scholarly journals Thioesterase induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin results in a futile cycle that inhibits hepatic β-oxidation

2021 ◽  
Author(s):  
Giovan N. Cholico ◽  
Russ R. Fling ◽  
Nicholas A. Zacharewski ◽  
Kelly A. Fader ◽  
Rance Nault ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Short Chain ◽  
Fatty Acid Binding Proteins ◽  
Acid Oxidation ◽  
Acid Activation ◽  
Futile Cycle ◽  
Fatty Acid Binding ◽  
Fatty Acid Activation ◽  
Enoyl Coa Hydratase

ABSTRACT2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis by increasing hepatic uptake of dietary and mobilized peripheral fats, inhibiting lipoprotein export, and repressing β-oxidation. In this study, the mechanism of β-oxidation inhibition was investigated by testing the hypothesis that TCDD dose-dependently repressed straight-chain fatty acid oxidation gene expression in mice following oral gavage every 4 days for 28 days. Untargeted metabolomic analysis revealed a dose-dependent decrease in hepatic acyl-CoA levels, while octenoyl-CoA and dicarboxylic acid levels increased. TCDD also dose-dependently repressed the hepatic gene expression associated with triacylglycerol and cholesterol ester hydrolysis, fatty acid binding proteins, fatty acid activation, and 3-ketoacyl-CoA thiolysis while inducing acyl-CoA hydrolysis. Moreover, octenoyl-CoA blocked the hydration of crotonyl-CoA suggesting short chain enoyl-CoA hydratase (ECHS1) activity was inhibited. Collectively, the integration of metabolomics and RNA-seq data suggested TCDD induced a futile cycle of fatty acid activation and acyl-CoA hydrolysis resulting in incomplete β-oxidation, and the accumulation octenoyl-CoA levels that inhibited the activity of short chain enoyl-CoA hydratase (ECHS1).

scholarly journals Thioesterase induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin results in a futile cycle that inhibits hepatic β-oxidation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giovan N. Cholico ◽  
Russell R. Fling ◽  
Nicholas A. Zacharewski ◽  
Kelly A. Fader ◽  
Rance Nault ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Short Chain ◽  
Fatty Acid Binding Proteins ◽  
Acid Oxidation ◽  
Acid Activation ◽  
Futile Cycle ◽  
Fatty Acid Binding ◽  
Fatty Acid Activation ◽  
Enoyl Coa Hydratase

Abstract2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis by increasing hepatic uptake of dietary and mobilized peripheral fats, inhibiting lipoprotein export, and repressing β-oxidation. In this study, the mechanism of β-oxidation inhibition was investigated by testing the hypothesis that TCDD dose-dependently repressed straight-chain fatty acid oxidation gene expression in mice following oral gavage every 4 days for 28 days. Untargeted metabolomic analysis revealed a dose-dependent decrease in hepatic acyl-CoA levels, while octenoyl-CoA and dicarboxylic acid levels increased. TCDD also dose-dependently repressed the hepatic gene expression associated with triacylglycerol and cholesterol ester hydrolysis, fatty acid binding proteins, fatty acid activation, and 3-ketoacyl-CoA thiolysis while inducing acyl-CoA hydrolysis. Moreover, octenoyl-CoA blocked the hydration of crotonyl-CoA suggesting short chain enoyl-CoA hydratase (ECHS1) activity was inhibited. Collectively, the integration of metabolomics and RNA-seq data suggested TCDD induced a futile cycle of fatty acid activation and acyl-CoA hydrolysis resulting in incomplete β-oxidation, and the accumulation octenoyl-CoA levels that inhibited the activity of short chain enoyl-CoA hydratase (ECHS1).

scholarly journals Classification of the multigene family of fatty acid binding proteins (FABPs) and transcription profile of the genes in striped catfish (Pangasianodon hypophthalmus)

2021 ◽  
Vol 19 (2) ◽  
pp. 259-270
Author(s):  
Le Thi Nguyen Binh ◽  
Tran Son Hoang ◽  
Tran Thi Huyen Trang ◽  
Nguyen Thi Hoa ◽  
Kim Thi Phuong Oanh
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Regulation Of Gene Expression ◽  
High Fatty Acid ◽  
Fatty Acid Binding Proteins ◽  
Genome Database ◽  
Fatty Acid Binding ◽  
Pangasianodon Hypophthalmus ◽  
Catfish Fillets ◽  
Striped Catfish

