb. LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters. We also demonstrate that Mce1 functions as an important fatty acid transporter in Mtb and we determine that the integration of cholesterol and fatty acid transport by LucA is required for full bacterial virulencein vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key role for LucA in coordinating both transport activities.

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Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00419.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. E491-E495 ◽

Cited By ~ 139

Author(s):

Joost J. F. P. Luiken ◽

David J. Dyck ◽

Xiao-Xia Han ◽

Narendra N. Tandon ◽

Yoga Arumugam ◽

...

Keyword(s):

Plasma Membrane ◽

Fatty Acid ◽

Muscle Contraction ◽

Kinase Inhibitor ◽

Fatty Acid Uptake ◽

Fatty Acid Transport ◽

Acid Uptake ◽

Hindlimb Muscles ◽

Fatty Acid Transporter ◽

Acid Transporter

It is well known that muscle contraction and insulin can independently translocate GLUT-4 from an intracellular depot to the plasma membrane. Recently, we have shown that the fatty acid transporter FAT/CD36 is translocated from an intracellular depot to the plasma membrane by muscle contraction (<30 min) (Bonen et al. J Biol Chem 275: 14501–14508, 2000). In the present study, we examined whether insulin also induced the translocation of FAT/CD36 in rat skeletal muscle. In studies in perfused rat hindlimb muscles, we observed that insulin increased fatty acid uptake by +51%. Insulin increased the rate of palmitate incorporation into triacylglycerols, diacylglycerols, and phospholipids ( P < 0.05) while reducing muscle palmitate oxidation ( P < 0.05). Perfusing rat hindlimb muscles with insulin increased plasma membrane FAT/CD36 by +48% ( P < 0.05), whereas concomitantly the intracellular FAT/CD36 depot was reduced by 68% ( P < 0.05). These insulin-induced effects on FAT/CD36 translocation were inhibited by the phosphatidylinositol 3-kinase inhibitor LY-294002. Thus these studies have shown for the first time that insulin can induce the translocation of FAT/CD36 from an intracellular depot to the plasma membrane.This reveals a previously unknown level of regulation of fatty acid transport by insulin and may well have important consequences in furthering our understanding of the relation between fatty acid metabolism and insulin resistance.

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Increased placental fatty acid transporter 6 and binding protein 3 expression and fetal liver lipid accumulation in a mouse model of obesity in pregnancy

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00385.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. R1569-R1577 ◽

Cited By ~ 32

Author(s):

Paula Díaz ◽

Jessica Harris ◽

Fredrick J. Rosario ◽

Theresa L. Powell ◽

Thomas Jansson

Keyword(s):

Fatty Acid ◽

Mrna Expression ◽

Lipid Accumulation ◽

Plasma Membranes ◽

Fetal Liver ◽

Fatty Acid Transport ◽

Acid Transport ◽

Fatty Acid Binding ◽

Obesity In Pregnancy ◽

In Pregnancy

Obesity in pregnancy is associated with increased fetal growth and adiposity, which, in part, is determined by transplacental nutrient supply. Trophoblast uptake and intracellular trafficking of lipids are dependent on placental fatty acid transport proteins (FATP), translocase (FAT/CD36), and fatty acid binding proteins (FABP). We hypothesized that maternal obesity in mice leads to increased placental expression of FAT/CD36, FATPs, and FABPs, and lipid accumulation in the fetal liver. C57/BL6J female mice were fed either a control (C; n = 10) or an obesogenic (OB; n = 10) high-fat, high-sugar diet before mating and throughout pregnancy. At E18.5, placentas and fetal livers were collected. Trophoblast plasma membranes (TPM) were isolated from placental homogenates. Expression of FAT/CD36 and FATP (TPM) and FABP (homogenates) was determined by immunoblotting. Gene expression was assessed by RT-quantitative PCR. Sections of fetal livers were stained for Oil Red O, and lipid droplets were quantified. TPM protein expression of FAT/CD36, FATP 2, and FATP 4 was comparable between C and OB groups. Conversely, TPM FATP 6 expression was increased by 35% in OB compared with C placentas without changes in mRNA expression. FABPs 1, 3–5 and PPARγ were expressed in homogenates, and FABP 3 expression increased 27% in OB compared with C placentas; however, no changes were observed in mRNA expression. Lipid droplet accumulation was 10-fold higher in the livers of fetuses from OB compared with C group. We propose that increased lipid transport capacity in obese mice promotes transplacental fatty acid transport and contributes to excess lipid accumulation in the fetal liver.

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Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins

PLoS ONE ◽

10.1371/journal.pone.0038952 ◽

2012 ◽

Vol 7 (6) ◽

pp. e38952 ◽

Cited By ~ 17

Author(s):

Samir Softic ◽

Michelle Kirby ◽

Nicholas G. Berger ◽

Noah F. Shroyer ◽

Stephen C. Woods ◽

...

Keyword(s):

Transcriptional Regulation ◽

Fatty Acid ◽

Lipid Accumulation ◽

Transport Proteins ◽

Insulin Concentration ◽

Fatty Acid Transport ◽

Acid Transport ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Fatty Acid Transport Proteins

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Extremely rapid increase in fatty acid transport and intramyocellular lipid accumulation but markedly delayed insulin resistance after high fat feeding in rats

Diabetologia ◽

10.1007/s00125-015-3691-8 ◽

2015 ◽

Vol 58 (10) ◽

pp. 2381-2391 ◽

Cited By ~ 26

Author(s):

Arend Bonen ◽

Swati S. Jain ◽

Laelie A. Snook ◽

Xiao-Xia Han ◽

Yuko Yoshida ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Lipid Accumulation ◽

Fatty Acid Transport ◽

Intramyocellular Lipid ◽

Acid Transport ◽

High Fat ◽

Fat Feeding

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Obesity-Induced Upregulation of ZBTB7A Promotes Lipid Accumulation through SREBP1

BioMed Research International ◽

10.1155/2020/4087928 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Jing-ping Zhou ◽

Yan-dan Ren ◽

Qin-yu Xu ◽

Yang Song ◽

Fei Zhou ◽

...

