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Fatty acid transport protein (FATP)2, a member of the FATP family of fatty acid uptake mediators, has independently been identified as a hepatic peroxisomal very long-chain acyl-CoA synthetase (VLACS). Here we address whether FATP2 is 1) a peroxisomal enzyme, 2) a plasma membrane-associated long-chain fatty acid (LCFA) transporter, or 3) a multifunctional protein. We found that, in mouse livers, only a minor fraction of FATP2 localizes to peroxisomes, where it contributes to approximately half of the peroxisomal VLACS activity. However, total hepatic (V)LACS activity was not significantly affected by loss of FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent role in hepatic LCFA uptake. This suggests FATP2 as a potential target for a therapeutic intervention of hepatosteatosis. Adeno-associated virus 8-based short hairpin RNA expression vectors were used to achieve liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis in the face of continued high-fat feeding, concomitant with improvements in liver physiology, fasting glucose, and insulin levels. Based on our findings, we propose a model in which FATP2 is a multifunctional protein that shows subcellular localization-dependent activity and is a major contributor to peroxisomal (V)LACS activity and hepatic fatty acid uptake, suggesting FATP2 as a potential novel target for the treatment of nonalcoholic fatty liver disease. nonalcoholic fatty liver disease doi: 10.1152/ajpendo.00226.2010.

Examination of the role of conserved charged residues at the cytoplasmic surface of the GLUT4 transporter through site-directed mutagenesis and expression of constructs in COS 7 cells found that seven of the eight polar residues are essential for the full function of the transporter. Results show that mutation of three of the residues stops the transporter in an inward facing conformation. Data suggest that interaction between Arg and Glu residues is needed for the proper conformation of the transporter and its alteration during transport.

The recent identification of several additional members of the family of sugar transport facilitators (gene symbol SLC2A, protein symbol GLUT) has created a heterogeneous and, in part, confusing nomenclature. Therefore, this letter provides a summary of the family members and suggests a systematic nomenclature for SLC2A and GLUT symbols. membrane transport; glucose transporters; glucose transporter genes

Nonshivering thermogenesis in brown adipose tissue (BAT) generates heat through the uncoupling of mitochondrial β-oxidation from ATP production. The principal energy source for this process is fatty acids that are either synthesized de novo in BAT or are imported from circulation. How uptake of fatty acids is mediated and regulated has remained unclear. Here, we show that fatty acid transport protein (FATP)1 is expressed on the plasma membrane of BAT and is upregulated in response to cold stimuli, concomitant with an increase in the rate of fatty acid uptake. In FATP1-null animals, basal fatty acid uptake is reduced and remains unchanged following cold exposure. As a consequence, FATP1 knockout (KO) animals display smaller lipid droplets in BAT and fail to defend their core body temperature at 4°C, despite elevated serum free fatty acid levels. Similarly, FATP1 is expressed by the BAT-derived cell line HIB-1B upon differentiation, and both fatty acid uptake and FATP1 protein levels are rapidly elevated following isoproterenol stimulation. Stimulation of fatty uptake by isoproterenol required both protein kinase A and mitogen-activated kinase signaling and is completely dependent on FATP1 expression, as small-hairpin RNA-mediated knock down of FATP1 abrogated the effect. Diabetes 55:3229-3237, 2006 [ABSTRACT FROM AUTHOR]

Fatty acid transport protein 1 (FATP1), a member of the FATP/Slc27 protein family, enhances the cellular uptake of long-chain fatty acids (LCFAs) and is expressed in several insulin-sensitive tissues. In adipocytes and skeletal muscle, FATP1 translocates from an intracellular compartment to the plasma membrane in response to insulin. Here we show that insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected. Moreover, loss of FATP1 function altered regulation of postprandial serum LCFA, causing a redistribution of lipids from adipocyte tissue and muscle to the liver, and led to a complete protection from diet-induced obesity and insulin desensitization. This is the first in vivo evidence that insulin can regulate the uptake of LCFA by tissues via FATP1 activation and that FATPs determine the tissue distribution of dietary lipids. The strong protection against diet-induced obesity and insulin desensitization observed in FATP1-null animals suggests FATP1 as a novel antidiabetic target. [ABSTRACT FROM AUTHOR]

Abstract: Activation of adenosine A1 receptors was reported to promote fatty acid synthesis in AML-12 cells, by increasing the expression of SREBP-1c (sterol regulatory binding protein 1c) and FAS (fatty acid synthase). Since these findings have important therapeutic implications for the discovery of adenosine A1 receptor agonists, further studies were undertaken to determine the expression and functional relevance of adenosine A1 receptor in the liver. To that end, we used two classes of distinct adenosine A1 receptor agonists: CPA (N6-cyclopentyl-adenosine), a full agonist and GS-9667 (2-{6-[((1R,2R)-2-hydroxycyclopentyl)-amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]-oxolane-3,4-diol), a partial agonist. Treatment of AML-12 cells, HepG2 cells and primary human hepatocytes with either CPA or GS-9667 did not increase the gene expression of SREBP-1c or FAS. Furthermore, in AML-12 and HepG2 cells, CPA did not antagonize forskolin-stimulated cAMP production, a characteristic of adenosine A1 receptor activation, indicating that these cells lack adenosine A1 receptor function. Consistent with this finding, adenosine A1 receptor gene expression was found to be very low and adenosine A1 receptor protein levels were hardly detectable by radioligand binding assays in hepatic cell lines such as AML-12 and HepG2 as well as in both mouse and human liver tissues. Finally, acute treatment with adenosine A1 receptor agonist GS-9667 had no significant effect on gene expression of both SREBP-1c and FAS in livers of Sprague Dawley rats. Taken together, our data suggest that the expression of adenosine A1 receptor is too low to play a major role in the regulation of lipogenic gene expression in hepatocytes. [Copyright &y& Elsevier]