Acetyl-CoA carboxylase, usually shortened to ACC, is the enzyme that commits your body to making fat. It catalyzes the first and rate-limiting step in fatty acid synthesis, converting a small molecule called acetyl-CoA into malonyl-CoA, the universal building block for new fat molecules. That single reaction sits at a crossroads of metabolism so important that it influences everything from liver disease and obesity to appetite, heart function, and even cancer growth. Researchers across medicine, agriculture, and drug development all have reasons to care about this one enzyme, and the science around it has accelerated in recent years.
What ACC Actually Does
ACC works in two steps. First, a portion of the enzyme called biotin carboxylase grabs a carbon dioxide molecule and, using energy from ATP, attaches it to a small carrier molecule called biotin. Then a second portion, called carboxyltransferase, moves that carbon unit from biotin onto acetyl-CoA, producing malonyl-CoA.1PubMed. Complex formation and regulation of Escherichia coli acetyl-CoA carboxylase The whole process is sometimes described as a “ping-pong” reaction because the biotin swings between two active sites, picking up a carbon group from one and dropping it off at the other.
Malonyl-CoA, the product, then feeds into a downstream assembly line (fatty acid synthase) that chains together carbon units to build palmitate and other fatty acids. But malonyl-CoA is not just a building material. It doubles as a signaling molecule that tells cells whether to burn fat or store it, a dual role that makes ACC uniquely powerful in metabolic regulation.
Two Isoforms With Different Jobs
Mammals have two versions of the enzyme, ACC1 and ACC2, encoded by separate genes. They carry out the same chemical reaction but in different places and for different purposes. ACC1 lives in the cytoplasm and produces the malonyl-CoA that feeds directly into new fat production.2PubMed. The subcellular localization of acetyl-CoA carboxylase 2 ACC2, by contrast, is anchored to the outer membrane of mitochondria, and the malonyl-CoA it makes acts as a brake on fat burning. It does this by blocking an enzyme called CPT-1, which is the gatekeeper that shuttles fatty acids into mitochondria to be oxidized for energy.3PubMed. The subcellular localization of acetyl-CoA carboxylase 2
Knockout experiments in mice confirmed these distinct roles. Deleting ACC1 is lethal to embryos, underscoring that fat synthesis is essential for development.4PubMed Central. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal Deleting ACC2 produces viable mice that burn more fat and resist weight gain, consistent with its role as the oxidation gatekeeper. These experiments also showed that the malonyl-CoA produced by each isoform stays in its own cellular neighborhood rather than mixing freely, supporting the idea that cells maintain two functionally independent pools of the same molecule.5PubMed Central. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal
One wrinkle is that the tissue distribution of these isoforms differs between species. In rats, ACC1 dominates in fat-producing tissues like the liver, while ACC2 dominates in oxidative tissues like muscle. In humans, though, ACC2 is heavily expressed in both oxidative and lipogenic tissues, meaning its regulatory role may be broader than rodent studies would suggest.6PubMed. Acetyl-CoA carboxylases 1 and 2 show distinct expression patterns in rats and humans and alterations in obesity and diabetes That species difference is worth keeping in mind when translating animal research into human drug development.
How Cells Turn ACC On and Off
Because ACC sits at such a critical metabolic junction, cells regulate it tightly using multiple mechanisms. The most studied is phosphorylation by AMP-activated protein kinase (AMPK), an enzyme sometimes called the body’s fuel gauge. When cellular energy is low, AMPK switches on and phosphorylates ACC1 and ACC2, shutting them down.7PubMed Central. AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold-induced appetite but not thermogenesis The effect is twofold: fat synthesis drops (because ACC1 is off) and fat burning ramps up (because ACC2 stops making the malonyl-CoA that would otherwise block CPT-1). Exercise, fasting, and several diabetes drugs all activate AMPK, and their fat-burning effects flow in part through this ACC connection.
