The transport of long chain fatty acids across the cell plasma membrane and through the cell cytoplasm as well as their subsequent utilization for energy production and glycerolipid synthesis may depend, in part, upon their interaction with fatty acid binding proteins (FABP) present in both the cell plasma membrane and cytoplasm. Although only one molecular form of membrane-associated FABP has been characterized in liver (LPM- FABP; 40 dDa), three distinct 14-15 kDa cytoplamic FABP have been purified, respectively, from liver (L-FABP), intestine (I- FABP), and heart muscle (M-FABP). The cytoplasmic FABP may perform specialized functions in fatty acid transport and utilization in these different tissues. The nature of the precise functions of the FABP, however, remains undefined. L-FABP, in addition, is not uniformly expressed in liver cells, but predominates in lobular zone I (periportal) hepatocytes. However, the significance of the differential hepatocellular expression of L- FABP in relation to specific pathways of fatty acid metabolism and in relation to the ability of hepatocytes to withstand potentially toxic effects of long chain fatty acids is unknown.
The aims of this proposal have as their broad goal, the elucidation of the function of the cellular FABP and are to: (1) determine the relationship between L-FABP abundance and long chain fatty acid utilization and toxicity in (a) hepatocytes isolated from zones abundant (periportal hepatocytes) and sparse (perivenous hepatocytes) in their expression of L-FABP, as well as in (b) hepatocyte monolayer cultures following alteration of the L- FABP pool size by liposome-mediated injection of anti-L-FABP IgG or pure L-FABPl (2) determine the comparative mechanisms of L-FABP and M-FABP effects on mitochondrial and microsomal long chain acyl-CoA synthesis and to determine whether radiolabeled L-FABP and M-FABP bind in a specific manner to microsomal and mitochondrial membranes; (3) define the putative function of LPM-FABP in membrane fatty acid translocation by identifying and characterizing liver plasma membrane proteins labeled with photoreactive long chain fatty acid probes and by developing improved methods for purifying LPM-FABP in order to determined its fatty acid transport function reconstituted in liposomes. Collectively, the proposed studies will provide important new information regarding the poorly understood function of cellular FABP and their role in the cellular transport and regulation of fatty acid metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032926-06
Application #
3231299
Study Section
Metabolism Study Section (MET)
Project Start
1985-01-01
Project End
1992-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kaikaus, R M; Chan, W K; Lysenko, N et al. (1993) Induction of peroxisomal fatty acid beta-oxidation and liver fatty acid-binding protein by peroxisome proliferators. Mediation via the cytochrome P-450IVA1 omega-hydroxylase pathway. J Biol Chem 268:9593-603
Kaikaus, R M; Sui, Z; Lysenko, N et al. (1993) Regulation of pathways of extramitochondrial fatty acid oxidation and liver fatty acid-binding protein by long-chain monocarboxylic fatty acids in hepatocytes. Effect of inhibition of carnitine palmitoyltransferase I. J Biol Chem 268:26866-71
Ockner, R K; Kaikaus, R M; Bass, N M (1993) Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: review and hypothesis. Hepatology 18:669-76
Kaikaus, R M; Chan, W K; Ortiz de Montellano, P R et al. (1993) Mechanisms of regulation of liver fatty acid-binding protein. Mol Cell Biochem 123:93-100
Bass, N M (1993) Cellular binding proteins for fatty acids and retinoids: similar or specialized functions? Mol Cell Biochem 123:191-202
Schurer, N Y; Bass, N M; Jin, S et al. (1993) High-affinity fatty acid-binding activity in epidermis and cultured keratinocytes is attributable to high-molecular-weight and not low-molecular-weight fatty acid-binding proteins. J Invest Dermatol 100:82-6
Medzihradszky, K F; Gibson, B W; Kaur, S et al. (1992) The primary structure of fatty-acid-binding protein from nurse shark liver. Structural and evolutionary relationship to the mammalian fatty-acid-binding protein family. Eur J Biochem 203:327-39
Ortiz de Montellano, P R; Chan, W K; Tuck, S F et al. (1992) Mechanism-based probes of the topology and function of fatty acid hydroxylases. FASEB J 6:695-9
Ockner, R K; Kaikaus, R M; Bass, N M (1992) Fatty acid binding proteins: recent concepts of regulation and function. Prog Clin Biol Res 375:189-204
Bass, N M; Manning, J A; Luer, C A (1991) Isolation and characterization of fatty acid binding protein in the liver of the nurse shark, Ginglymostoma cirratum. Comp Biochem Physiol A Comp Physiol 98:355-62

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