Association of L‐FABP T94A and MTP I128T Polymorphisms with Hyperlipidemia in Chinese Subjects

Tian, Yingying; Li, Hui; Wang, Shanbo; Yan, Jin; Chen, Zhiheng; Li, Zhenyu; Feng, Han; Zhou, Hong‐Hao; Ouyang, Dongsheng

doi:10.1007/s11745-015-3990-3

Cited by 9 publications

(9 citation statements)

References 44 publications

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“…Further, a highly prevalent human L-FABP SNP (26-38% allele frequency) [66-72] resulting in L-FABP T94A substitution alters uptake/metabolism of another branched-chain lipid, cholesterol [29,67,71,73]. Human subjects expressing the L-FABP T94A variant exhibit marked triglyceride accumulation in liver [29,71], elevated triglyceride and LDL cholesterol in serum [67,74,75], and increased incidence of cardiovascular disease [67,69,74]. Although less prevalent, a mutation in the human SCP-x gene completely abolishes SCP-x activity, markedly elevates serum levels of branched chain fatty acids (phytanic acid, pristanic acid), and induces neurodegeneration [76,77].…”

Section: Discussionmentioning

confidence: 99%

Impact of dietary phytol on lipid metabolism in SCP2/SCPX/L-FABP null mice

Milligan

Martin

Landrock

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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In vitro studies suggest that liver fatty acid binding protein (L-FABP) and sterol carrier protein-2/sterol carrier protein-x (SCP2/SCPx) gene products facilitate uptake and metabolism and detoxification of dietary-derived phytol in mammals. However, concomitant upregulation of L-FABP in SCP2/SCPx null mice complicates interpretation of their physiological phenotype. Therefore, the impact of ablating both the L-FABP gene and SCP2/SCPx gene (L-FABP/SCP2/SCPx null or TKO) was examined in phytol-fed female wild-type (WT) and TKO mice. TKO increased hepatic total lipid accumulation, primarily phospholipid, by mechanisms involving increased hepatic levels of proteins in the phospholipid synthetic pathway. Concomitantly, TKO reduced expression of proteins in targeting fatty acids towards the triacylglycerol synthetic pathway. Increased hepatic lipid accumulation was not associated with any concomitant upregulation of membrane fatty acid transport/translocase proteins involved in fatty acid uptake (FATP2, FATP4, FATP5 or GOT) or cytosolic proteins involved in fatty acid intracellular targeting (ACBP). In addition, TKO exacerbated dietary phytol-induced whole body weight loss, especially lean tissue mass. Since individually ablating SCPx or SCP2/SCPx elicited concomitant upregulation of L-FABP, these findings with TKO mice help to resolve the contributions of SCP2/SCPx gene ablation on dietary phytol-induced whole body and hepatic lipid phenotype independent of concomitant upregulation of L-FABP.

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Section: Discussionmentioning

confidence: 99%

Impact of dietary phytol on lipid metabolism in SCP2/SCPX/L-FABP null mice

Milligan

Martin

Landrock

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Genome wide array studies (GWAS) of NAFLD estimate a 39% heritability of liver lipid accumulation as a continuous trait after controlling for age, gender, race, and BMI (219). The highly prevalent human L-FABP T94A variant (175–177, 195–198) is associated with TAG accumulation in liver (NAFLD) (176), primary hepatocytes (63), and serum (174, 175, 224). Hepatic levels of endocannabinoids and/or receptors (CB1 and/or CB2) of the endocannabinoid system are elevated in NAFLD (101–103), alcoholic liver disease (AFLD) (102, 104), high-fat diet-induced obesity (102, 104), and in response to cannabis with CB1 agonists (e.g.…”

Section: Fabp1 In Human Health: Impact Of the Human Fabp1 T94a Variantmentioning

confidence: 99%

Fatty Acid Binding Protein‐1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias

