Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
J Lipid Res ; 50(7): 1429-47, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19289417

ABSTRACT

Although in vitro studies suggest a role for sterol carrier protein-2 (SCP-2) in cholesterol trafficking and metabolism, the physiological significance of these observations remains unclear. This issue was addressed by examining the response of mice overexpressing physiologically relevant levels of SCP-2 to a cholesterol-rich diet. While neither SCP-2 overexpression nor cholesterol-rich diet altered food consumption, increased weight gain, hepatic lipid, and bile acid accumulation were observed in wild-type mice fed the cholesterol-rich diet. SCP-2 overexpression further exacerbated hepatic lipid accumulation in cholesterol-fed females (cholesterol/cholesteryl esters) and males (cholesterol/cholesteryl esters and triacyglycerol). Primarily in female mice, hepatic cholesterol accumulation induced by SCP-2 overexpression was associated with increased levels of LDL-receptor, HDL-receptor scavenger receptor-B1 (SR-B1) (as well as PDZK1 and/or membrane-associated protein 17 kDa), SCP-2, liver fatty acid binding protein (L-FABP), and 3alpha-hydroxysteroid dehydrogenase, without alteration of other proteins involved in cholesterol uptake (caveolin), esterification (ACAT2), efflux (ATP binding cassette A-1 receptor, ABCG5/8, and apolipoprotein A1), or oxidation/transport of bile salts (cholesterol 7alpha-hydroxylase, sterol 27alpha-hydroxylase, Na(+)/taurocholate cotransporter, Oatp1a1, and Oatp1a4). The effects of SCP-2 overexpression and cholesterol-rich diet was downregulation of proteins involved in cholesterol transport (L-FABP and SR-B1), cholesterol synthesis (related to sterol regulatory element binding protein 2 and HMG-CoA reductase), and bile acid oxidation/transport (via Oapt1a1, Oatp1a4, and SCP-x). Levels of serum and hepatic bile acids were decreased in cholesterol-fed SCP-2 overexpression mice, especially in females, while the total bile acid pool was minimally affected. Taken together, these findings support an important role for SCP-2 in hepatic cholesterol homeostasis.


Subject(s)
Carrier Proteins/metabolism , Cholesterol, Dietary , Cholesterol , Liver/metabolism , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Bile Acids and Salts/blood , Bile Acids and Salts/metabolism , Body Weight , Carrier Proteins/genetics , Caveolin 1/genetics , Caveolin 1/metabolism , Cholestanetriol 26-Monooxygenase/genetics , Cholestanetriol 26-Monooxygenase/metabolism , Cholesterol/administration & dosage , Cholesterol/metabolism , Cholesterol 7-alpha-Hydroxylase/genetics , Cholesterol 7-alpha-Hydroxylase/metabolism , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/metabolism , Female , Humans , Lipid Metabolism , Lipids/chemistry , Liver/anatomy & histology , Male , Mice , Mice, Transgenic , Organ Size , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Phenotype , Phospholipids/blood , Scavenger Receptors, Class B/genetics , Scavenger Receptors, Class B/metabolism , Tissue Distribution
2.
Arch Biochem Biophys ; 485(2): 160-73, 2009 May 15.
Article in English | MEDLINE | ID: mdl-19285478

ABSTRACT

The effect of liver type fatty acid binding protein (L-FABP) gene ablation on the uptake and distribution of long chain fatty acids (LCFA) to the nucleus by real-time laser scanning confocal imaging and peroxisome proliferator-activated receptor-alpha (PPARalpha) activity was examined in cultured primary hepatocytes from livers wild-type L-FABP+/+ and gene ablated L-FABP-/- mice. Cultured primary hepatocytes from livers of L-FABP-/- mice exhibited: (i) reduced oxidation of palmitic acid, a common dietary long chain fatty acid (LCFA); (ii) reduced expression of fatty acid oxidative enzymes-proteins transcriptionally regulated by PPARalpha; (iii) reduced palmitic acid-induced PPARalpha co-immunoprecipitation with coactivator SRC-1 concomitant with increased PPARalpha co-immunoprecipitation with coinhibitor N-CoR; (iv) reduced palmitic acid-induced PPARalpha. Diminished PPARalpha activation in L-FABP null hepatocytes was associated with lower uptake of common dietary LCFA (palmitic acid as well as its fluorescent derivative BODIPY FL C(16)), reduced level of total unesterified LCFA, and real-time redistribution of BODIPY FL C(16) from the central nucleoplasm to the nuclear envelope. Taken together, these studies support the hypothesis that L-FABP may facilitate ligand (LCFA)-activated PPARalpha transcriptional activity at least in part by increasing total LCFA ligand available to PPARalpha for inducing PPARalpha-mediated transcription of proteins involved in LCFA metabolism.


