Expression of fatty acid binding proteins inhibits lipid  accumulation and alters toxicity in L cell fibroblasts

Atshaves, Barbara P.; Storey, Stephen M.; Petrescu, Anca D.; Greenberg, Cynthia C.; Lyuksyutova, Olga I.; Smith, Roger; Schroeder, Friedhelm

doi:10.1152/ajpcell.00586.2001

Cited by 79 publications

(58 citation statements)

References 100 publications

(101 reference statements)

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“…Thus, L-FABP-deficient mice provide a system to learn more about the coordinate regulation of SCP-2/SCP-x. Finally, these mice will also be of use to resolve the mechanism behind the previously observed toxicity of phytanic acid in SCP-x/ SCP-2 null mice (49), which may in fact be due to the increased levels of L-FABP (55).…”

Section: Discussionmentioning

confidence: 99%

Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

Martin

Danneberg

Kumar

et al. 2003

Journal of Biological Chemistry

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156

183

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Although liver fatty acid-binding protein (L-FABP) isan important binding site for various hydrophobic ligands in hepatocytes, its in vivo significance is not understood. We have therefore created L-FABP null mice and report here their initial analysis, focusing on the impact of this mutation on hepatic fatty acid binding capacity, lipid composition, and expression of other lipid-binding proteins. Gel-filtered cytosol from L-FABP null liver lacked the main fatty acid binding peak in the fraction that normally comprises both L-FABP and sterol carrier protein-2 (SCP-2). The binding capacity for cis-parinaric acid was decreased >80% in this region. Molar ratios of cholesterol/cholesterol ester, cholesteryl ester/triglyceride, and cholesterol/phospholipid were 2-to 3-fold greater, reflecting up to 3-fold absolute increases in specific lipid classes in the order cholesterol > cholesterol esters > phospholipids. In contrast, the liver pool sizes of nonesterified fatty acids and triglycerides were not altered. However, hepatic deposition of a bolus of intravenously injected family (1-3), is found in the liver, intestine, and kidney, but only in liver is it not co-expressed with other members of its family. L-FABP is known to bind fatty acids and various other hydrophobic molecules, although its actual contribution to the lipid-binding capacity of liver cytosol is not known. Given that L-FABP is expressed at very high levels (2-5% of cytosolic protein) in the differentiated hepatocyte (4, 5) and that these levels correlate well with lipid metabolism (2), it can be speculated that L-FABP contributes considerably to hepatic lipidbinding and lipid metabolism. Work with cell-free systems and transfected cells has further strengthened this view. For example, in cell-free preparations L-FABP was shown to stimulate the esterification of oleic acid while inhibiting that of palmitic acid (6). L cells overexpressing L-FABP show increased rates of fatty acid uptake and esterification (7) as well as increased contents of phospholipid and cholesterol esters (8, 9). HepG2 hepatoma cells expressing an L-FABP antisense RNA showed a dose-dependent reduction of fatty acid uptake (10). Furthermore, overexpression of L-FABP in McA-RH7777 hepatoma cells incubated with palmitic acid decreased the synthesis and secretion of triglycerides while increasing beta oxidation and the secretion of apolipoprotein B100 (11). Thus, the various in vitro systems have allowed researchers to propose specific functions of L-FABP in vivo.However, in vitro studies of FABPs have inherent limitations. The only firmly established function of FABPs is the reversible binding of hydrophobic ligands, and these proteins do not exhibit any enzymatic function or energy requirement. This suggests that these proteins play passive (facilitative) roles that, almost by definition, are strongly dependent on the cellular context. One context of the highly expressed L-FABP is the highly differentiated hepatocyte, a cell type featuring an intense lipid metabolism that is not eas...

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Section: Discussionmentioning

confidence: 99%

Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

Martin

Danneberg

Kumar

et al. 2003

Journal of Biological Chemistry

Self Cite

156

183

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“…Although their complete tertiary structure, gene organization, and binding properties are known, the functional aspects of these proteins are still undergoing investigation. FABP's protective role is evidenced by: (1) controlling the availability of free fatty acids and their metabolites in the cytosol, and which prevents their cellular toxicity 14,15 ; (2) modulating the interaction of fatty acids with nuclear receptors 16 ; (3) sequestrating or removing cytotoxic drugs 17 ; and (4) trapping or scavenging ROS. 4,[18][19][20][21] However, no significant protective effects of FABP had been observed for chemical-induced anoxia or transport of intracellular fatty acid using the FABP-transfected kidney cell (MDCK) model.…”

