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AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression.

Rodríguez-Calvo R, Vázquez-Carrera M, Masana L, Neumann D - PPAR Res (2015)

Bottom Line: Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake.These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.

ABSTRACT
Here we studied the impact of 5-aminoimidazole-4-carboxamide riboside (AICAR), a well-known AMPK activator, on cardiac metabolic adaptation. AMPK activation by AICAR was confirmed by increased phospho-Thr(172)-AMPK and phospho-Ser(79)-ACC protein levels in HL-1 cardiomyocytes. Then, cells were exposed to AICAR stimulation for 24 h in the presence or absence of the AMPK inhibitor Compound C, and the mRNA levels of the three PPARs were analyzed by real-time RT-PCR. Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK. Next, we exposed HL-1 cells to high palmitate/high insulin (HP/HI) conditions either in presence or in absence of AICAR, and we evaluated the expression of selected PPAR-targets genes. HP/HI induced insulin resistance and lipid storage was accompanied by increased Cd36, Acot1, and Ucp3 mRNA levels. AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake. These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the potential mechanisms by which AICAR regulates cardiac metabolism and protects HL-1 cardiomyocytes from the HP/HI-induced lipotoxicity and insulin resistance. HP/HI stimulation induces insulin resistance by promoting the intramyocellular lipid build-up, which in turn inhibits the insulin signalling pathway and the AKT-mediated GLUT4 membrane translocation and glucose uptake. AICAR treatment takes part in the regulation of the cardiac metabolic adaptation at several levels. First, AICAR short-term stimulation promotes the inhibition of ACC, thereby reducing the levels of the allosteric inhibitor of CPT-1 malonyl-CoA and regulating the fatty acid mitochondrial β-oxidation. In addition, AICAR-induced AMPK activation promotes GLUT4 membrane translocation through non-insulin dependent mechanisms. Finally, AICAR stimulation induces the three PPARs mRNA levels and controls the expression of some key PPAR-target genes, such as Acadvl and Glut4, involved in both glucose and fatty acid cardiac metabolism. Therefore, through these different mechanisms, AICAR is able to regulate both the acute metabolic response and the long-term metabolic adaptation in cardiac cells.
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Related In: Results  -  Collection


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fig6: Schematic representation of the potential mechanisms by which AICAR regulates cardiac metabolism and protects HL-1 cardiomyocytes from the HP/HI-induced lipotoxicity and insulin resistance. HP/HI stimulation induces insulin resistance by promoting the intramyocellular lipid build-up, which in turn inhibits the insulin signalling pathway and the AKT-mediated GLUT4 membrane translocation and glucose uptake. AICAR treatment takes part in the regulation of the cardiac metabolic adaptation at several levels. First, AICAR short-term stimulation promotes the inhibition of ACC, thereby reducing the levels of the allosteric inhibitor of CPT-1 malonyl-CoA and regulating the fatty acid mitochondrial β-oxidation. In addition, AICAR-induced AMPK activation promotes GLUT4 membrane translocation through non-insulin dependent mechanisms. Finally, AICAR stimulation induces the three PPARs mRNA levels and controls the expression of some key PPAR-target genes, such as Acadvl and Glut4, involved in both glucose and fatty acid cardiac metabolism. Therefore, through these different mechanisms, AICAR is able to regulate both the acute metabolic response and the long-term metabolic adaptation in cardiac cells.

Mentions: Although further studies are necessary to fully clarify the role of AMPK-PPAR axis in the metabolic cardiac adaptation, here we show that the AMPK activator AICAR is able to protect cardiac HL-1 cells from the HP/HI-induced intramyocellular lipid accumulation and insulin resistance at several levels. First, after AICAR short-term exposure, AMPK acts as kinase regulating by phosphorylation key enzymes involved in the acute cellular response to counter energy deficiency. In addition, AMPK is also able to regulate metabolic adaptation in response to sustained AICAR stimulation through transcriptional control of genes involved in the metabolic response, such as the PPAR-target genes Acadvl and Glut4 (Figure 6).


AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression.