Schroeder

McIntosh

Martin

et al. 2016

Lipids

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The first discovered member of the mammalian FABP family, liver fatty acid binding protein (FABP1, L-FABP), occurs at high cytosolic concentration in liver, intestine and in the case of humans also in kidney. While the rat FABP1 is well studied, the extent these findings translate to human FABP1 is not clear—especially in view of recent studies showing that endocannabinoids and cannabinoids represent novel rat FABP1 ligands and FABP1 gene ablation impacts the hepatic endocannabinoid system, known to be involved in non-alcoholic fatty liver (NAFLD) development. Although not detectable in brain, FABP1 ablation nevertheless also impacts brain endocannabinoids. Despite overall tertiary structure similarity, human FABP1 differs significantly from rat FABP1 in secondary structure, much larger ligand binding cavity, and affinities/specificities for some ligands. Moreover, while both mouse and human FABP1 mediate ligand induction of peroxisome proliferator activated receptor-α, (PPARα), they differ markedly in pattern of genes induced. This is critically important because a highly prevalent human SNP (26–38% minor allele frequency and 8.3±1.9% homozygous) results in a FABP1 T94A substitution that further accentuates these species differences. The human FABP1 T94A variant is associated with altered body mass index (BMI), clinical dyslipidemias (elevated plasma triglycerides and LDL cholesterol), atherothrombotic cerebral infarction, and non-alcoholic fatty liver disease (NAFLD). Resolving human FABP1 and the T94A variant’s impact on the endocannabinoid and cannabinoid system is an exciting challenge due to the importance of this system on hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety.

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“…An explanation for these characteristics was that the T94A variant resulted in a total loss of function (39). Others observed no change in ligand binding specificity or changes in the affinity for binding fibrates (14), steric acid or oleic acid (15) between the wild type and the T94A variant protein. Slight changes were seen in the secondary structure binding affinities between the T94A protein and palmitic or linoleic acid (15) and differences in cholesterol affinity and uptake (16).…”

Section: Discussionmentioning

confidence: 99%

“…Initially, the T94A substitution was thought to completely abolish the binding and function properties of the protein. Recent studies revealed the substitution did not alter ligand binding affinity, however, it significantly altered conformational and functional response to fibrates as well as stability (14). The altered function was also demonstrated with fatty acids and triglyceride intermediates (15).…”

mentioning

confidence: 98%

The Antioxidant Activity of Recombinant Rat Hepatic Fatty Acid Binding Protein T94A Variant

Gong

Davies

et al. 2018

J Pharm Pharm Sci

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PURPOSE: Liver fatty acid binding protein (FABP1) is a cytoplasmic polypeptide that transports substrates throughout the cytosol and functions as an antioxidant. A common polymorphic variant, FABP1 T94A has a minor allele frequency of 26-38%, 8.3±1.9% homozygous in the human population. The purpose of this study was to mutate and isolate recombinant rat FABP1 to the T94A variant to evaluate the mutant’s antioxidant activity using in vitro studies. METHODS: Site-directed mutagenesis was used to generate a mutation in rat cDNA within a pGEX-6p-2 vector. This plasmid was transformed into competent cells and cultured for expression of FABP1 T94A mutant. The mutated protein was purified using GSTrap Fastflow columns within an ÄKTA FPLC system. A 2,7-dichlorofluorescein (DCF) assay was used to screen the T94A variant antioxidant activity. Additionally, Thiobarbituric Acid Reactive Substances (TBARS) assay was used in determining T94A mutant antioxidant activity in hydrophilic and lipophilic environments through the use of the azo compounds AAPH and MeO-AMVN, respectively and in the presence and absence of the long-chain fatty acid palmitate and α-bromo palmitate. RESULTS: Although the FABP1 T94A (20 μM) mutant significantly reduced DCF fluorescence compared to control (no protein; P< 0.001), there were no significant difference when compared to the wild-type (WT) FABP1. T94A was able to diminish the formation of malondialdehyde (MDA) in both lipophilic and hydrophilic systems. There were significant differences between T94A mutant and WT FABP1 at concentrations 1 and 10 μM (P< 0.05) in the hydrophilic milieu, however, this was not seen at 20 μM and also not seen in the lipophilic milieu at all concentrations. When T94A was pre-incubated with the long-chain fatty acids palmitate or α -bromo palmitate, MDA formation was decreased in both lipid peroxidation systems. There were no statistical differences between the WT FABP1 and T94A bound with fatty acids in both lipid peroxidation systems, however, there was a slight statistical difference when the T94A and WT FABP1 bound α-Br-PA in the AAPH lipid peroxidation system only. CONCLUSIONS: The T94A has antioxidant activity in both hydrophilic and lipophilic environments. The T94A variant of FABP1 does not have a loss of function in regard to acting as an antioxidant but the extent of function may be influenced by ligand binding. We conclude that populations having the minor T94A allele frequency would have similar ROS scavenging potential as those with nascent FABP1.

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Association of L‐FABP T94A and MTP I128T Polymorphisms with Hyperlipidemia in Chinese Subjects

Cited by 9 publications

References 44 publications

Impact of dietary phytol on lipid metabolism in SCP2/SCPX/L-FABP null mice

Impact of dietary phytol on lipid metabolism in SCP2/SCPX/L-FABP null mice

Fatty Acid Binding Protein‐1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias

The Antioxidant Activity of Recombinant Rat Hepatic Fatty Acid Binding Protein T94A Variant

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