Disease relevance of Slc27a1

• FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity [1].
• These results characterize the murine FATP gene and its insulin responsiveness as well as present a framework for future studies of its role in lipid metabolism, obesity, and type II diabetes mellitus [2].
• Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy [3].
• With the use of adenoviruses, FATP1 and FAT genes were delivered to primary cultured human muscle cells [4].
• Fatty acid transport proteins are key mediators of cellular fatty acid uptake and recent transgenic and knockout animal models have provided new insights into their contribution to energy homeostasis and to pathological processes, including obesity and insulin desensitization [5].

High impact information on Slc27a1

• Immunocytochemistry and subcellular fractionation of 3T3-L1 adipocytes show that FATP is localized to the plasma membrane [6].
• We propose that FATP is a plasma membrane transporter for LCFAs [6].
• This cDNA encodes a novel 646 amino acid fatty acid transport protein (FATP) with six predicted membrane-spanning regions and that is integrally associated with membranes [6].
• These findings demonstrate an important role of intramuscular fatty acid metabolites in causing insulin resistance and suggest that FATP1 may be a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes [7].
• Whole-body adiposity, adipose tissue expression of adiponectin, intramuscular fatty acid metabolites, and insulin sensitivity were not altered in FATP1 KO mice fed a regular chow diet [7].

Biological context of Slc27a1

• To determine whether the FATP PPRE was functional, and responded to lipid activators, transient transfection of FATP-luciferase reporter constructs into CV-1 and 3T3-L1 cells was carried out [8].
• In 3T3-L1 cells, the PPRE conferred a small but significant increase in expression in preadipocytes, as well as a more robust up-regulation of FATP expression in adipocytes [8].
• Based upon the sequence of the FATP gene upstream region (Hui, T. Y., Frohnert, B. I., Smith, A. J., Schaffer, J. A., and Bernlohr, D. A. (1998) J. Biol. Chem. 273, 27420-27429) a putative peroxisome proliferator-activated receptor response element (PPRE) is present from -458 to -474 [8].
• FATP1 exhibited similar substrate specificity for fatty acids 16-24 carbons in length, whereas ACS1 was 10-fold more active on long chain fatty acids relative to very long chain fatty acids [9].
• Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle [7].

Anatomical context of Slc27a1

• Nuclear extracts from 3T3-L1 adipocytes also showed a specific gel-shift complex with the FATP PPRE [8].
• Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene [8].
• FATP mRNA levels were not increased in liver or adipose tissue [10].
• Isolation of detergent-resistant membranes (DRMs) from 3T3-L1 cell homogenates revealed that FAT/CD36 was expressed in both DRMs and detergent-soluble membranes (DSMs), whereas FATP1 and FATP4 were present only in DSMs but not DRMs [11].
• Fatty acid transport protein 1 (FATP1) is an approximately 63-kDa plasma membrane protein that facilitates the influx of fatty acids into adipocytes as well as skeletal and cardiac myocytes [9].

Associations of Slc27a1 with chemical compounds

• To correlate the expression of FATP to its physiological function, treatment of 3T3-L1 adipocytes with PPARgamma and RXRalpha activators resulted in an increased uptake of oleate [8].
• Moreover, linoleic acid, a physiological ligand, up-regulated FATP expression 2-fold in a PPRE-dependent manner [8].
• The very long chain acyl-CoA synthetase activity of the two enzymes was comparable as were the Km values for both ATP and coenzyme A. Interestingly, FATP1 was insensitive to inhibition by triacsin C, whereas ACS1 was inhibited by micromolar concentrations of the compound [9].
• To investigate the role of FATP1 in glucose homeostasis and in the pathogenesis of insulin resistance, we examined the effect of acute lipid infusion or chronic high-fat feeding on insulin action in FATP1 KO mice [7].
• These results are consistent with a mechanism of action for FATP involving ATP binding that is dependent on serine 250 of the IYTSGTTGXPK motif [12].

Regulatory relationships of Slc27a1

• These results demonstrate that the FATP gene possesses a functional PPRE and is up-regulated by activators of PPARalpha and PPARgamma, thereby linking the activity of the protein to the expression of its gene [8].
• In contrast, treatment with TNF-alpha inhibited basal and insulin-induced LCFA uptake and reduced FATP1 and -4 levels [13].

Other interactions of Slc27a1

• PPARalpha and PPARdelta activators did not up-regulate FATP expression in 3T3-L1 adipocytes, however, suggesting that these two subtypes do not play a significant role in differentiation-dependent activation in fat cells [8].
• Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid transport protein (FATP)4 [1].
• Initial uptake of phytanic acid uptake was unaltered apparently due to concomitant 5.3-, 1.6-, and 1.4-fold up-regulation of plasma membrane fatty acid transporter/translocase proteins (glutamic-oxaloacetic transaminase, fatty acid transport protein, and fatty acid translocase, respectively) [14].
• To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the alpha-myosin heavy chain gene promoter [3].
• In contrast, FATP1 deletion protected the KO mice from fat-induced insulin resistance and intramuscular accumulation of fatty acyl-CoA without alteration in whole-body adiposity [7].

Analytical, diagnostic and therapeutic context of Slc27a1

• To address the enzymatic activity of the isolated protein, murine FATP1 and ACS1 were engineered to contain a C-terminal Myc-His tag expressed in COS1 cells via adenoviral-mediated infection and purified to homogeneity using nickel affinity chromatography [9].
• Additionally, enhanced green fluorescent protein fusion constructs containing predicted membrane-associated or soluble portions of FATP1 were expressed in Cos7 cells and analyzed by immunofluorescence and subcellular fractionation [15].
• Western blot analysis of 3T3-L1 adipocytes that natively express FATP1 demonstrate a prominent 130-kDa species as well as the expected 63-kDa FATP1, suggesting that this protein may participate in a cell surface transport protein complex [16].
• Indirect immunofluorescence studies with selective permeabilization conditions and protease protection studies of sealed membrane vesicles from cells expressing epitope-tagged FATP1 were performed [15].
• Fluorescence in situ hybridization analysis revealed that the murine FATP gene is localized to chromosome 8, band 8B3 [2].

References