ACC also responds to allosteric signals, molecules that change its activity by binding outside the active site. Citrate, which accumulates when cells have plenty of fuel, activates ACC by promoting its assembly into long polymer chains. Conversely, palmitoyl-CoA, a product of fat synthesis, inhibits ACC by breaking those polymers apart. Early work showed that insulin shifted the enzyme toward its active polymeric form, while adrenaline pushed it toward the inactive form, tracking with the broader metabolic logic that insulin promotes fat storage and adrenaline promotes fat mobilization.8Biochemical Journal. Hormonal regulation of adipose-tissue acetyl-coenzyme A carboxylase by changes in the polymeric state of the enzyme
Recent cryo-electron microscopy work has provided stunning detail on this polymerization. Human ACC1 forms filament structures in its inactive state, and when activated by dephosphorylation and citrate, the enzyme rearranges into a different conformation resolved at a resolution of 2.55 angstroms. Biotin, the carrier that shuttles the carbon group between the two half-reactions, binds to a site far from the acetyl-CoA binding pocket when substrate is absent, hinting at a built-in coordination mechanism that prevents wasted catalytic cycles.9PubMed Central. Filament structures unveil the dynamic organization of human acetyl-CoA carboxylase
Malonyl-CoA as a Metabolic Traffic Light
The discovery that malonyl-CoA does double duty, serving as both the raw material for fat synthesis and the signal that blocks fat burning, was a pivotal moment in metabolism research. That finding dates to 1977 and fundamentally changed how scientists think about the relationship between fat storage and fat oxidation.10PubMed Central. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation The two processes are not just opposite directions on the same pathway; they are actively coordinated through a single molecule.
In the liver after a meal, ACC ramps up, malonyl-CoA rises, and three things happen simultaneously: new fat is built, fat burning is suppressed, and the liver shifts toward processing incoming nutrients rather than tapping stored fuel. Recent research has further shown that this malonyl-CoA surge in the liver also restrains sugar production by suppressing fat oxidation and limiting the availability of certain amino acids that feed into glucose-making pathways.11PubMed Central. Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability So ACC’s influence extends beyond fat metabolism into blood sugar control.
ACC and Fatty Liver Disease
Metabolic dysfunction-associated steatotic liver disease, or MASLD (previously called non-alcoholic fatty liver disease), is the most common chronic liver condition worldwide. Its hallmark is excessive fat accumulation in the liver, and a growing body of evidence points to ramped-up de novo lipogenesis, the pathway that ACC controls, as one of the earliest metabolic changes that tips a healthy liver into disease.12PubMed Central. Targeting acetyl-CoA carboxylases for the treatment of MASLD In people with MASLD, ACC and other enzymes in the fat-synthesis pathway are upregulated, meaning the liver is making more fat than it should be.13Journal of Clinical and Translational Hepatology. Mechanism of Metabolic Dysfunction-associated Steatotic Liver Disease: Important role of lipid metabolism
This has made ACC inhibitors one of the most actively pursued drug strategies for liver disease. In clinical trials, the results have been dramatic in some ways and frustrating in others. One ACC inhibitor called firsocostat (GS-0976) reduced liver fat by about 29% relative to placebo in a phase 2 trial of patients with advanced fatty liver disease after just 12 weeks of treatment.14PubMed Central. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH) A different ACC inhibitor, PF-05221304, achieved even more striking reductions in liver fat at higher doses, reaching 50 to 65% at doses of 10 mg or more daily.15PubMed. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials
The Triglyceride Problem
For all their promise, ACC inhibitors have come with a consistent side effect that has complicated their path to the clinic: they raise blood triglycerides, sometimes to dangerously high levels. In the firsocostat trial, 16 patients developed triglyceride concentrations above 500 mg/dL, a threshold that carries meaningful cardiovascular risk.16PubMed Central. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH)
The reason is a feedback loop. When ACC is fully blocked, levels of polyunsaturated fatty acids drop sharply. The liver interprets this as a shortage and compensatorily ramps up a fat-production master regulator called SREBP1, which increases lipogenic gene expression and simultaneously reduces breakdown and clearance of triglycerides from the blood.17Trends in Molecular Medicine. New avenues for NASH therapy by targeting ACC In other words, blocking one fat-synthesis step at the front of the pipeline triggers compensatory upregulation elsewhere that ends up flooding the bloodstream with fats. Researchers have tried to work around this by combining ACC inhibitors with other drugs, such as DGAT2 inhibitors that target a later step in triglyceride assembly, or by adjusting dosing strategies to find a sweet spot that reduces liver fat without spiking blood lipids.