Section: Discussionmentioning

confidence: 99%

Antioxidative function of L-FABP in L-FABP stably transfected Chang liver cells

et al. 2005

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C ellular oxidative stress is one of the factors responsible for the propagation of liver diseases, such as hepatitis, cirrhosis, and hepatoma. 1 Several primary antioxidant defense systems such as superoxide dismutase (SOD), catalase, glutathione (GSH), and glutathione peroxidase are present intracellularly. These systems scavenge reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, lipid peroxides, and free radicals. Exposure to oxidative stress may, however, deplete the cellular antioxidant capacity. Therefore, other antioxidant defense systems are expected to play an important role in oxidative stress.Liver fatty acid binding protein (L-FABP) is a 14-kd protein found abundantly in the cytoplasm and the nucleus of hepatocytes. 2,3 L-FABP is very likely to be an effective endogenous antioxidant, because it has high affinity and capacity to bind long-chain fatty acid oxidation products. 4,5 Hepatocyte L-FABP concentration could be as high as 0.4 mmol/L, 6 and it contains a large number of reducing amino acid residues (1 cysteine and 7 methionine residues) in its molecular structure. With an accessible volume enclosed by the molecular surface of L-FABP of 28,600 Å 3,7 the concentration of total methionine residues in L-FABP could be as high as approximately 400 mmol/L. Methionine and cysteine amino acids are regarded as cellular scavengers of activated xenobiotics and

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“…Studies with intact cells overexpressing SCP-2 show that SCP-2 accelerates the intracellular transfer of fatty acids (26,27). The responses of both SCP-x and SCP-2 overexpression to supplementation with phytanic acid was shown to be highly dose dependent: i ) at low phytanic acid levels, SCP-x and SCP-2 stimulate phytanic acid oxidation severalfold more than that of straight-chain fatty acids (SCP-x ϾϾ SCP-2), with concomitant enhancement of the esterification of both branched-and straight-chain fatty acids (28); ii ) at high phytanic acid levels, phytanic acid oxidation is inhibited (SCP-x ϾϾ SCP-2) and cells exhibit signs of toxicity (29). Both SCP-x and SCP-2 contain a peroxisomal targeting signal at the C terminus, suggesting peroxisomal localization [reviewed in ref.…”

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confidence: 99%

Sexually dimorphic metabolism of branched-chain lipids in C57BL/6J mice

Atshaves

Payne

McIntosh

et al. 2004

Journal of Lipid Research

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118

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Despite the importance of branched chain lipid oxidation in detoxification, almost nothing is known regarding factors regulating peroxisomal uptake, targeting, and metabolism. One peroxisomal protein, sterol carrier protein-x (SCP-x), is thought to catalyze a key thiolytic step in branched chain lipid oxidation. When mice with substantially lower hepatic levels of SCP-x were tested for susceptibility to dietary stress with phytol (a phytanic acid precursor and peroxisome proliferator), livers of phytol-fed female but not male mice i ) accumulated phytol metabolites (phytanic acid, pristanic acid, and ⌬ -2,3-pristanic acid); ii ) exhibited decreased fat tissue mass and increased liver mass/ body mass; iii ) displayed signs of histopathological lesions in the liver; and iv ) demonstrated significant alterations in hepatic lipid distributions. Moreover, both male and female mice exhibited phytol-induced peroxisomal proliferation, as demonstrated by liver morphology and upregulation of the peroxisomal protein catalase. In addition, levels of liver fatty acid binding protein, along with SCP-2 and SCP-x, increased, suggesting upregulation mediated by phytanic acid, a known ligand agonist of the peroxisomal proliferator-activated receptor ␣ . In summary, the present work establishes a role for SCP-x in branched chain lipid catabolism and demonstrates a sexual dimorphic response to phytol, a precursor of phytanic acid, in lipid parameters and hepatotoxicity.

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Expression of fatty acid binding proteins inhibits lipid accumulation and alters toxicity in L cell fibroblasts

Cited by 79 publications

References 100 publications

Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

Antioxidative function of L-FABP in L-FABP stably transfected Chang liver cells

Sexually dimorphic metabolism of branched-chain lipids in C57BL/6J mice

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