Keyword(s):

Fatty Acid ◽

Western Blotting ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Luciferase Reporter ◽

Rt Pcr ◽

Fatty Acid Transporter ◽

Direct Binding ◽

Acid Transporter

Objective. Nonalcoholic fatty liver disease (NAFLD) is among the most common chronic liver diseases. However, the pathogenesis of NAFLD is not still unclear. This study aims at evaluating the role of zinc finger and BTB domain-containing 7A (ZBTB7A) in NAFLD. Methods. Western blotting, real-time reverse transcription PCR (RT-PCR), and immunohistochemistry were submitted to evaluate the level of ZBTB7A in the high fatty diet- (HFD-) induced NAFLD mouse model. In vitro, the expression of ZBTB7A was assessed in oleic acid- (OA-) induced HepG2 cells with western blotting and RT-PCR. The luciferase reporter assay was used to estimate the effect of ZBTB7A on the SREBP1 and NF-κB, and the ChIP assay was subjected to evaluate the direct binding to the SREBP1 promoter. Oil Red staining was used to detect lipid accumulation, and the ELISA was used to verify the levels of TG, T-CHO, and MDA. ZBTB7A was knocked down with siRNA, and RT-PCR was performed to analyze the lipogenesis-, fatty acid transporter-, and oxidation metabolism-related genes expression. The levels of ZBTB7A in primary hepatocyte, Kupffer, and hepatic stellate cells (HSCs) were tested by RT-PCR. Results. The upregulation of ZBTB7A expression was assessed in NAFLD mice, and ZBTB7A expression was positively correlated with TNFα, IL-6, TG, T-CHO, and MDA. ZBTB7A was highly expressed in the hepatocytes. In vitro, OA-induced ZBTB7A expression and ZBTB7A expression were closely associated with SREBP1c. ZBTB7A could activate the promoter activity of SREBP1 and activate NF-κB activity. Interestingly, the direct binding of ZBTB7A in the SREBP1 promoter was acquired in HepG2 cells. Inhibition of ZBTB7A expression could attenuate OA-induced lipid accumulation, inhibit the expression of the lipogenesis-related genes and fatty acid transporter genes, and promote the expression of oxidation metabolism-related genes. Conclusion. ZBTB7A plays a significant role in the development process of NAFLD, and obesity-induced upregulation of ZBTB7A promotes lipid accumulation through activation of SREBP1 and NF-κB. ZBTB7A may be a potential novel target for the therapy of NAFLD.

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Overexpression of membrane-associated fatty acid binding protein (FABPpm) in vivo increases fatty acid sarcolemmal transport and metabolism

Physiological Genomics ◽

10.1152/physiolgenomics.00190.2003 ◽

2004 ◽

Vol 17 (1) ◽

pp. 31-37 ◽

Cited By ~ 68

Author(s):

David C. Clarke ◽

Dragana Miskovic ◽

Xiao-Xia Han ◽

Jorge Calles-Escandon ◽

Jan F. C. Glatz ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Binding Protein ◽

Binding Protein ◽

Fatty Acid Transport ◽

Mammalian Tissue ◽

Fatty Acid Binding ◽

Acid Binding Protein ◽

Fatty Acid Transporter ◽

Acid Transporter

Fatty acid translocase (FAT/CD36) is a key fatty acid transporter in skeletal muscle. However, the effects on fatty acid transport by another putative fatty acid transporter, plasma membrane-associated fatty acid binding protein (FABPpm), have not been determined in mammalian tissue. We examined the functional effects of overexpressing FABPpm on the rates of 1) palmitate transport across the sarcolemma and 2) palmitate metabolism in skeletal muscle. One muscle (soleus) was transfected with pTracer containing FABPpm cDNA. The contralateral muscle served as control. After injecting the FABPpm cDNA, muscles were electroporated. FABPpm overexpression was directly related to the quantity of DNA administered. Electrotransfection (200 μg/muscle) rapidly induced FABPpm protein overexpression ( day 1, +92%, P < 0.05), which was further increased during the next few days ( days 3–7; range +142% to +160%, P < 0.05). Sarcolemmal FABPpm was comparably increased ( day 7, +173%, P < 0.05). Neither FAT/CD36 expression nor sarcolemmal FAT/CD36 content was altered. FABPpm overexpression increased the rates of palmitate transport (+79%, P < 0.05). Rates of palmitate incorporation into phospholipids were also increased +36%, as were the rates of palmitate oxidation (+20%). Rates of palmitate incorporation into triacylglycerol depots were not altered. These studies demonstrate that in mammalian tissue FABPpm overexpression increased the rates of palmitate transport across the sarcolemma, an effect that is independent of any changes in FAT/CD36. However, since the overexpression of plasmalemmal FABPpm (+173%) exceeded the effects on the rates of palmitate transport and metabolism, it appears that the overexpression of FABPpm alone is not sufficient to induce completely parallel increments in palmitate transport and metabolism. This suggests that other mechanisms are required to realize the full potential offered by FABPpm overexpression.

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