Liver, fatty acid-binding proteins

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. 

Hsu, K.-T. and Storch, J. (1996) Fatty acid transfer from liver and intestinal fatty acid-binding proteins to membranes occurs by different mechanisms. Journal of Biological Chemistry 271,13317—13323. 

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.

Glutathione S transferases bind bile acids in vitro but doubt has been cast over whether this happens in vivo as these enzymes were not labelled by fluorescently labelled bile acids in experiments to identify the carrier proteins but may play a role with the raised levels in cholestasis. Liver fatty-acid-binding protein has been shown to bind bile acids by using a displacement assay with fluorescent fatty-acid ligand. This work clearly showed displacement to be directly related to hydrophobicity, such that lithocholate conjugates had the greatest effect. This may indicate a mechanism to minimise toxicity within the hepatocyte. 

Several studies have evaluated the effects of oral di(2-ethylhexyl) adipate on various aspects of hepatic lipid metabolism. Feeding di(2-ethylhexyl) adipate (2% of diet) to male Wistar rats for seven days resulted in increased hepatic fatty acid-binding protein as well as in increased microsomal stearoyl-CoA desaturation activity (Kawashima et al., 1983a,b). Feeding the compound at this dose for 14 days resulted in increased levels of hepatic phospholipids and a decline in phosphatidyl-choline phosphatidylethanolamine ratio (Yanagita et al., 1987). Feeding di(2-ethyl-hexyl) adipate (2% of diet) to male NZB mice for five days resulted in induction of fatty acid translocase, fatty acid transporter protein and fatty acid binding protein in the liver (Motojima et al., 1998). 

Kawashima, Y., Nakagawa, S., Tachibana, Y. Kozuka, H. (1983a) Effects of peroxisome proliferators on fatty acid-binding protein in rat liver. Biochim. biophys. Acta, 754, 21-27 Kawashima, Y, Hanioka, N., Matsumura, M. Kozuka, H. (1983b) Induction of microsomal stearoyl-CoA desaturation by the administration of various peroxisome proliferators. 

Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435(7045) 1108-12 Howlett AC, Qualy JM, Khachatrian LL (1986) Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol 29(3) 307-13 Hsu K-T, Storch J (1996) Fatty acid transfer from liver and intestinal fatty acid-binding proteins to membranes occurs by different mechanisms. J Biol Chem 271(23) 13317—23... 

The EFA metabolism is presented in several extensive reviews.9 16 17 Much of the information concerning EFA physiology and biochemistry has been derived from work in hepatocytes and may be of limited relevance to epidermis since a major role of the liver is to convert dietary lipids into energy stores. Meanwhile, keratinocytes are involved in the fatty acid metabolism required both for normal cellular processes and the specialized role in the permeability barrier. Unlike the liver, the epidermis does not possess the capacity to desaturate at the A5 or A6 position, and therefore the skin relies on a supply of AA, LA, and ALA from the bloodstream. There is evidence for a distinct fatty acid binding protein in keratinocyte plasma membranes that is involved in EFA uptake into the skin and also recycling of free fatty acids from the stratum corneum.18 The transport mechanism in epidermis differs from that in hepatocytes since there is preferential uptake of LA over OA, which may function to ensure adequate capture of LA for barrier lipid synthesis.18... 

H22. Hitomi, M., Odani, S., and Ono, T., Glutathione-protein mixed disulfide decreases the affinity of rat liver fatty acid-binding protein for unsaturated fatty acid. Em J. Biochem. 187, 713-719 (1990). 

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]. 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

Dormann, P., Botchers, X, Korf, U Hojrup, P., Roepstorff, F, and Spencer, F. (1993). Amino acid exchange and covalent modification by cysteine and glutathione explain isoforms of fatty acid-binding protein occurring itt bovine liver. /. Bib . Cfiem. 268,16286 8292. 

Bartsal, M. R, Cook, R. G., Danielson, K C, and Medina, D. (I9 J9). A 14-kilodalton sele-njum-binding protein in mouse liver is fatty acid-binding protein., Biol. Chem. 264, 13780-137S4. 

M.A. Lunzer, J.a. Manning, and R. K. OcKNER, Inhibition of rat liver acetyl coenzyme A carboxylase by long chain acyl coenzyme A and fatty acid. Modulation by fatty acid-binding protein, J. Biol. Chem., 1977, 252, 5483-5487. 

W. Stremmel, G. Strohmeyee, F. Borchard, S. Kochwa, and P.D. Berk, Isolation and partial characterization of a fatty acid binding protein in rat liver plasma membranes, Proc. Natl. Acad. Sci. USA, 1985, 82, 4-8. 

Massolini, G., De Lorenzi, E., Calleri, E., Bertucci, C., Monaco, H. L., Perduca, M., Caccialanza, G.,Wainer, 1. W. Properties of a stationary phase based on immobilized chicken liver basic fatty acid-binding protein,/. Chromatogr. B, 2001, 751, 117-130. 

Transport of fatty acids inside the parenchymal cells, that is, from the plas-malentma to the intracellular site of conversion, is most likely mediated by fatty acid-binding proteins (FABPs). At least seven different isoforms of this low molecular weight protein (15 kDa) have been described, among which there is the liver-type and muscle-type FABP (Glatz and Van der Vusse, 1990). FABPs facilitate intracellular transport of fatty acids by increasing their solubility in the aqueous environment. 

Luebker, D. J., Hansen, K. J., Bass, N. M., Butenhoff, J. L., and Seacat, A. M. (2002). Interactions of fiuorochemicals with rat liver fatty acid-binding protein. Toxicology 176, 175-185. 

Simon, T. C., Cho, A., Tso, P., and Gordon, J. I. (1997) Suppressor and activator functions mediated by a repeated heptad sequence in the liver fatty acid-binding protein gene (Fabpl). Effects on renal, small intestinal, and colonic epithelial cell gene expression in transgenic mice. J. Biol. Chem. 272, 10652-10663. 

Thompson, J., A. Reese-Wagoner, and L. Banaszak. 1999. Liver fatty acid binding protein species variation and the accommodation of different ligands. Biochim. Biophys. Acta 1441(2-3) 117-130. 

Woifrum, C., Borrmann, C. M., Borchers, T., and Spener, F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein a signaling path to the nucleus. Proc Natl Acad Sci U S A 98 (2001) 2323-2328. 

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