Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance

Holloway, Graham P.; Chou, Chieh Jason; Lally, Jamie; Stellingwerff, Trent; Maher, Amy C.; Гаврилова, Оксана; Haluzı́k, Martin; Alkhateeb, Hakam; Reitman, Marc L.; Bonen, Arend

doi:10.1007/s00125-011-2114-8

Cited by 47 publications

(43 citation statements)

References 45 publications

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“…5B). Studies have shown SLC27A1 directs fatty acids for oxidation in both heart (23) and skeletal muscle (42), is particularly effective at facilitating long-chain fatty acid transport (25), and is protective against intramuscular lipid accumulation (42). We postulate the increased expression of SLC27A1 allows for increased ability to transport unsaturated fats across the membrane and that this is a key difference between fasting and hibernation-associated fasting.…”

Section: Fuel Utilizationmentioning

confidence: 89%

Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal

Vermillion

Anderson

Hampton

et al. 2015

Physiological Genomics

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Throughout the hibernation season, the thirteen-lined ground squirrel ( Ictidomys tridecemlineatus) experiences extreme fluctuations in heart rate, metabolism, oxygen consumption, and body temperature, along with prolonged fasting and immobility. These conditions necessitate different functional requirements for the heart, which maintains contractile function throughout hibernation, and the skeletal muscle, which remains largely inactive. The adaptations used to maintain these contractile organs under such variable conditions serves as a natural model to study a variety of medically relevant conditions including heart failure and disuse atrophy. To better understand how two different muscle tissues maintain function throughout the extreme fluctuations of hibernation we performed Illumina HiSeq 2000 sequencing of cDNAs to compare the transcriptome of heart and skeletal muscle across the circannual cycle. This analysis resulted in the identification of 1,076 and 1,466 differentially expressed genes in heart and skeletal muscle, respectively. In both heart and skeletal muscle we identified a distinct cold-tolerant mechanism utilizing peroxisomal metabolism to make use of elevated levels of unsaturated depot fats. The skeletal muscle transcriptome also shows an early increase in oxidative capacity necessary for the altered fuel utilization and increased oxygen demand of shivering. Expression of the fetal gene expression profile is used to maintain cardiac tissue, either through increasing myocyte size or proliferation of resident cardiomyocytes, while skeletal muscle function and mass are protected through transcriptional regulation of pathways involved in protein turnover. This study provides insight into how two functionally distinct muscles maintain function under the extreme conditions of mammalian hibernation.

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Section: Fuel Utilizationmentioning

confidence: 89%

Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal

Vermillion

Anderson

Hampton

et al. 2015

Physiological Genomics

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“…This apparent defect in the channeling of FA towards oxidation is supported by studies using adenovirus-overexpressed Fatp1 in L6E9 myotubes, in which the protein physically interacts with CPT1, and the resulting increase in mitochondrial FA oxidation is blocked by etomoxir, an inhibitor of CPT1 (169). In related studies, transient Fatp1 overexpression in rat soleus muscle increases the oxidation of 16:0 by 35% (65). …”

Section: The Fatp/acsvl/scl27a Familymentioning

confidence: 98%

Acyl-CoA Metabolism and Partitioning

Grevengoed¹,

Klett

Coleman³

2014

Annu. Rev. Nutr.

365

330

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Long-chain fatty acyl-CoAs are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids like triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs towards or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.

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“…Sarcolemmal staining and pronounced intracellular FATP1 localization in an undefined vesicle population has been observed in isolated mouse soleus muscle [14], as well as the presence of FATP1 in the t-tubule and sarcolemma fractions of lower hindlimb rat muscles [15]. However, no evidence was obtained for the localization of transfected FATP1 on mitochondrial membranes in mature rat skm [16].…”

Section: Introductionmentioning

confidence: 95%

“…FATP1 is able to enhance fatty acid uptake in cultured skm cells [11] and in rodent muscle tissue [16]. However, on the basis of its subcellular localization, it is argued whether FATP1-mediated cell fatty acid import is due to transbilayer movement of fatty acids in the plasma membrane or to a driving force associated with its intrinsic acyl-CoA synthetase, which might trap the entering fatty acids as acyl-CoAs [10], [17] and direct its metabolism.…”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Transport Protein 1 (FATP1) Localizes in Mitochondria in Mouse Skeletal Muscle and Regulates Lipid and Ketone Body Disposal

et al. 2014

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FATP1 mediates skeletal muscle cell fatty acid import, yet its intracellular localization and metabolic control role are not completely defined. Here, we examine FATP1 localization and metabolic effects of its overexpression in mouse skeletal muscle. The FATP1 protein was detected in mitochondrial and plasma membrane fractions, obtained by differential centrifugation, of mouse gastrocnemius muscle. FATP1 was most abundant in purified mitochondria, and in the outer membrane and soluble intermembrane, but not in the inner membrane plus matrix, enriched subfractions of purified mitochondria. Immunogold electron microscopy localized FATP1-GFP in mitochondria of transfected C2C12 myotubes. FATP1 was overexpressed in gastrocnemius mouse muscle, by adenovirus-mediated delivery of the gene into hindlimb muscles of newborn mice, fed after weaning a chow or high-fat diet. Compared to GFP delivery, FATP1 did not alter body weight, serum fed glucose, insulin and triglyceride levels, and whole-body glucose tolerance, in either diet. However, fatty acid levels were lower and β-hydroxybutyrate levels were higher in FATP1- than GFP-mice, irrespective of diet. Moreover, intramuscular triglyceride content was lower in FATP1- versus GFP-mice regardless of diet, and β-hydroxybutyrate content was unchanged in high-fat-fed mice. Electroporation-mediated FATP1 overexpression enhanced palmitate oxidation to CO2, but not to acid-soluble intermediate metabolites, while CO2 production from β-hydroxybutyrate was inhibited and that from glucose unchanged, in isolated mouse gastrocnemius strips. In summary, FATP1 was localized in mitochondria, in the outer membrane and intermembrane parts, of mouse skeletal muscle, what may be crucial for its metabolic effects. Overexpressed FATP1 enhanced disposal of both systemic fatty acids and intramuscular triglycerides. Consistently, it did not contribute to the high-fat diet-induced metabolic dysregulation. However, FATP1 lead to hyperketonemia, likely secondary to the sparing of ketone body oxidation by the enhanced oxidation of fatty acids.

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Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance

Cited by 47 publications

References 45 publications

Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal

Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal

Acyl-CoA Metabolism and Partitioning

Fatty Acid Transport Protein 1 (FATP1) Localizes in Mitochondria in Mouse Skeletal Muscle and Regulates Lipid and Ketone Body Disposal

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