Albumin fatty acid binding

Acetoacetate and /3-hydroxybutyrate are transported through the blood from liver to target organs and tissues, where they are converted to acetyl-CoA (Figure 24.29). Ketone bodies are easily transportable forms of fatty acids that move through the circulatory system without the need for eomplexation with serum albumin and other fatty acid—binding proteins. 

Free fatty acids—also called unesterified (UFA) or non-esterified (NEFA) fatty acids—are fatty acids that are in the unesterified state. In plasma, longer-chain FFA are combined with albumin, and in the cell they are attached to a fatty acid-binding protein, so that in fact they are never really free. Shorter-chain fatty acids are... 

The free fatty acid uptake by tissues is related directly to the plasma free fatty acid concentration, which in turn is determined by the rate of lipolysis in adipose tissue. After dissociation of the fatty acid-albumin complex at the plasma membrane, fatty acids bind to a membrane tty acid transport protein that acts as a transmembrane cotransporter with Na. On entering the cytosol, free fatty acids are bound by intracellular fatty acid-binding proteins. The role of these proteins in intracellular transport is thought to be similar to that of serum albumin in extracellular transport of long-chain fatty acids. 

Figure 13.2 Schematic representation of the creation of hPXR humanized mice. The humanization was achieved in the liver only when the liver-specific albumin promoter was used to direct the transgene expression, or in both the liver and the intestine when the fatty acid binding protein promoter was used. PCN, pregnenolone-16a-carbonitrile RIF, rifampicin. + and mean induction and lack of induction, respectively.

Fatty acid utilized by muscle may arise from storage triglycerides from either adipose tissue depot or from lipid stores within the muscle itself. Lipolysis of adipose triglyceride in response to hormonal stimulation liberates free fatty acids (see Section 9.6.2) which are transported through the bloodstream to the muscle bound to albumin. Because the enzymes of fatty acid oxidation are located within subcellular organelles (peroxisomes and mitochondria), there is also need for transport of the fatty acid within the muscle cell this is achieved by fatty acid binding proteins (FABPs). Finally, the fatty acid molecules must be translocated across the mitochondrial membranes into the matrix where their catabolism occurs. To achieve this transfer, the fatty acids must first be activated by formation of a coenzyme A derivative, fatty acyl CoA, in a reaction catalysed by acyl CoA synthetase. 

W. C. Galley, Heterogeneity in protein emission spectra, in Concepts of Biochemical Fluorescence Vol. 2 (R. F. Chen and H. Edelhoch, eds.), pp. 409-439, Marcel Dekker, New York (1976).32. S.-Y. Mao and A. H. Maki, Comparative phosphorescence and optically detected magnetic resonance studies of fatty acid binding to serum albumin, Biochemistry 26, 3576-3582 (1987). 

FlC. 9. Nonparallel regeneration of the functions for bilirubin binding and fatty acid binding in bovine plasma albumin. The oxidative regeneration of reduced albumin was carried out at protein concentrations of 1 ft,M at 25°C in 0.10 M Tris-chloride buffer, pH 8.0, containing 1 mM EDTA and 1 mM reduced and 0.10 mM oxidized glutathione (Johanson et al, 1977, 1981). 

Long-chain fatty acid binding to albumin a problem of transport, pathology and terminology... 

The FFA released by the adipocytes is collected by albumin and is transported to the various tissues in the blood. The albumin-FFA complex is able to cross the endothelial barrier in the capillaries and enter the interstitial space and so deliver this important fuel to the plasma membrane of the cell. To facilitate the transport of free fatty acids across the plasma membrane and within the cell, other transport proteins are present these are known as fatty acid binding proteins (FABP). 

Figure 7.8 Comparison of oxygen transport from lung to a cell and then into a mitochondrion with fatty acid transport from an adipocyte to a cell and then into the mitochondria in various tissues/ organs. Fatty add is transported in blood bound to albumin, oxygen is transported in blood bound to haemoglobin. Fatly add is transported within the cell attached to the fatty acid-binding protein (BP), oxygen is transported within a cell attached to myoglobin (Mb). Alb represents albumin, Hb haemoglobin.