ACC and Cancer
Tumors need a lot of fat to build new cell membranes and sustain rapid growth, and many cancers ramp up their fat-synthesis machinery to meet that demand. Because ACC catalyzes the first committed step in that process, it has attracted interest as a potential anticancer target.18PubMed Central. Targeting acetyl-CoA carboxylase 1 for cancer therapy The idea is straightforward: starve a tumor of the building blocks it needs to grow. In practice, the picture is more complex. Some studies suggest that ACC1 inhibition can slow tumor growth in certain cancer types, but the same triglyceride rebound seen in liver disease trials is a concern in oncology too. The field is still sorting out whether ACC inhibitors can be dosed or combined in ways that would be useful against tumors without causing unacceptable metabolic side effects.
ACC in the Brain and Appetite Control
One of the more surprising chapters in ACC research involves the hypothalamus, the brain region that controls hunger and energy balance. It turns out that malonyl-CoA in the brain acts as an appetite suppressant. When the hormone leptin, which signals that the body has enough fat stores, reaches the hypothalamus, it activates ACC in specific brain nuclei. The resulting rise in malonyl-CoA suppresses production of hunger-promoting signals and reduces food intake.19PubMed Central. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake Blocking ACC in the brain with a chemical inhibitor was enough to counteract leptin’s appetite-suppressing effect in animal experiments, confirming that ACC activation is not just correlated with leptin signaling but necessary for it.20PubMed Central. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake
The hunger-promoting hormone adiponectin works through the opposite side of the same switch. Adiponectin activates AMPK in the hypothalamus, which phosphorylates and inactivates ACC, lowering malonyl-CoA and increasing expression of hunger-promoting neuropeptides.21PubMed. Globular adiponectin regulates energy homeostasis through AMP-activated protein kinase-acetyl-CoA carboxylase (AMPK/ACC) pathway in the hypothalamus Malonyl-CoA in the hypothalamus has thus emerged as a central node in appetite regulation, a mediator where multiple hormonal signals converge.22PubMed Central. Hypothalamic malonyl-CoA and the control of food intake
This creates an interesting tension for drug development. An ACC inhibitor designed to reduce liver fat or slow tumor growth could, if it reaches the brain, also lower hypothalamic malonyl-CoA and stimulate appetite, exactly the wrong outcome in patients already struggling with metabolic disease. Mouse studies using genetically engineered animals that cannot be phosphorylated by AMPK at the ACC sites showed that the AMPK-ACC axis is required for the surge of appetite that normally accompanies fasting and cold exposure.23PubMed Central. AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold-induced appetite but not thermogenesis Designing liver-directed ACC inhibitors that do not cross into the central nervous system is therefore a practical priority.
ACC and the Heart
The heart is one of the body’s most metabolically active organs, and it relies heavily on fatty acid oxidation for fuel. ACC2’s role as the gatekeeper of fat burning makes it especially relevant in cardiac physiology. In mice lacking ACC2 specifically in the heart, fat oxidation increased by roughly 60%, yet the hearts maintained normal function and oxygen consumption under baseline conditions.24PubMed Central. Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy
Where the difference became dramatic was under stress. When hearts were subjected to pressure overload, a model for the kind of strain that leads to heart failure, normal hearts shifted away from fat burning and toward sugar-based metabolism, a pattern called metabolic remodeling that is associated with declining cardiac performance. Hearts lacking ACC2, however, maintained their normal fuel mix even under pressure overload, suggesting that keeping fat oxidation “unlocked” could protect against the harmful metabolic shift that accompanies heart failure.25PubMed Central. Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy Separately, whole-body ACC2-mutant mice had smaller hearts with reduced stored triglycerides but increased oxidation of both fat and glucose, and they functioned normally despite their reduced size.26PubMed Central. Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice
Bacterial ACC as an Antibiotic Target
The ACC found in bacteria is structurally different from the mammalian version. Instead of one large multidomain protein, bacterial ACC is assembled from several separate protein subunits. That difference opens a window for selective drug targeting: a molecule that fits into a bacterial ACC active site might have no effect on the human enzyme. The biotin carboxylase subunit of bacterial ACC has been the focus of antibiotic discovery efforts, and several inhibitor classes have been identified that specifically block fatty acid synthesis in bacteria at concentrations consistent with those that kill the organisms.27ACS Chemical Biology. Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches One optimized compound achieved an inhibition potency of 20 nanomolar and could kill a sensitized strain of E. coli at concentrations below 1 microgram per milliliter.28Bioorganic & Medicinal Chemistry Letters. Discovery and optimization of antibacterial AccC inhibitors
None of these compounds have yet made it to the clinic, and a recurring challenge is that many Gram-negative bacteria have outer membranes that block drug entry, limiting the spectrum of activity to either Gram-positive organisms or strains with compromised efflux pumps. Still, as antibiotic resistance continues to narrow treatment options, fatty acid synthesis remains one of the few genuinely novel target spaces that researchers keep returning to.
