Impact of <i>Fabp1</i> Gene Ablation on Uptake and Degradation of Endocannabinoids in Mouse Hepatocytes

McIntosh, Avery L.; Huang, Huan; Landrock, Danilo; Martin, Gregory G.; Li, Shengrong; Kier, Ann B.; Schroeder, Friedhelm

doi:10.1002/lipd.12071

Cited by 12 publications

(17 citation statements)

References 63 publications

(123 reference statements)

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“…However, precedent for this possibility is suggested by recent studies showing that, although not found in the brain, at least one other FABP family member (i.e. FABP1) significantly stimulated MAGL in vitro and in cultured primary hepatocytes (McIntosh et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Most importantly, SCP‐2 has high affinity for AEA and 2‐AG, as well as a series of inhibitors (Hillard et al, ; Liedhegner et al, ; Martin et al, ). SCP2 stimulates MAGL in vitro and in cultured primary hepatocytes (McIntosh et al, ). Finally, overexpression of SCP‐2 in transfected cells enhances AEA uptake and AEA levels (Liedhegner et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…As cellular uptake of AEA is coupled to its intracellular inactivation by FAAH in the endoplasmic reticulum (Deutsch et al, ), loss of SCP‐2 could negatively impact AEA transport to FAAH in the endoplasmic reticulum to decrease AEA hydrolysis—thereby increasing, rather than decreasing, brain AEA. Cytosolic AEA binding/“Chaperone” proteins such as FABP7 (Kaczocha et al, ) and SCP‐2 (McIntosh et al, ) do not alter AEA hydrolysis in homogenates of the vector transfected cells or liver in vitro —indicating that they did not increase AEA uptake by directly modulating the activity of the FAAH enzyme itself. On the other hand, cytosolic 2‐AG binding proteins such as FABP1 (Huang et al, ) and SCP‐2 (Hillard et al, ; Martin et al, ) bind and directly stimulate MAGL‐mediated hydrolysis in vitro (McIntosh et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Cytosolic AEA binding/“Chaperone” proteins such as FABP7 (Kaczocha et al, ) and SCP‐2 (McIntosh et al, ) do not alter AEA hydrolysis in homogenates of the vector transfected cells or liver in vitro —indicating that they did not increase AEA uptake by directly modulating the activity of the FAAH enzyme itself. On the other hand, cytosolic 2‐AG binding proteins such as FABP1 (Huang et al, ) and SCP‐2 (Hillard et al, ; Martin et al, ) bind and directly stimulate MAGL‐mediated hydrolysis in vitro (McIntosh et al, ). However, this suggests that the loss of SCP‐2 in the TKO mouse brain would decrease 2‐AG hydrolysis and thereby increase brain 2‐AG—in contrast to what was observed in the TKO mouse brain.…”

Section: Discussionmentioning

confidence: 99%

“…The increased brain free ARA in HFD‐fed TKO females was not associated with altered levels of most membrane fatty acid transport/translocases, net alteration in cytosolic binding/“Chaperone” proteins (FABP3 and HSP70 increased, while FABP7 decreased), or net change in synthetic/degrading enzymes [synthetic enzyme (DAGLα) increased, while degrading enzyme (MAGL) decreased]. However, SCP‐2 does enhance the delivery of bound 2‐AG to and degradation by MAGL (McIntosh et al, )—suggesting that the increased brain free ARA was associated with loss of SCP‐2 in brain, which would contribute to decreased 2‐AG hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

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Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

Martin

Seeger

McIntosh

et al. 2019

Lipids

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Brain endocannabinoids (EC) such as arachidonoylethanolamine (AEA) and 2‐arachidonoylglycerol (2‐AG) primarily originate from serum arachidonic acid (ARA), whose level is regulated in part by a cytosolic ARA‐binding protein, that is, liver fatty acid binding protein‐1 (FABP1), not expressed in the brain. Ablation of the Fabp1 gene (LKO) increases brain AEA and 2‐AG by decreasing hepatic uptake of ARA to increase serum ARA, thereby increasing ARA availability for uptake by the brain. The brain also expresses sterol carrier protein‐2 (SCP‐2), which is also a cytosolic ARA‐binding protein. To further resolve the role of SCP‐2 independent of FABP1, mice ablated in the Scp‐2/Scp‐x gene (DKO) were crossed with mice ablated in the Fabp1 gene (LKO) mice to generate triple knock out (TKO) mice. TKO impaired the ability of LKO to increase brain AEA and 2‐AG. While a high‐fat diet (HFD) alone increased brain AEA, TKO impaired this effect. Overall, these TKO‐induced blocks were not attributable to altered expression of brain proteins in ARA uptake, AEA/2‐AG synthesis, or AEA/2‐AG degrading enzymes. Instead, TKO reduced serum levels of free ARA and/or total ARA and thereby decreased ARA availability for uptake to the brain and downstream synthesis of AEA and 2‐AG therein. In summary, Scp‐2/Scp‐x gene ablation in Fabp1 null (LKO) mice antagonized the impact of LKO and HFD on brain ARA and, subsequently, EC levels. Thus, both FABP1 and SCP‐2 participate in regulating the EC system in the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