Subject(s)
Fatty Acid-Binding Proteins/physiology , Hepatocytes/metabolism , PPAR alpha/metabolism , Animals , COS Cells , Cells, Cultured , Chlorocebus aethiops , Fatty Acid-Binding Proteins/genetics , Immunoprecipitation , Ligands , Male , Mice , Mice, Knockout , Microscopy, Confocal
4.
J Biol Chem ; 279(30): 30954-65, 2004 Jul 23.
Article in English | MEDLINE | ID: mdl-15155724

ABSTRACT

Whereas the role of liver fatty acid-binding protein (L-FABP) in the uptake, transport, mitochondrial oxidation, and esterification of normal straight-chain fatty acids has been studied extensively, almost nothing is known regarding the function of L-FABP in peroxisomal oxidation and metabolism of branched-chain fatty acids. Therefore, phytanic acid (most common dietary branched-chain fatty acid) was chosen to address these issues in cultured primary hepatocytes isolated from livers of L-FABP gene-ablated (-/-) and wild type (+/+) mice. These studies provided three new insights: First, L-FABP gene ablation reduced maximal, but not initial, uptake of phytanic acid 3.2-fold. Initial uptake of phytanic acid uptake was unaltered apparently due to concomitant 5.3-, 1.6-, and 1.4-fold up-regulation of plasma membrane fatty acid transporter/translocase proteins (glutamic-oxaloacetic transaminase, fatty acid transport protein, and fatty acid translocase, respectively). Second, L-FABP gene ablation inhibited phytanic acid peroxisomal oxidation and microsomal esterification. These effects were consistent with reduced cytoplasmic fatty acid transport as evidenced by multiphoton fluorescence photobleaching recovery, where L-FABP gene ablation reduced the cytoplasmic, but not membrane, diffusional component of NBD-stearic acid movement 2-fold. Third, lipid analysis of the L-FABP gene-ablated hepatocytes revealed an altered fatty acid phenotype. Free fatty acid and triglyceride levels were decreased 1.9- and 1.6-fold, respectively. In summary, results with cultured primary hepatocytes isolated from L-FABP (+/+) and L-FABP (-/-) mice demonstrated for the first time a physiological role of L-FABP in the uptake and metabolism of branched-chain fatty acids.


Subject(s)
Carrier Proteins/genetics , Carrier Proteins/metabolism , Fatty Acids/metabolism , Hepatocytes/metabolism , Animals , Biological Transport, Active , Cell Membrane/metabolism , Cells, Cultured , Fatty Acid-Binding Proteins , Fatty Acids/chemistry , Gene Targeting , Intracellular Fluid/metabolism , Male , Mice , Mice, Knockout , Models, Biological , Oxidation-Reduction
5.
Am J Physiol Cell Physiol ; 283(3): C688-703, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12176726

ABSTRACT

High levels of saturated, branched-chain fatty acids are deleterious to cells and animals, resulting in lipid accumulation and cytotoxicity. Although fatty acid binding proteins (FABPs) are thought to be protective, this hypothesis has not previously been examined. Phytanic acid (branched chain, 16-carbon backbone) induced lipid accumulation in L cell fibroblasts similar to that observed with palmitic acid (unbranched, C(16)): triacylglycerol >> free fatty acid > cholesterol > cholesteryl ester >> phospholipid. Although expression of sterol carrier protein (SCP)-2, SCP-x, or liver FABP (L-FABP) in transfected L cells reduced [(3)H]phytanic acid uptake (57-87%) and lipid accumulation (21-27%), nevertheless [(3)H]phytanic acid oxidation was inhibited (74-100%) and phytanic acid toxicity was enhanced in the order L-FABP >> SCP-x > SCP-2. These effects differed markedly from those of [(3)H]palmitic acid, whose uptake, oxidation, and induction of lipid accumulation were not reduced by L-FABP, SCP-2, or SCP-x expression. Furthermore, these proteins did not enhance the cytotoxicity of palmitic acid. In summary, intracellular FABPs reduce lipid accumulation induced by high levels of branched-chain but not straight-chain saturated fatty acids. These beneficial effects were offset by inhibition of branched-chain fatty acid oxidation that correlated with the enhanced toxicity of high levels of branched-chain fatty acid.


Subject(s)
Carrier Proteins/biosynthesis , Fibroblasts/metabolism , Lipid Metabolism , Neoplasm Proteins , Nerve Tissue Proteins , Palmitic Acid/toxicity , Phytanic Acid/toxicity , Plant Proteins , Acetyl-CoA C-Acetyltransferase/biosynthesis , Acetyl-CoA C-Acetyltransferase/genetics , Animals , Blotting, Western , Carrier Proteins/genetics , Cholesterol/metabolism , Cholesterol Esters/metabolism , Fatty Acid-Binding Protein 7 , Fatty Acid-Binding Proteins , Fatty Acids, Nonesterified/metabolism , Fibroblasts/cytology , Fibroblasts/drug effects , L Cells , Mice , Mitochondria/metabolism , Mitochondria/ultrastructure , Oxidation-Reduction , Palmitic Acid/metabolism , Palmitic Acid/pharmacokinetics , Peroxisomes/metabolism , Peroxisomes/ultrastructure , Phospholipids/metabolism , Phytanic Acid/metabolism , Phytanic Acid/pharmacokinetics , Serum Albumin, Bovine/metabolism , Serum Albumin, Bovine/pharmacology , Subcellular Fractions/metabolism , Subcellular Fractions/ultrastructure , Transfection , Triglycerides/metabolism , Tritium
SELECTION OF CITATIONS
SEARCH DETAIL
...