Striped catfish (Pangasianodon hypophthalmus) is an economically important fish in Vietnam. The catfish fillets contain high fatty acid composition. The FABP family is involved in lipid transport and metabolism as well as in the regulation of gene expression and cell development. In this study, the catfish genome database was searched for fabp gene family; then, gene structure, classification and phylogenetic relationships were analyzed. In striped catfish genome, we found 10 fabp genes that are homologous to other fish species and other 5 novel fabp genes that have not been clearly annotated. These newly identified fabp genes cluster separately from the known members of the fabp family on the phylogenetic tree, and further studies are needed to understand their roles and functions. We examined transcriptional gene expression of fabp3, fabp7 and fabp10a genes in muscle, liver and brain tissues of the stripped catfish. The results showed that fabp10a gene was not strongly expressed in all 3 types of tissues; fabp3 gene was most strongly expressed in liver tissue and fabp7 was highly up-regulated in brain tissue. The results of this study provide a resource for further research on the function of fabp genes and their genetic diversity in striped catfish.

scholarly journals Perfluoroalkyl Acid Binding with Peroxisome Proliferator-Activated Receptors α, γ, and δ, and Fatty Acid Binding Proteins by Equilibrium Dialysis with a Comparison of Methods

Toxics ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 45
Author(s):  
Manoochehr Khazaee ◽  
Emerson Christie ◽  
Weixiao Cheng ◽  
Mandy Michalsen ◽  
Jennifer Field ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Chain Length ◽  
Binding Proteins ◽  
Equilibrium Dialysis ◽  
Short Chain ◽  
Fatty Acid Binding Proteins ◽  
Peroxisome Proliferator ◽  
Binding Affinities ◽  
Fatty Acid Binding

The biological impacts of per- and polyfluorinated alkyl substances (PFAS) are linked to their protein interactions. Existing research has largely focused on serum albumin and liver fatty acid binding protein, and binding affinities determined with a variety of methods show high variability. Moreover, few data exist for short-chain PFAS, though their prevalence in the environment is increasing. We used molecular dynamics (MD) to screen PFAS binding to liver and intestinal fatty acid binding proteins (L- and I-FABPs) and peroxisome proliferator activated nuclear receptors (PPAR-α, -δ and -γ) with six perfluoroalkyl carboxylates (PFCAs) and three perfluoroalkyl sulfonates (PFSAs). Equilibrium dissociation constants, KDs, were experimentally determined via equilibrium dialysis (EqD) with liquid chromatography tandem mass spectrometry for protein-PFAS pairs. A comparison was made between KDs derived from EqD, both here and in literature, and other in vitro approaches (e.g., fluorescence) from literature. EqD indicated strong binding between PPAR-δ and perfluorobutanoate (0.044 ± 0.013 µM) and perfluorohexane sulfonate (0.035 ± 0.0020 µM), and between PPAR-α and perfluorohexanoate (0.097 ± 0.070 µM). Unlike binding affinities for L-FABP, which increase with chain length, KDs for PPARs showed little chain length dependence by either MD simulation or EqD. Compared with other in vitro approaches, EqD-based KDs consistently indicated higher affinity across different proteins. This is the first study to report PPARs binding with short-chain PFAS with KDs in the sub-micromolar range.

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

2002 ◽  
Vol 283 (3) ◽  
pp. C688-C703 ◽  
Author(s):  
Barbara P. Atshaves ◽  
Stephen M. Storey ◽  
Anca Petrescu ◽  
Cynthia C. Greenberg ◽  
Olga I. Lyuksyutova ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Lipid Accumulation ◽  
Phytanic Acid ◽  
Chain Fatty Acid ◽  
Fatty Acid Binding Proteins ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Branched Chain

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, C16): 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 [3H]phytanic acid uptake (57–87%) and lipid accumulation (21–27%), nevertheless [3H]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 [3H]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.

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