In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes

Long chain fatty acids (LCFAs) are an important source of energy for most organisms. They also function as blood hormones, regulating key metabolic functions such as hepatic glucose production. Although LCFAs can diffuse through the hydrophobic core of the plasma membrane into cells, this nonspecific transport cannot account for the high affinity and specific transport of LCFAs exhibited by cells such as cardiac muscle, hepatocytes, and adipocytes. Long chain fatty acids (LCFAs) are an important energy source for pro-and eukaryotes and are involved in diverse cellular processes such as membrane synthesis, intracellular signaling, protein modification, and transcriptional regulation. In developed Western countries, human dietary lipids are mainly di-and triglycerides and account for approximately 40% of caloric intake (1). These lipids are broken down into fatty acids and glycerol by pancreatic lipases in the small intestine (2); LCFAs are then transported into brush border cells where the majority is re-esterified and secreted into the lymphatic system as chylomicrons (3). Fatty acids are liberated from lipoproteins by the enzyme lipoprotein lipase which is bound to the luminal side of endothelial cells (4). ''Free'' fatty acids in the circulation are bound to serum albumin (5) and are rapidly incorporated by adipocytes, hepatocytes, and cardiac muscle cells. The latter derive 60-90% of their energy through the ␤ oxidation of LCFAs (6). Although saturable and specific uptake of LCFAs has been demonstrated for intestinal cells, hepatocytes, cardiac myocytes, and adipocytes, the molecular mechanisms of LCFA transport across the plasma membrane have remained controversial (7,8). Five proteins have been suggested to mediate LCFA uptake into cells. Four candidate LCFA transporters, FABPpm (9), 56-kDa renal FABP (10), caveolin (11), and fatty acid translocase (12), were identified by their ability to bind fatty acids. The fifth, fatty acid transport protein (FATP), was identified by Schaffer and Lodish (13) using an expression-cloning strategy. FATP is a 63-kDa plasma membrane protein which increases LCFA uptake when stably expressed in cell lines but has no effect on either glucose or short chain fatty acid transport. FATP is induced during adipocyte differentiation in vitro and is expressed in brain, skeletal muscle, heart, fat, and kidney but not liver (13). Since the liver has a large capacity for fatty acid uptake (14), we started a search for FATP homologues. Here, we describe a large family of highly homologous mammalian LCFA transporters which are widely expressed, including all tissues relevant to fatty acid metabolism. Furthermore, we also identified novel members of this family in other species including mycobacterial and nematode FATPs which, like their mammalian counterparts, are functional fatty acid transporters. MATERIALS AND METHODSSequence Alignment of FATP Clones. The DNA sequence for FATP1 was obtained from the National Center for Biotechnology Information nonredundant database. cDNAs for m...

While intestinal transport systems for metabolites such as carbohydrates have been well characterized, the molecular mechanisms of fatty acid (FA) transport across the apical plasmalemma of enterocytes have remained largely unclear. Here, we show that FATP4, a member of a large family of FA transport proteins (FATPs), is expressed at high levels on the apical side of mature enterocytes in the small intestine. Further, overexpression of FATP4 in 293 cells facilitates uptake of long chain FAs with the same specificity as enterocytes, while reduction of FATP4 expression in primary enterocytes by antisense oligonucleotides inhibits FA uptake by 50%. This suggests that FATP4 is the principal fatty acid transporter in enterocytes and may constitute a novel target for antiobesity therapy.

Fatty acid uptake into 3T3 L1 adipocytes is predominantly transporter mediated. Here we show that, during 3T3 L1 adipocyte differentiation, expression of fatty acid transport proteins (FATPs) 1 and 4 is induced. Using subcellular membrane fractionation and immunofluorescence microscopy, we demonstrate that, in adipocytes, insulin induces plasma membrane translocation of FATPs from an intracellular perinuclear compartment to the plasma membrane. This translocation was observed within minutes of insulin treatment and was paralleled by an increase in long chain fatty acid (LCFA) uptake. In contrast, treatment with TNF-alpha inhibited basal and insulin-induced LCFA uptake and reduced FATP1 and -4 levels. Thus, hormonal regulation of FATP activity may play an important role in energy homeostasis and metabolic disorders such as type 2 diabetes.

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.

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Long-chain fatty acids (LCFAs) are not only important metabolites but contribute to many cellular functions including activation of protein kinase C (PKC) isoforms and nuclear transcription factors such as peroxisome proliferator-activated receptors (PPAPs). To assert their diverse effects LCFAs have first to traverse the plasma membrane, a process that can occur either through diffusion or be mediated by proteins. Considerable evidence has accumulated to show that in addition to a diffusional component, the intestine, heart, adipose tissue, and the liver express a saturable and specific LCFA transport system. Identifying the postulated fatty acid transporters is of considerable importance, since both increased and decreased fatty acid uptake have been implicated in diseases such as type-2 diabetes and acute liver failure. Fatty acid transport proteins (FATPs/solute carrier family 27) are integral transmembrane proteins that enhance the uptake of long-chain and very long chain fatty acids into cells. In humans FATPs comprise a family of six highly homologous proteins, hsFATP1-6, which are found in all fatty acid-utilizing tissues of the body. This review will focus on a brief discussion of FATP expression patterns, regulation, structure, and mechanism of transport.