BADERC-Asish Saha

Asish Saha, Ph.D.

Malonyl CoA and fuel sensing mechanism in skeletal muscle

The principal objective of my research is to determine how malonyl CoA is regulated in skeletal muscle with emphasis on the role of the enzyme AMP-activated protein kinase (AMPK). Malonyl CoA is both an intermediate in the synthesis of fatty acids and an inhibitor of carnitine palmitoyl transferase 1, the enzyme that catalyzes the transfer of long chain fatty acyl CoA into the mitochondria where they are oxidized. Over the past 8 years we have shown that the concentration of malonyl CoA in skeletal muscle is acutely regulated by changes in its fuel supply and energy expenditure (Am. J. Physiol. 276:E1-E18, 1999). Key players in the schema we have proposed are acetyl CoA carboxylase (ACC), the rate limiting enzyme in malonyl CoA synthesis; citrate, an allosteric activator of ACC; and an AMP-activated protein kinase (AMPK) that is activated during exercise, and phosphorylates and inhibits ACC. For the last few years I have been working on the malonyl CoA decarboxylase (MCD), an enzyme involved in malonyl CoA catabolism. We had demonstrated that both muscle contraction and incubation with AICAR (5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside), a cell-permeable activator of AMPK, increased MCD activity in skeletal muscle and that this is likely due to its phosphorylation by AMP-activated protein kinase (AMPK). The results strongly suggest a dual control of malonyl CoA concentration by acetyl CoA carboxylase and MCD via AMPK and that alterations in MCD activity could complement changes in ACC in decreasing malonyl CoA and increasing fatty acid oxidation for energy production (J. Biol. Chem. 275: 24279-24288, 2000). We have also shown that the activity of sn-glycerol-3-phosphate acyltransferase (GPAT), like MCD and ACC, is regulated by AMPK (J. Biol. Chem. 277: 32571-32577, 2002) and that acyl coenzyme A:diacylglycerol acyiltranferase (DGAT), an enzyme unique to triglycertide synthesis, is inhibited during exercise Recently we have found that Pioglitazone, a PPAR_g agonist, diminishes malonyl CoA levels and that this is associated with an increase in hepatic and adipose tissue AMPK phosphorylation. These results suggest that PPAR_g agonists such as Pioglitazone could improve insulin sensitivity and dyslipidemia by leading to the activation of AMPK in liver and adipose tissue.

References

1. Saha, A.K., Laybutt, D.S., Dean, D., Vavvas, D., Ellis, B., Kraegen, E.W., Shafrir, E.and Ruderman, N.B.: Increases in cytosolic citrate regulate malonyl CoA levels in rat muscle in vivo. Am. J. Physiol. 276:E1030-E1037, 1999.

2. Ruderman, N.B., Saha, A.K., Vavvas, D. and Witters, L.A.: Malonyl CoA, fuel sensing and insulin resistance. Am. J. Physiol. 276:E1-E18, 1999.

3. Saha, A.K., Schwarsin, A.J., Roduit, R, Masse, F., Kaushik, V., Tornheim, K., prentki, M. and Ruderman, N.B.: Activation of malonyl CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboximide-1-b-D-ribofuranoside. J. Biol. Chem. 275: 24279-24288, 2000.

4. Park, H, Kaushik, V.K., Constant, S., Prentki, M., Przybytkowski, E., and Saha, A.K. :Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise J. Biol. Chem, 277: 32571-32577, 2002.

5. Ruderman, N.B., Park, H., Kaushik, V., Dean, D., Constant, S., Prentki, M. and Saha, A.K. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol. Scand., 178:435-42, 2003.

6. Itani, S.I., Saha, A.K., Kurowski, T.G., Coffin, H.R., Tornheim, K. and Ruderman, N.B. Glucose autoregulates its uptake in skeletal muscle: involvement of AMP-activated protein kinase. Diabetes, 52:1635-40, 2003.

7. Saha, A.K. and Ruderman, N.B. Malonyl CoA and AMP-activated protein kinase: an expanding partnership. Mol. Cell. Biochem.,2003;253:65-70.

8. Saha AK, Avilucea PR, Ye JM, Assifi MM, Kraegen EW, Ruderman NB. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo.Biochem Biophys Res Commun. 2004;314:580-5.






