Acetyl-CoA Carboxylase (ACC) is an enzyme that performs a specific function related to how the body produces and manages fats. It is present in most cells and initiates fatty acid synthesis, the body’s method for creating fats from dietary building blocks. This function positions ACC at a metabolic crossroads. It directs the flow of energy from carbohydrates and other sources toward either immediate use or long-term storage as lipids. Understanding its function is important for comprehending broader concepts of metabolic health.
The Core Function of Acetyl-CoA Carboxylase
Acetyl-CoA Carboxylase performs the first committed step in de novo lipogenesis, the creation of new fatty acids. It carries out the conversion of acetyl-CoA into malonyl-CoA. Acetyl-CoA is a two-carbon molecular unit derived from the breakdown of carbohydrates, fats, and proteins. It represents a pool of building materials available to the cell.
Before these two-carbon units can be assembled into a fatty acid chain, they must be chemically primed. ACC performs this priming by adding a carboxyl group to acetyl-CoA, transforming it into the three-carbon molecule malonyl-CoA. This conversion is irreversible and requires energy from ATP. The creation of malonyl-CoA is the rate-limiting step of fatty acid synthesis, meaning the speed at which ACC works sets the pace for the entire fat production line.
Once produced, malonyl-CoA serves as the donor of two-carbon units for the growing fatty acid chain, a process carried out by the fatty acid synthase enzyme complex. These newly synthesized fats can then be used to build cell membranes. They can also be stored as triglycerides for future energy needs.
Regulation of Enzyme Activity
The activity of Acetyl-CoA Carboxylase is controlled to align fatty acid synthesis with the body’s energy status. Hormonal signals provide one layer of regulation. When blood sugar is high, insulin promotes ACC activation by stimulating enzymes that remove inhibitory phosphate groups, turning it on to convert excess sugar into fat. Conversely, when blood sugar is low, glucagon leads to the phosphorylation and inactivation of ACC, halting fat synthesis to conserve energy.
ACC is also subject to allosteric regulation by metabolites that signal the cell’s internal energy. Citrate, which accumulates when the cell has abundant energy, acts as an allosteric activator. High citrate indicates the cell’s primary energy-producing pathway, the Krebs cycle, is saturated and excess acetyl-CoA can be diverted to fat storage. Citrate binding causes ACC enzymes to polymerize into long, active filaments. In contrast, the end products of fatty acid synthesis, like palmitoyl-CoA, act as feedback inhibitors, signaling that enough fat has been produced.
A third layer of control comes from AMP-activated protein kinase (AMPK). AMPK becomes active when cellular energy levels are low, indicated by a high ratio of AMP to ATP. Once activated, AMPK directly phosphorylates ACC, which strongly inhibits its activity. This mechanism prevents the cell from using energy to build fats when it needs to generate ATP for more immediate functions. This integrated system of controls allows the cell to tune fat production in response to both whole-body and local energy needs.
Distinct Roles of ACC Isoforms
Fatty acid metabolism is regulated by two distinct isoforms of Acetyl-CoA Carboxylase: ACC1 and ACC2. These are encoded by different genes and catalyze the same reaction. However, their different locations within the cell dictate their specialized roles. This separation of function allows for independent control over fat synthesis and breakdown.
ACC1 is found in the cytoplasm and is highly expressed in lipogenic tissues like the liver and adipose (fat) tissue. The malonyl-CoA produced by ACC1 serves as the building block for fatty acid synthase to create long-chain fatty acids. These fats can then be incorporated into triglycerides for energy storage. They can also be used as structural components for cellular membranes.
ACC2 is targeted to the outer membrane of the mitochondria. While it also produces malonyl-CoA, this molecule serves a regulatory purpose. The malonyl-CoA from ACC2 inhibits carnitine palmitoyltransferase 1 (CPT1), an enzyme on the mitochondrial membrane. CPT1 is responsible for transporting fatty acids into the mitochondria to be burned for energy. By inhibiting CPT1, ACC2 blocks fat breakdown, preventing a wasteful scenario where the cell would be simultaneously synthesizing and oxidizing fats.
Implications in Health and Disease
Dysregulation of Acetyl-CoA Carboxylase activity is implicated in several diseases. In conditions like obesity and metabolic syndrome, ACC activity is often elevated. This leads to excessive de novo lipogenesis, contributing to fat accumulation in the liver, a condition known as non-alcoholic fatty liver disease (NAFLD). The buildup of lipids in non-adipose tissues can interfere with cellular signaling, including insulin signaling.
This interference contributes to type 2 diabetes. When tissues like the liver and muscle become laden with fat, they can become resistant to insulin. This means cells do not properly take up glucose from the blood, and ACC may remain active when it should be off. This creates a cycle where insulin resistance promotes more fat synthesis via ACC, which worsens insulin resistance.
ACC is also relevant in cancer research. Many cancer cells show a high rate of fatty acid synthesis. These rapidly dividing cells require a large supply of new lipids to build the membranes of new cells. To meet this demand, cancer cells often upregulate the expression and activity of ACC1, making the enzyme a target for anticancer therapies.