FA uptake and transport proteins

From LipidomicsWiki

During catabolic episodes, fatty acids within the adipose cells are mobilised, transported and distributed to various tissues via the blood stream as lipoprotein complexes. The mechanisms of cellular uptake and intracellular trafficking of fatty acids are complex and not clearly understood (McArthur et al. 1999). The short chain and medium-chain fatty acids (C4- C6 and C8-C12 carbon atom chain lengths, respectively) diffuse freely across the plasma and mitochondrial membranes into the mitochondrial matrix. In contrast, there is growing evidence that the mechanism of cellular uptake of long-chain fatty acids (C14-C20) depends on both passive diffusion and active carrier-mediated transmembrane translocation (Berk et al. 1999, Stump et al. 2001).

Ensembl - ID	Transporter	Chromo-some	Acyl-CoA synthetase activity/specificity	Subcellular localisation	Tissue-specific expression
ENSG00000135218	CD36/FAT	7q11.2	-	plasma membrane	heart, intestine, monocytes, macrophages, platelets, spleen, skeletal muscle
---	FABP-PM	16q21	-	plasma membrane	liver, adipose tissue, cardiac muscle, intestine, vascular endothelium
ENSG00000130304	FATP1 (Slc27A1)	19p13.1	very long chain (C20 – C24)	plasma membrane	muscle, adipose tissue, heart, lung, kidney, pancreas
ENSG00000140284	FATP2 (Slc27A2)	15q21.2	very long chain (C20 – C24)	plasma membrane	kidney, intestine, liver
ENSG00000143554	FATP3 (Slc27A3)	1q21.1	?	plasma membrane	lung, liver, pancreas, kidney, intestine
ENSG00000167114	FATP4 (Slc27A4)	9q34	+	plasma membrane	intestine (apical membrane), lung, keratinocytes, liver, testis
ENSG00000083807	FATP5 (VLCS-H2)	19q13.43	very long chain (C20 – C24)	plasma membrane	liver, small intestine, heart, brain, lung, kidney
ENSG00000113396	FATP6 (VLCS-H1)	5q31.1	?	plasma membrane	heart

Several different proteins have been shown to facilitate transport of long-chain fatty acids have been characterised in different species at the protein and/or gene levels (Tab.1). These include the long-chain fatty acid transporter protein family, with six different FATP, designated FATP1 to 6, identified in humans (Hirsch et al. 1998), the fatty acid translocase (FAT) (Abumrad et al. 1993), and the membrane-associated plasmalemmal fatty acid-binding protein (FABPpm) (Stremmel et al. 1985). Co-expression of genes coding for FATP, FAT and FABPpm in rat heart and muscle cells (Van Nieuwenhoven et al. 1999), and human skeletal muscle (Bonen et al. 1999) suggests that the uptake processes may involve the co-operation of a number of proteins.

fatty acids are converted to their respective acyl-CoA esters by different fatty acyl-CoA synthetases. The imported long-chain fatty acids are esterified by long-chain acyl-CoA synthetase (LACS) located at the outer leaflet of the plasma membrane in adipocytes (Gargiulo et al. 1999), the outer mitochondrial membrane of skeletal muscle and microsomes in the liver, whereas the short- and medium-chain fatty acids are activated within the mitochondrial matrix (Trevisan et al. 1995).

Following their uptake, the fatty acids and derivatives translocate through the aqueous cytoplasm to the mitochondria, possibly with the aid of cytoplasmic fatty acid-binding proteins (FABPc) (Glatz et al. 1998). FABPs belong to the conserved multigene family of the intracellular lipid binding proteins (iLBPs). These proteins are ubiquitously expressed in vertebrate tissues, with distinct expression patterns for the individual FABPs. Various functions have been proposed for these proteins, including the promotion of cellular uptake and transport of fatty acids, the targeting of fatty acids to specific metabolic pathways, and the participation in the regulation of gene expression and cell growth.

Transgenic cell lines, animals, and knockout mice have helped to define essential cellular functions of individual FABP-types or of combinations of several different FABPs. The deletion of particular FABP genes, however, has not led to gross phenotypical changes, most likely because of compensatory overexpression of other members of the iLBP gene family, or even of unrelated fatty acid transport proteins. In recent years, a numerical nomenclature for the various FABP genes has been introduced (Haunerland and Spener, 2004; Hertzel and Bernlohr, 2000), but the various FABPs are still named after the tissues in which they have been discovered, or are prominently expressed (Tab.2).

Ensembl - ID	Gene	iLBP type	Expression	Ligands
Subfamily I
---	---	CRBP I, II, III, and IV	Ubiquitous in mammalian cells	Retinol
---	---	CRABP I and II	Ubiquitous in mammalian cells	Retinoic acids
Subfamily II
ENSG00000163586	Fabp1	L-FABP	Liver, intestine, kidney, lung, and pancreas	Long-chain fatty acids, acyl-CoAs, and heme
ENSG00000170231	Fabp6	I-BABP	Ileum	bile acids
ENSDARG00000038439	Fabp10	Lb-FABP	Fish and bird liver	Long-chain fatty acids
Subfamily III
ENSG00000145384	Fabp2	I-FABP	Intestine, liver	Long-chain fatty acids
Subfamily IV
ENSG00000121769	Fabp3	H-FABP	Heart, skeletal muscle, brain, kidney, lung, mammary, placenta, testis, ovary, and stomach	Long-chain fatty acids
ENSG00000170323	Fabp4	A-FABP	Adipose tissue and macrophages liver	Long-chain fatty acids
ENSG00000164687	Fabp5	E-FABP	Skin, adipose tissue, lung, brain, heart, skeletal muscle, testis, retina, and kidney	Long-chain fatty acids
ENSG00000164434	Fabp7	B-FABP	Brain, glia cells, and retina	Long-chain fatty acids
ENSG00000147588	Fabp8	M-FABP	Brain and Schwann cells	Long-chain fatty acids
ENSRNOG00000011082	Fabp9	T-FABP	Testis	Long-chain fatty acids

It should be recognized, however, that such a classification is somewhat misleading, since no FABP is specific for a given tissue, and most tissues express various FABP-types. L-FABP, for example, is strongly expressed in the liver, and was thought to be the only FABP expressed in this tissue, at least in adult animals (recent studies have reported the presence of E-FABP, I-FABP, and A-FABP in liver as well [13,14]). But L-FABP is also found, albeit in far smaller concentrations, in the intestine, kidney, lung, and pancreas. In contrast, I-FABP and I-BABP are confined to the digestive tract and not expressed prominently in other tissues (Chmurzynska 2006). H-FABP and E-FABP are the most ubiquitously expressed iLBPs; the former is most prominent in cardiac and skeletal muscle, but also present in kidney, lung, mammary tissue, placenta, testis, stomach, ovary, and the brain.

The latter protein is widely expressed in skin, lung, heart and skeletal muscle, kidney, testis, and adipose tissue, as well as in the brain and the retina. In addition to H- and E-FABP, the nervous system contains two other FABPs, B-FABP that is present in brain and retina, and the M-FABP that seems to be specific for the Schwann cells forming the myelin sheath. A-FABP was originally thought to be confined to adipocytes, but has been detected in macrophages as well.