Carbon monoxide, an activator of guanylyl cyclase, is formed by the action of the enzyme heme oxygenase. By in situ hybridization in brain slices, discrete neuronal localization of messenger RNA for the constitutive form of heme oxygenase throughout the brain has been demonstrated. This localization is essentially the same as that for soluble guanylyl cyclase messenger RNA. In primary cultures of olfactory neurons, zinc protoporphyrin-9, a potent selective inhibitor of heme oxygenase, depletes endogenous guanosine 3',5'-monophosphate (cGMP). Thus, carbon monoxide, like nitric oxide, may be a physiologic regulator of cGMP. These findings, together with the neuronal localizations of heme oxygenase, suggest that carbon monoxide may function as a neurotransmitter.

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.