Rodríguez-Calvo R, Vázquez-Carrera M, Masana L, Neumann D - PPAR Res (2015)

Schematic representation of the potential mechanisms by which AICAR regulates cardiac metabolism and protects HL-1 cardiomyocytes from the HP/HI-induced lipotoxicity and insulin resistance. HP/HI stimulation induces insulin resistance by promoting the intramyocellular lipid build-up, which in turn inhibits the insulin signalling pathway and the AKT-mediated GLUT4 membrane translocation and glucose uptake. AICAR treatment takes part in the regulation of the cardiac metabolic adaptation at several levels. First, AICAR short-term stimulation promotes the inhibition of ACC, thereby reducing the levels of the allosteric inhibitor of CPT-1 malonyl-CoA and regulating the fatty acid mitochondrial β-oxidation. In addition, AICAR-induced AMPK activation promotes GLUT4 membrane translocation through non-insulin dependent mechanisms. Finally, AICAR stimulation induces the three PPARs mRNA levels and controls the expression of some key PPAR-target genes, such as Acadvl and Glut4, involved in both glucose and fatty acid cardiac metabolism. Therefore, through these different mechanisms, AICAR is able to regulate both the acute metabolic response and the long-term metabolic adaptation in cardiac cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4663352&req=5

fig6: Schematic representation of the potential mechanisms by which AICAR regulates cardiac metabolism and protects HL-1 cardiomyocytes from the HP/HI-induced lipotoxicity and insulin resistance. HP/HI stimulation induces insulin resistance by promoting the intramyocellular lipid build-up, which in turn inhibits the insulin signalling pathway and the AKT-mediated GLUT4 membrane translocation and glucose uptake. AICAR treatment takes part in the regulation of the cardiac metabolic adaptation at several levels. First, AICAR short-term stimulation promotes the inhibition of ACC, thereby reducing the levels of the allosteric inhibitor of CPT-1 malonyl-CoA and regulating the fatty acid mitochondrial β-oxidation. In addition, AICAR-induced AMPK activation promotes GLUT4 membrane translocation through non-insulin dependent mechanisms. Finally, AICAR stimulation induces the three PPARs mRNA levels and controls the expression of some key PPAR-target genes, such as Acadvl and Glut4, involved in both glucose and fatty acid cardiac metabolism. Therefore, through these different mechanisms, AICAR is able to regulate both the acute metabolic response and the long-term metabolic adaptation in cardiac cells.
Mentions: Although further studies are necessary to fully clarify the role of AMPK-PPAR axis in the metabolic cardiac adaptation, here we show that the AMPK activator AICAR is able to protect cardiac HL-1 cells from the HP/HI-induced intramyocellular lipid accumulation and insulin resistance at several levels. First, after AICAR short-term exposure, AMPK acts as kinase regulating by phosphorylation key enzymes involved in the acute cellular response to counter energy deficiency. In addition, AMPK is also able to regulate metabolic adaptation in response to sustained AICAR stimulation through transcriptional control of genes involved in the metabolic response, such as the PPAR-target genes Acadvl and Glut4 (Figure 6).

Bottom Line: Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake.These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.

ABSTRACT
Here we studied the impact of 5-aminoimidazole-4-carboxamide riboside (AICAR), a well-known AMPK activator, on cardiac metabolic adaptation. AMPK activation by AICAR was confirmed by increased phospho-Thr(172)-AMPK and phospho-Ser(79)-ACC protein levels in HL-1 cardiomyocytes. Then, cells were exposed to AICAR stimulation for 24 h in the presence or absence of the AMPK inhibitor Compound C, and the mRNA levels of the three PPARs were analyzed by real-time RT-PCR. Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK. Next, we exposed HL-1 cells to high palmitate/high insulin (HP/HI) conditions either in presence or in absence of AICAR, and we evaluated the expression of selected PPAR-targets genes. HP/HI induced insulin resistance and lipid storage was accompanied by increased Cd36, Acot1, and Ucp3 mRNA levels. AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake. These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms.

No MeSH data available.


Related in: MedlinePlus