ACC in Plants and Herbicide Resistance
Plants have their own versions of ACC, and the enzyme plays an equally central role in plant fat metabolism. Across life, ACC exists in two structural forms: a homomeric form, where all catalytic activities reside in a single large polypeptide, and a heteromeric form, where separate subunits carry the different functions.29PubMed Central. Plant acetyl-CoA carboxylase: The homomeric form and the heteromeric form Most grasses rely on the homomeric form in their chloroplasts, and this is the form targeted by a major class of herbicides. These herbicides, grouped into chemical families called FOPs, DIMs, and DENs, are competitive inhibitors that bind in the carboxyltransferase domain of the grass homomeric ACC, blocking the step where the carboxyl group is transferred to acetyl-CoA.30Scientia Agricola. ACCase-inhibiting herbicides: mechanism of action, resistance evolution and stewardship Broadleaf crops, which use the structurally distinct heteromeric form in their chloroplasts, are naturally resistant, making these herbicides useful for selectively killing grass weeds in broadleaf fields.
Resistance to ACC-targeting herbicides has become a growing agricultural headache. Weeds can evolve single amino acid substitutions in the ACC gene that prevent the herbicide from binding without significantly impairing the enzyme’s normal function. One of the most widespread is the Ile-1781-Leu mutation, which has been documented across multiple weed species and confers broad-spectrum resistance to FOPs, DIMs, and other ACC-inhibiting chemicals.31PubMed. Ile-1781-Leu Target Mutation and Non-Target-Site Mechanism Confer Resistance to Acetyl-CoA Carboxylase-Inhibiting Herbicides in Digitaria ciliaris var. chrysoblephara Other mutations, like Ile-2041-Asn, tend to give resistance to narrower sets of herbicides.32PubMed Central. Target-site mutations Ile1781Leu and Ile2041Asn in the ACCase2 gene confer resistance to fluazifop-p-butyl and pinoxaden herbicides in a johnsongrass accession from Arkansas, USA On top of target-site mutations, some weed populations develop non-target-site resistance mechanisms, such as enhanced metabolism that breaks down the herbicide before it reaches ACC, making the resistance problem even harder to manage with chemistry alone.
Skin, Sebum, and ACC
A less publicized application of ACC research involves the skin. Sebaceous glands produce sebum, the oily substance that lubricates hair and skin, and de novo lipogenesis driven by ACC is a key part of that production. The logic for targeting ACC in dermatology parallels the liver story: if you can tamp down ACC activity in sebaceous glands, you reduce sebum output, which could help treat acne and other conditions linked to excessive oiliness. Early-stage drug discovery work has identified small-molecule ACC inhibitors aimed specifically at this application, though topical delivery and tissue selectivity remain significant hurdles.
An Ancient Enzyme With Deep Roots
ACC belongs to a larger family of biotin-dependent carboxylases that traces back to the earliest life on Earth. Phylogenomic analyses suggest that the last common ancestor of all living organisms already possessed at least two biotin-dependent carboxylases, one specific for pyruvate and another capable of carboxylating various CoA-bearing substrates, likely including the ancestor of modern ACC.33PubMed Central. Early evolution of the biotin-dependent carboxylase family Eukaryotes appear to have acquired their ACC enzymes through the ancient endosymbiotic events that gave rise to mitochondria and chloroplasts, essentially inheriting them from the bacterial ancestors of those organelles. The fact that the same fundamental chemistry, biotin shuttling a carboxyl group between two active sites, has been conserved for billions of years speaks to how central this reaction is to life’s basic metabolic toolkit.