Fatty acid binding protein isoforms: structure and function

The physiological role of long-chain fatty acyl-CoA is thought to be primarily in intermediary metabolism of fatty acids. However, recent data show that nM to μM levels of these lipophilic molecules are potent regulators of cell functionsin vitro. Although long-chain fatty acyl-CoA are present at several hundred μM concentration in the cell, very little long-chain fatty acyl-CoA actually exists as free or unbound molecules, but rather is bound with high affinity to membrane lipids and/or proteins. Recently, there is growing awareness that cytosol contains nonenzymatic proteins also capable of binding long-chain fatty acyl-CoA with high affinity. Although the identity of the cytosolic long-chain fatty acyl-CoA binding protein(s) has been the subject of some controversy, there is growing evidence that several diverse nonenzymatic cytosolic proteins will bind long-chain fatty acyl-CoA. Not only does acyl-CoA binding protein specifically bind medium and long-chain fatty acyl-CoA (LCFA-CoA), but ubiquitous proteins with multiple ligand specificities such as the fatty acid binding proteins and sterol carrier protein-2 also bind LCFA-CoA with high affinity. The potential of these acyl-CoA binding proteins to influence the level of free LCFA-CoA and thereby the amount of LCFA-CoA bound to regulatory sites in proteins and enzymes is only now being examined in detail. The purpose of this article is to explore the identity, nature, function, and pathobiology of these fascinating newly discovered long-chain fatty acyl-CoA binding proteins. The relative contributions of these three different protein families to LCFA-CoA utilization and/or regulation of cellular activities are the focus of new directions in this field.

Acyl-CoA binding proteins: Multiplicity and function

Placental metabolism and its regulation in health and diabetes

When a 105,000 x g supernatant of human placenta was incubated with [1-14C]oleate and subjected to Sephadex G-75 gel filtration and HPLC, two fatty-acid-binding protein (FABP) peaks were obtained. One of these, when further purified by carboxymethyl-cellulose, gave one 15.3-kDa FABP with pI5.3. The other, when chromatographed on DEAE cellulose, separated into two 14.2-kDa FABP with pI6.9 and 5.4. Purity of the proteins was checked by SDS/PAGE. Molecular mass, pI, immunochemical properties and amino acid compositions all indicated that 15.3-kDa FABP was of the cardiac type, whereas both 14.2-kDa FABP were of the hepatic type. Cardiac FABP did not cross-react with hepatic proteins. When tested for the acceptor/donor properties of these FABP, hepatic types were found to be better candidates than cardiac in uptaking fatty acids from liposomes. Cardiac FABP, on the other hand, acted in a more efficient way as a donor, indicating a distinct role of these proteins in human placenta, which furnishes a multiorgan system for the developing fetus.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1993.tb17602.x

Characterization of cardiac fatty-acid-binding protein from human placenta. Comparison with placenta hepatic types.

Although physiologic jaundice of neonates is common, persistent neonatal cholestasis is life-threatening and has multiple etiologies. Among these etiologies, biliary atresia (BA) requires rapid diagnosis and treatment. In diagnosing BA, the surgical pathologist must recognize subtle histologic changes, often with only a small core liver biopsy. To aid in the differential diagnosis of neonatal cholestasis, we investigated Yes-associated protein (YAP), a regulator of organ size and bile duct development. We examined whether a YAP immunostain can highlight emerging hepatobiliary epithelium in BA (n = 28) versus other causes of persistent cholestasis (non-BA; n = 15) and thus serve as a useful diagnostic marker in persistent neonatal jaundice. We show significantly (P < .01) more high-grade (<2) fibrosis and ductular proliferation among BA versus non-BA cases. Likewise, there was significantly more high-grade (2-3/3) cytoplasmic and nuclear YAP staining in BA (97% and 89%) versus non-BA (20% and 13%). High-grade nuclear YAP staining was both sensitive (88%) and specific (87%) for the diagnosis of BA. In contrast to neonatal cholestasis, the differences in YAP localization in cholestatic/obstructed versus nonobstructed adult livers were not significant. Lastly, we found that pharmacologic inhibition of the YAP complex in both cholangiocyte and cholangiocarcinoma cell lines blocked compensatory bile duct proliferation, an early marker of BA that requires nuclear YAP expression, in a time- and dose-dependent manner. In summary, we show that YAP expression modulates both bile duct proliferation and liver damage/fibrosis while acting as a sensitive and specific marker in the differential diagnosis of persistent neonatal cholestasis.

