Adenosine A₁ receptors do not play a major role in the regulation of lipogenic gene expression in hepatocytes.

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.

FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase.

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.

Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.

Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease.

Fatty acid transport protein 1 is required for nonshivering thermogenesis in brown adipose tissue.

Nonshivering thermogenesis in brown adipose tissue (BAT) generates heat through the uncoupling of mitochondrial beta-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.

Protein-mediated fatty acid uptake: novel insights from in vivo models.

Long-chain fatty acids are both important metabolites as well as signaling molecules. 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.

Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity.

Background & Aims: Fatty Acid Transport Protein 5 (FATP5) is a liver-specific member of the FATP/Slc27 family, which has been shown to exhibit both fatty acid transport and bile acid-CoA ligase activity in vitro. Here, we investigate its role in bile acid metabolism and body weight homeostasis in vivo by using a novel FATP5 knockout mouse model.

Methods: Bile acid composition was analyzed by mass spectroscopy.

Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.

Background & Aims: Fatty acid transport protein 5 (FATP5/Slc27a5) has been shown to be a multifunctional protein that in vitro increases both uptake of fluorescently labeled long-chain fatty acid (LCFA) analogues and bile acid/coenzyme A ligase activity on overexpression. The aim of this study was to further investigate the diverse roles of FATP5 in vivo.

Methods: We studied FATP5 expression and localization in liver of C57BL/6 mice in detail.

FATP1 is an insulin-sensitive fatty acid transporter involved in diet-induced obesity.

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.

Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators.

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.

The glucose transport facilitator GLUT8 is predominantly associated with the acrosomal region of mature spermatozoa.

The glucose transporter 8 (GLUT8) is a recently identified member of the family of sugar transport facilitators. In human tissues GLUT8 is predominantly expressed in testis in a gonadotropin-dependent manner. It is shown here that the onset of mRNA synthesis of GLUT8 during the maturation of mouse testis coincides with the appearance of mature spermatozoa.

Mouse GLUT8: genomic organization and regulation of expression in 3T3-L1 adipocytes by glucose.

Glucose transporter 8 (GLUT8) is a class III sugar transport facilitator predominantly expressed in testis and insulin-regulated tissues. Here we describe its genomic organization, the identification of its promoter region, and the regulation of its expression in 3T3-L1 cells. The mouse Glut8 gene spans approximately 9 kb, consists of 10 exons, and is highly similar to the human GLUT6 gene.

Characterization of human glucose transporter (GLUT) 11 (encoded by SLC2A11), a novel sugar-transport facilitator specifically expressed in heart and skeletal muscle.

Human GLUT11 (encoded by the solute carrier 2A11 gene, SLC2A11) is a novel sugar transporter which exhibits significant sequence similarity with the members of the GLUT family. The amino acid sequence deduced from its cDNAs predicts 12 putative membrane-spanning helices and all the motifs (sugar-transporter signatures) that have previously been shown to be essential for sugar-transport activity. The closest relative of GLUT11 is the fructose transporter GLUT5 (sharing 41.

Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel member of the family of sugar-transport facilitators predominantly expressed in brain and leucocytes.

The GLUT9 gene encodes a cDNA which exhibits significant sequence similarity with members of the glucose transporter (GLUT) family. The gene is located on chromosome 9q34 and consists of 10 exons separated by short introns. The amino acid sequence deduced from its cDNA predicts 12 putative membrane-spanning helices and all the motifs (sugar-transporter signatures) that have previously been shown to be essential for transport activity.

GLUT8, a novel member of the sugar transport facilitator family with glucose transport activity.

GLUT8 is a novel glucose transporter-like protein that exhibits significant sequence similarity with the members of the sugar transport facilitator family (29.4% of amino acids identical with GLUT1). Human and mouse sequence (86.

Serine-294 and threonine-295 in the exofacial loop domain between helices 7 and 8 of glucose transporters (GLUT) are involved in the conformational alterations during the transport process.

The role of a conserved polar motif (STS) in the exofacial loop between helices 7 and 8 of GLUT4 for transporter function was investigated by site-directed mutagenesis and expression of the constructs in COS-7 cells. Reconstituted glucose-transport activity, cytochalasin B binding and photolabelling with the exofacial label 2-N4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1, 3-bis-(d-mannosyloxy)-2-propylamine (ATB-BMPA) were assayed in membranes from transfected cells and corrected for immunoreactivity of expressed transporters. Replacement of Ser-294 with Ala or Thr suppressed transport activity and cytochalasin B binding.

Role of conserved arginine and glutamate residues on the cytosolic surface of glucose transporters for transporter function.

The role of conserved arginine and glutamic acid residues at the cytoplasmic surface of the GLUT4 for transporter function was investigated by site-directed mutagenesis and expression of the constructs in COS-7 cells. Reconstituted glucose transport activity, cytochalasin B binding, and photolabeling with the exofacial label 2-N4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1, 3-bis(d-mannosyloxy)-2-propylamine (ATB-BMPA) was assayed in membranes from transfected cells and corrected for immunoreactivity of expressed transporters. Exchange of Arg 92 (R92L amino acid residues are numbered according to the corresponding residues in the GLUT1) or Arg 333/334 (RR333/4LA) reduced or suppressed transport activity with no or very little effect on photolabeling with ATB-BMPA and cytochalasin B binding.