What is the activity of Acetyl-CoA (Acetyl Coenzyme A) Carboxylase in a fasting state?

From the Guidelines

During the fasting state, acetyl-CoA carboxylase (ACC) activity is significantly decreased, allowing the body to prioritize fatty acid oxidation over synthesis to maintain energy homeostasis. This decrease in ACC activity is crucial for the body's adaptation to the fasting state, as it enables the shift from an anabolic to a catabolic state, where the breakdown of stored energy is prioritized over the synthesis of new fatty acids. The mechanism behind this decrease in ACC activity involves both allosteric regulation and covalent modification, with low insulin levels during fasting leading to increased activity of AMP-activated protein kinase (AMPK), which phosphorylates and inactivates ACC 1. Additionally, the increased glucagon levels during fasting activate protein kinase A, which also phosphorylates and inhibits ACC. The reduced ACC activity results in decreased malonyl-CoA levels, which not only reduces fatty acid synthesis but also removes the inhibition on carnitine palmitoyltransferase-1 (CPT-1), allowing increased fatty acid oxidation to provide energy during the fasting period. Some key points to consider in this context include:

• The role of AMPK in regulating ACC activity during fasting
• The impact of glucagon on protein kinase A and ACC activity
• The effects of decreased malonyl-CoA levels on fatty acid synthesis and oxidation
• The importance of CPT-1 in facilitating fatty acid oxidation during fasting. Overall, the decrease in ACC activity during fasting is a critical adaptation that enables the body to maintain energy homeostasis during periods of nutrient deprivation.

From the Research

Activity of Acetyl CoA Carboxylase in Fasting State

• The activity of acetyl CoA carboxylase (ACC) decreases in the fasting state, with specific activities of 2.75,1.85,1.7, and 0.9 units/mg after 12,18,24, and 48 hours of fasting, respectively 2.
• This decrease in activity is accompanied by an increase in the phosphate content of ACC, with values of 5.3,5.6.7, and 7.6 mol of Pi/mol of subunit obtained for preparations from rats fasted for 12,18,24, and 48 hours, respectively 2.
• Refeeding fasted rats results in increased specific activity of ACC (3.4 units/mg) and decreased phosphate content (5.1 mol of Pi/mol of subunit) 2.
• The low activity of ACC from fasted rats is due to its increased phosphate content, which can be reversed by dephosphorylation 2.
• ACC mRNA and activity also decrease in adipocytes and liver during fasting 3.
• The mechanism responsible for increasing fatty acid oxidation in adipose tissue during fasting involves mainly allosteric regulation, whereas altered gene expression may play a central role in the liver 3.

Regulation of Acetyl CoA Carboxylase

• Acetyl CoA carboxylase is a key enzyme in energy balance, controlling the synthesis of malonyl-CoA, an allosteric inhibitor of carnitine palmitoyltransferase-1 (CPT-1) 3.
• ACC is regulated by phosphorylation/dephosphorylation, with phosphorylation leading to decreased activity and dephosphorylation leading to increased activity 2.
• The activity of ACC is also regulated by citrate, which activates the enzyme 2.
• Acetyl CoA represents a key node in metabolism, with its levels monitored by cells as a key indicator of their metabolic state 4.
• High nucleocytosolic acetyl CoA amounts are a signature of a 'growth' or 'fed' state, while low amounts are a signature of a 'survival' or 'fasted' state 4.

Therapeutic Targeting of Acetyl CoA Carboxylase

• Acetyl CoA carboxylase is a therapeutic target for metabolic syndrome, with inhibitors of the enzyme showing promise in reducing hepatic steatosis and improving insulin sensitivity 5, 6.
• However, inhibition of ACC can also lead to hypertriglyceridemia, highlighting the need for further research into the therapeutic utility of ACC inhibitors 6.