The use of Yes-associated protein expression in the diagnosis of persistent neonatal cholestatic liver

Role of fatty acid binding proteins (FABPs) in modulating inhibition of human placental malate dehydrogenase by palmitoyl-CoA and oleate has been studied Activity of human placental cytosolic malate dehydrogenase is detected throughout the gestation, showing a peak at midgestation (20-25 weeks) Inhibition (50%) of the enzyme activity is obtained by 20 microM palmitoyl-CoA or 35 microM oleate FABPs enhance the activity of malate dehydrogenase in absence of palmitoyl-CoA or oleate and also protect against palmitoyl-CoA or oleate inhibition Such a modulatory effect of FABP may be due to the binding of long chain fatty acyl-CoA or fatty acid rather than a direct effect of FABPs on the enzyme

Effect of fatty acid binding proteins on developing human placental malate dehydrogenase activity.

The relationship between fatty acid binding proteins, ATP citrate lyase activity and fatty acid synthesis in developing human placenta has been studied. Fatty acid binding proteins reverse the inhibitory efect of palmitoyl-CoA and oleate on ATP citrate lyase and fatty acid synthesis. In the absence of these inhibitors fatty acid binding proteins activate ATP citrate lyase and stimulate [ 1-14 C] acetate incorporation into placental fatty acids indicating binding of endogenous inhibitors by these proteins. Thus these proteins regulate the supply of acetyl-CoA as well as the synthesis of fatty acids from that substrates. As gestation proceeds and more lipids are required by the developing placenta fatty acid binding protein content, activity of ATP citrate lyase and rate of fatty acid synthesis increase indicating a cause and efect relationship between the demand of lipids and supply of precursor fatty acids during human placental development.

Relationship between fatty acid binding proteins, acetyl-CoA formation and fatty acid synthesis in developing human placenta

Modulation of palmitoyl-CoA inhibition of human placental 6-phosphogluconate dehydrogenase activity by fatty acid binding proteins

The activities of the enzymes glycerol-3-phosphate dehydrogenase and fatty acid synthase are inhibited by palmitoyl-coenzyme A and oleate. The two isoforms of fatty acid binding proteins (PI 6.9 and PI 5.4) enhance the activities of glycerol-3-phosphate dehydrogenase and fatty acid synthase in the absence of palmitoyl-coenzyme A or oleate and also protect them against palmitoyl-coenzyme A or oleate inhibition. Levels of fatty acid binding proteins, the activities of the enzymes fatty acid synthase and glycerol-3-phosphate dehydrogenase increase with gestation showing a peak at term. However, the activity of fatty acid synthase showed the same trend up to the 30th week of gestation and then declined slightly at term. With the advancement of pregnancy when more lipids are required for the developing placenta, fatty acid binding proteins supply more fatty acids and glycerol-3-phosphate for the synthesis of lipids. Thus a correlation exists between glycerol-3-phosphate dehydrogenase, fatty acid synthase and fatty acid binding proteins in developing human placenta.

Anup K Bandyopadhyay

Papers

Effect of fatty acid binding proteins on developing human placental malate dehydrogenase activity.

Relationship between fatty acid binding proteins, acetyl-CoA formation and fatty acid synthesis in developing human placenta

Modulation of palmitoyl-CoA inhibition of human placental 6-phosphogluconate dehydrogenase activity by fatty acid binding proteins

Relationship between glycerol-3-phosphate dehydrogenase, fatty acid synthase and fatty acid binding proteins in developing human placenta