Chylomicrons deliver tiiacylglycerols to tissues, where lipoprotein lipase releases free fatty acids for entry into cells. Triacylglycerols stored in adipose tissue are mobilized by a hormone-sensitive triacylglycerol lipase. The released fatty acids bind to serum albumin and are carried in the blood to the heart, skeletal muscle, and other tissues that use fatty acids for fuel. 

Fate of fatty acids The free (unesterified) fatty acids move through the cell membrane of the adipocyte, and immediately bind to albumin in the plasma. They are transported to the tis sues, where the fatty acids enter cells, get activated to their CtA derivatives, and are oxidized for energy. [Note Active transport of fatty acids across membranes is mediated by a membrane fatty acid binding protein.] Regardless of their blood levels, plasma free fatty acids cannot be used for fuel by erythrocytes, which have no mitochondria, or by the brain because of the imperme able blood-brain barrier. rr f-... 

The pharmacokinetics of PFOS and PFOA have been investigated in animal studies [22-24]. Results indicate that both PFCs are well absorbed following oral exposure, and poorly eliminated. In addition, PFOS and PFOA are very persistent as they are not metabolized and undergo extensive enterohepatic circulation [25,26]. PFSAs and PFCAs are unique among other persistent halogenated organic contaminants as they do not preferentially accumulate in fatty tissues, but instead are predominately distributed in the liver, serum and kidney [22-24]. This may be explained by the fact that PFOS and PFOA bind to proteins, specifically )8-lipoproteins, albumin and liver fatty acid-binding proteins [27, 28]. 

Spector, A. A. (1975). Fatty acid binding to plasma albumin. /. Lijrid Res. 16,165-179. 

The function of most albumin isoforms is normal, although some have abnormal binding affinities for thyroxine (T4). Binding may be increased, as in familial dysalbu-minemic hyperthyroxinemia, or decreased. Individuals with famihal dysalbuminemic hyperthyroxinemia are euthyroid but have elevated serum T4 and free T4 index the variant albumin comigrates with Alb A. Two glycosylated variants. Alb RedhiU and Alb Casebrook, have altered fatty acid binding properties. 

Diagnosis of cardiac muscle injury relies on the detection of biomarkers such as troponin I (Tnl), troponin C (TnC), myoglobin, fatty acid binding protein (FABP), glycogen phosporylase isoenzyeme BB (GPBB), C-reactive protein (CP), urinary albumin, creatine kinase myocardial band (CK-MB), and brain (B-type) natriuretic peptide in blood and urine [28-30]. 

The liver is the main origin of ketones in laboratory animals, where the long chain fatty acids are released from plasma albumin and bound to fatty acid-binding proteins in the hepatocytes. The long chain fatty acids react with CoA and then can be used to synthesize triacylglycerol or undergo beta-oxidation to acetyl CoA. When the levels of plasma fatty acids are elevated, acetyl CoA can be metabolized to form acetoacetate and 3-hydroxybutyrate or enter the tricarboxylic acid cycle. In ketosis, the levels of acetone, acetoacetate, and 3-hydroxybutyrate (also known as beta-hydroxybutyrate) are increased in both plasma and urine these three compounds historically were collectively called ketone bodies. Urine test strips can be used to test for ketonuria, and there are several enzymatic assays for 3-hydroxybutyrate and acetoacetate. 

Fatty acids are amphipathic and form micelles like other detergents (Sec. 12.3), and they are transported in the Wood bound to albumin. This is the most ahnndant plasma protein, and each molecule of 68,500 contains fonr fatty acid binding sites. 

The benefit of a long and predictable half-life is related to the bnfifering capacity of albumin [12], and the associated favourable safety profile is related to a large excess of fatty acid binding sites on albumin at therapeutic levels of insulin/GLP-1, leading to a minimal risk of drag displacement interactions [10,12]. 

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