Martin

Seeger

McIntosh

et al. 2019

Lipids

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Linoleic acid in diets of mice increases total endocannabinoid levels in bowel and liver: modification by dietary glucose

Ghosh

O’Connell

Carlson

et al. 2019

Obesity Science & Practice

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Summary Aim Linoleic acid (LA) is an essential fatty acid involved in the biosynthesis of arachidonic acid and prostaglandins. LA is known to induce obesity and insulin resistance. In this study, two concentrations of LA with or without added glucose (G) were fed to mice to investigate their effects on endocannabinoid (EC) biology. Materials and Methods Four groups of C57BL/6 mice were provided with diets containing 1% or 8% LA with or without added G (LAG) for 8 weeks. Body weights, food intake, circulating glucose and insulin levels were measured throughout the study. Following euthanasia, plasma, bowel and hepatic ECs, monoacylglycerol lipase and fatty acid amide hydroxylase protein levels (enzymes responsible for EC degradation) and transcriptional activity of PPARα in liver were quantified. Liver was probed for evidence of insulin receptor activity perturbation. Results Increasing dietary LA from 1% to 8% significantly increased circulating, small bowel and hepatic ECs. 1%LAG fed mice had lowest feed efficiency, and only liver levels of both ECs were reduced by addition of G. Addition of G to 1% LA diets resulted in elevated monoacylglycerol lipase and fatty acid amide hydroxylase protein levels ( p < 0.001 and p < 0.001, respectively) in liver due to increased transcriptional activity of PPARα ( p < 0.05). The reduced EC levels with addition of G also correlated with a measure of enhanced insulin action. Conclusion In conclusion, body weight of mice is influenced by the source of calorie intake. Furthermore, tissue EC/g are dependent on tissue‐specific synthesis and degradation that are modulated by dietary LA and G which also influence food efficiency, and down‐stream insulin signalling pathways. The findings could potentially be useful information for weight management efforts in humans.

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Two fatty acid‐binding proteins expressed in the intestine interact differently with endocannabinoids

et al. 2020

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Two different members of the fatty acid‐binding protein (FABP) family are found in enterocyte cells of the gastrointestinal system, namely liver‐type and intestinal fatty acid‐binding proteins (LFABP and IFABP, also called FABP1 and FABP2, respectively). Striking phenotypic differences have been observed in knockout mice for either protein, for example, high fat‐fed IFABP‐null mice remained lean, whereas LFABP‐null mice were obese, correlating with differences in food intake. This finding prompted us to investigate the role each protein plays in directing the specificity of binding to ligands involved in appetite regulation, such as fatty acid ethanolamides and related endocannabinoids. We determined the binding affinities for nine structurally related ligands using a fluorescence competition assay, revealing tighter binding to IFABP than LFABP for all ligands tested. We found that the head group of the ligand had more impact on binding affinity than the alkyl chain, with the strongest binding observed for the carboxyl group, followed by the amide, and then the glycerol ester. These trends were confirmed using two‐dimensional 1H–15N nuclear magnetic resonance (NMR) to monitor chemical shift perturbation of the protein backbone resonances upon titration with ligand. Interestingly, the NMR data revealed that different residues of IFABP were involved in the coordination of endocannabinoids than those implicated for fatty acids, whereas the same residues of LFABP were involved for both classes of ligand. In addition, we identified residues that are uniquely affected by binding of all types of ligand to IFABP, suggesting a rationale for its tighter binding affinity compared with LFABP.

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Impact of Fabp1 Gene Ablation on Uptake and Degradation of Endocannabinoids in Mouse Hepatocytes

Cited by 12 publications

References 63 publications

Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

Linoleic acid in diets of mice increases total endocannabinoid levels in bowel and liver: modification by dietary glucose

Two fatty acid‐binding proteins expressed in the intestine interact differently with endocannabinoids

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