			Asish Saha, Ph.D. Malonyl CoA and fuel sensing mechanism in skeletal muscle The principal objective of my research is to determine how malonyl CoA is regulated in skeletal muscle with emphasis on the role of the enzyme AMP-activated protein kinase (AMPK). Malonyl CoA is both an intermediate in the synthesis of fatty acids and an inhibitor of carnitine palmitoyl transferase 1, the enzyme that catalyzes the transfer of long chain fatty acyl CoA into the mitochondria where they are oxidized. Over the past 8 years we have shown that the concentration of malonyl CoA in skeletal muscle is acutely regulated by changes in its fuel supply and energy expenditure (Am. J. Physiol. 276:E1-E18, 1999). Key players in the schema we have proposed are acetyl CoA carboxylase (ACC), the rate limiting enzyme in malonyl CoA synthesis; citrate, an allosteric activator of ACC; and an AMP-activated protein kinase (AMPK) that is activated during exercise, and phosphorylates and inhibits ACC. For the last few years I have been working on the malonyl CoA decarboxylase (MCD), an enzyme involved in malonyl CoA catabolism. We had demonstrated that both muscle contraction and incubation with AICAR (5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside), a cell-permeable activator of AMPK, increased MCD activity in skeletal muscle and that this is likely due to its phosphorylation by AMP-activated protein kinase (AMPK). The results strongly suggest a dual control of malonyl CoA concentration by acetyl CoA carboxylase and MCD via AMPK and that alterations in MCD activity could complement changes in ACC in decreasing malonyl CoA and increasing fatty acid oxidation for energy production (J. Biol. Chem. 275: 24279-24288, 2000). We have also shown that the activity of sn-glycerol-3-phosphate acyltransferase (GPAT), like MCD and ACC, is regulated by AMPK (J. Biol. Chem. 277: 32571-32577, 2002) and that acyl coenzyme A:diacylglycerol acyiltranferase (DGAT), an enzyme unique to triglycertide synthesis, is inhibited during exercise Recently we have found that Pioglitazone, a PPAR_g agonist, diminishes malonyl CoA levels and that this is associated with an increase in hepatic and adipose tissue AMPK phosphorylation. These results suggest that PPAR_g agonists such as Pioglitazone could improve insulin sensitivity and dyslipidemia by leading to the activation of AMPK in liver and adipose tissue. References 1. Saha, A.K., Laybutt, D.S., Dean, D., Vavvas, D., Ellis, B., Kraegen, E.W., Shafrir, E.and Ruderman, N.B.: Increases in cytosolic citrate regulate malonyl CoA levels in rat muscle in vivo. Am. J. Physiol. 276:E1030-E1037, 1999. 2. Ruderman, N.B., Saha, A.K., Vavvas, D. and Witters, L.A.: Malonyl CoA, fuel sensing and insulin resistance. Am. J. Physiol. 276:E1-E18, 1999. 3. Saha, A.K., Schwarsin, A.J., Roduit, R, Masse, F., Kaushik, V., Tornheim, K., prentki, M. and Ruderman, N.B.: Activation of malonyl CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboximide-1-b-D-ribofuranoside. J. Biol. Chem. 275: 24279-24288, 2000. 4. Park, H, Kaushik, V.K., Constant, S., Prentki, M., Przybytkowski, E., and Saha, A.K. :Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise J. Biol. Chem, 277: 32571-32577, 2002. 5. Ruderman, N.B., Park, H., Kaushik, V., Dean, D., Constant, S., Prentki, M. and Saha, A.K. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol. Scand., 178:435-42, 2003. 6. Itani, S.I., Saha, A.K., Kurowski, T.G., Coffin, H.R., Tornheim, K. and Ruderman, N.B. Glucose autoregulates its uptake in skeletal muscle: involvement of AMP-activated protein kinase. Diabetes, 52:1635-40, 2003. 7. Saha, A.K. and Ruderman, N.B. Malonyl CoA and AMP-activated protein kinase: an expanding partnership. Mol. Cell. Biochem.,2003;253:65-70. 8. Saha AK, Avilucea PR, Ye JM, Assifi MM, Kraegen EW, Ruderman NB. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo.Biochem Biophys Res Commun. 2004;314:580-5.