AMPK-Dependent Inhibitory Phosphorylation of ACC Is Not Essential for Maintaining Myocardial Fatty Acid Oxidation

Abstract

A cetyl coenzyme A carboxylase (ACC) plays an important role in regulating fatty acid oxidation (FAO) in the heart. 1,2 ACC catalyzes the conversion of acetyl CoA to malonyl-CoA. 3 In muscle, malonyl-CoA is an endogenous inhibitor of carnitine palmitoyl CoA transferase 1, which regulates long-chain fatty acyl CoA import into the mitochondria for β-oxidation. 4,5Two isoforms of ACC exist in the heart (ACC 1 and 2), 3,6 and both ACC1/2 can be regulated by inhibitory phosphorylation by AMP-activated protein kinase (AMPK).7 AMPK phosphorylates ACC1/2 on serine residues (Ser79/212), 7-9 leading to inhibition of ACC activity and decreased malonyl-CoA production.10 Despite the role that AMPK plays in regulating ACC activity and subsequent FAO, whether AMPK-mediated inactivation of ACC plays an obligate role in the maintenance of myocardial FAO rates has not been tested. In This Issue, see p 471To address this, we generated mutant mice with alanine knock-in mutations in both ACC1 (at Ser79) and ACC2 (at Ser212). In the liver and skeletal muscle, these mice maintain functional ACC and AMPK but express a mutant form of ACC that is no longer inhibited by AMPK phosphorylation. 11Consistent with the loss of AMPK-mediated inactivation of ACC, we have previously shown that these ACC-double knock-in (ACC-DKI) mice have significantly elevated ACC activity and impaired FAO in the liver.11 However, the effect of preventing AMPK-mediated phosphorylation of ACC in the heart has not been investigated. Herein, we show that hearts from ACC-DKI mice have increased malonyl-CoA levels compared with wild-type (WT) mice, but their FAO rates

Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet

“…In that study, treatment of hepatocytes with A769662, a direct activator of AMPK, caused a modest increase in FAO in cells expressing wild-type ACC but had no effect in cells expressing the mutant ACC enzymes (Fullerton et al., 2013). Although we are unable to explain the difference between our results and those obtained in the previous study, it is interesting to note that, using the same ACC phosphorylation-deficient mouse model, phosphorylation of ACC by AMPK was not required for regulation of FAO in heart (Zordoky et al., 2014). In a more recent study, canagliflozin, which was shown to activate AMPK in the liver, decreased RER independently of ACC phosphorylation (Hawley et al., 2016).…”

AMPK: energy sensor and survival mechanism in the ischemic heart

“…Since malonyl- CoA is a negative regulator of carnitine palmitoyltransferase 1 (CPT–1), AMPK activation effectively reduces the inhibition of CPT-1 and promotes fatty acyl- carnitine entry into the mitochondria [6]. In the presence of oxygen, this mechanism accelerates fatty acid oxidation, although recent findings indicate that ACC activity and malonyl-CoA levels do not necessarily correlate with rates of heart fatty acid oxidation [45]. Although FA oxidation is limited by the lack of oxygen in the setting of ischemia, when oxygen delivery is restored during reperfusion, AMPK accelerates fatty acid oxidation [45].…”

“…In the presence of oxygen, this mechanism accelerates fatty acid oxidation, although recent findings indicate that ACC activity and malonyl-CoA levels do not necessarily correlate with rates of heart fatty acid oxidation [45]. Although FA oxidation is limited by the lack of oxygen in the setting of ischemia, when oxygen delivery is restored during reperfusion, AMPK accelerates fatty acid oxidation [45]. The degree of residual AMPK activation following reperfusion appears to depend on the severity and duration of ischemia, so that the extent to which fatty acid oxidation is enhanced may be somewhat variable.…”

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Hence, ACC1, the downstream target of AMPK, primarily responds to metabolic stresses through adaptive adjustments instead of transcriptional alterations [145]. Similar to ACC1, AMPK is the major upstream kinase of ACC2 by phosphorylating its Ser212 residue to inhibit its physiological ability [146].…”