A family of fatty acid transporters conserved from mycobacterium to man

Abstract

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...

Differences in adipocyte long chain fatty acid uptake in Osborne–Mendel and S5B/Pl rats in response to high-fat diets

“…23,[37][38][39][40] At least four proteins have been proposed as LCFA transporters: plasma membrane fatty acid-binding protein (FABPpm), 32,37-39 fatty acid translocase (FAT), 30 the fatty acid transport polypeptide family (FATP) [41][42][43] and caveolin-1. 44,45 While there is good evidence supporting a role in LCFA transport for these proteins, there are also unresolved issues that have led to persistent doubts about each.…”

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…Upon reaching their target cell, short and medium chain fatty acids (C 4 -C 12 ) traverse the cell membrane by passive diffusion. However, saturated and unsaturated long chain fatty acids cross the cell membrane by sodium dependent fatty acid transporters [38]. These include fatty acid transport proteins (FATPs), plasma membrane fatty acid binding proteins and the fatty acid translocase protein CD36.…”

Acute Hepatic Failure and Defective Fatty Acid Transport: Clinical Proof of A Physiologic Hypothesis

“…11 Recently, homologues of FATP1, designated FATP2-FATP5, have been identified. 12 Of these, FATP5 is expressed exclusively in the liver and FATP2 in the liver and kidney. All seven of these putative FFA transporters increase cellular FFA uptake after transfection of their complementary DNAs into nonexpressing cell types.…”