Glucose-mediated inactivation of AMP-activated protein kinase reduces the levels of L-type amino acid transporter 1 mRNA in C2C12 cells

Yamamoto, Yu; Sawa, Ran; Wake, Ikumi; Morimoto, Ayaka; Okimura, Yasuhiko

doi:10.1016/j.nutres.2017.08.003

Cited by 18 publications

(14 citation statements)

References 25 publications

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“…Interestingly, levels of LAT1 were markedly increased upon glucose starvation. Previous studies have shown that LAT1 mRNA expression is elevated in C2C12 myotubes cultured in glucose-free medium (30). BCAAs are major substrates for LAT1 (31).…”

Section: Discussionmentioning

confidence: 92%

Induction of Autophagy and Changes in Cellular Metabolism in Glucose Starved C2C12 Myotubes

Nakai

Kitai

Iida

et al. 2020

J Nutr Sci Vitaminol

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Mouse myoblast C2C12 cells are commonly used as a model system for investigating the metabolic regulation of skeletal muscle. As it is therefore important to understand the metabolic features of C2C12 cells, we examined the effect of glucose starvation on autophagy in C2C12 myotubes. After culture of C2C12 myotubes with high (HG, 25.0 mm) or low (LG, 5.6 mm) glucose concentrations, the concentration of glucose in the LG group had decreased to 0 mm after 24 h of culture and was around 17 mm after 48 h of culture in the HG group. The concentration of lactate increased from 0 to approximately 9 mm at 24 h and then dropped slightly in the LG group, while it increased linearly to 21 mm in the HG group at 48 h. The phosphorylation of p70 S6 kinase, marker for the protein translation initiation was significantly lower and the ratio of LC3-II/LC3-I, marker for the induction of autophagy was significantly higher in the LG group. GLUT1 and hexokinase II expression were significantly higher in the LG group. Together, these changes in glucose and lactate concentrations in the culture media suggest that C2C12 myotubes depend on anaerobic glycolysis. Our findings also suggest that glucose depletion stimulates the expression of key molecules involved in glycolysis and that cellular autophagy is also activated in C2C12 myotubes.

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Section: Discussionmentioning

confidence: 92%

Induction of Autophagy and Changes in Cellular Metabolism in Glucose Starved C2C12 Myotubes

Nakai

Kitai

Iida

et al. 2020

J Nutr Sci Vitaminol

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“…Moreover, DNA methylation occurring at promoter region seems to play a role in the regulation of LAT1 gene expression in human placenta across gestation (Simner et al, 2017 ). Glucose and insulin also modulate LAT1 expression: increase of glucose in diabetes induces a down-regulation of LAT1 expression with consequent sarcopenia in diabetes patients (Yamamoto et al, 2017 ). Conversely, glucose deprivation induces up-regulation of LAT1 in retina (Matsuyama et al, 2012 ).…”

Section: Regulation Of Lat1 Expressionmentioning

confidence: 99%

The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

et al. 2018

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SLC7A5, known as LAT1, belongs to the APC superfamily and forms a heterodimeric amino acid transporter interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide. The complex is responsible for uptake of essential amino acids in crucial body districts such as placenta and blood brain barrier. LAT1/CD98 heterodimer has been studied over the years to unravel the transport mechanism and the role of each subunit. Studies conducted in intact cells demonstrated that LAT1/CD98 mediates a Na+ and pH independent antiport of amino acids. Some novel insights into the function of LAT1 derived from studies conducted in proteoliposomes reconstituted with the recombinant human LAT1. Using this experimental tool, it has been demonstrated that the preferred substrate is histidine and that CD98 is not required for transport being, plausibly, involved in routing LAT1 to the plasma membrane. Since a 3D structure of LAT1 is not available, homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. Over the years, the interest around LAT1 increased because this transporter is involved in important human diseases such as neurological disorders and cancer. Therefore, LAT1 became an important pharmacological target together with other nutrient membrane transporters. Moving from knowledge on structure/function relationships, two cysteine residues, lying on the substrate binding site, have been exploited for designing thiol reacting covalent inhibitors. Some lead compounds have been characterized whose efficacy has been tested in a cancer cell line.

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“…1C). One study also highlighted the role of LAT-1 in muscle tissue by showing that glucose can reduce the mRNA levels of LAT1 in myocytes after inactivating the regulator of cellular energetics, 5' adenosine monophosphate-activated protein kinase (AMPK) (228). Downregulation of LAT-1 could reduce the uptake of BCAAs in skeletal muscle and increase BCAA levels in plasma.…”

Section: Slc38 Family Of Neutral Amino Acid Symportersmentioning

confidence: 99%

Amino acid transporters in the regulation of insulin secretion and signalling

Javed

Fairweather

2019

Biochemical Society Transactions

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Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid transporters. This review focuses on amino acid transporters linked to the regulation of insulin secretion and signalling with a focus on those of the small intestine, pancreatic β-islet cells and insulin-responsive tissues, liver and skeletal muscle. We summarise the role of the amino acid transporter B0AT1 (SLC6A19) and peptide transporter PEPT1 (SLC15A1) in the modulation of global insulin signalling via the liver-secreted hormone fibroblast growth factor 21 (FGF21). The role of vesicular vGLUT (SLC17) and mitochondrial SLC25 transporters in providing glutamate for the potentiation of insulin secretion is covered. We also survey the roles SNAT (SLC38) family and LAT1 (SLC7A5) amino acid transporters play in the regulation of and by insulin in numerous affective tissues. We hypothesise the small intestine amino acid transporter B0AT1 represents a crucial nexus between insulin, FGF21 and incretin hormone signalling pathways. The aim is to give an integrated overview of the important role amino acid transporters have been found to play in insulin-regulated nutrient signalling.

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Glucose-mediated inactivation of AMP-activated protein kinase reduces the levels of L-type amino acid transporter 1 mRNA in C2C12 cells

Cited by 18 publications

References 25 publications

Induction of Autophagy and Changes in Cellular Metabolism in Glucose Starved C2C12 Myotubes

Induction of Autophagy and Changes in Cellular Metabolism in Glucose Starved C2C12 Myotubes

The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

Amino acid transporters in the regulation of insulin secretion and signalling

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