Fatty Acid Synthesis Pathway: Key Steps and Regulation
Explore the fatty acid synthesis pathway, its regulation, and connections to metabolism, highlighting key enzymes, intermediates, and physiological relevance.
Fatty acid synthesis is a crucial process that enables cells to produce lipids for energy storage, membrane formation, and signaling. This pathway converts excess carbohydrates into fatty acids, which are stored as triglycerides or used for cellular functions. Disruptions in this pathway can significantly impact health.
Understanding how fatty acid synthesis is regulated and integrated with other metabolic pathways provides insight into both normal physiology and disease states.
Cellular Sites of Synthesis
Fatty acid synthesis primarily occurs in the cytoplasm, with hepatocytes and adipocytes being the main sites. The liver converts excess carbohydrates into fatty acids, packaging them into lipoproteins for transport. Adipose tissue specializes in storing these fatty acids as triglycerides for future energy needs. Other tissues, such as the lactating mammary gland, also engage in fatty acid production to support milk synthesis.
A multi-enzyme complex called fatty acid synthase (FAS) facilitates the stepwise elongation of acetyl-CoA into palmitate, the primary product of the pathway. However, acetyl-CoA is generated in the mitochondria and must be transported to the cytoplasm as citrate via the citrate shuttle. Once in the cytoplasm, ATP-citrate lyase cleaves citrate to regenerate acetyl-CoA for fatty acid synthesis.
The endoplasmic reticulum further modifies fatty acids by elongation and desaturation, producing complex lipids such as phospholipids and signaling molecules. This interplay between cytoplasmic synthesis and endoplasmic reticulum modifications ensures cells generate a diverse array of fatty acids for structural and functional needs.
Key Enzymes Involved
Fatty acid synthesis depends on a series of enzymes, each playing a distinct role in converting acetyl-CoA into long-chain fatty acids. Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, a key regulatory step in lipogenesis. ACC activity is controlled by phosphorylation via AMP-activated protein kinase (AMPK) and dephosphorylation by protein phosphatase 2A (PP2A), reflecting the cell’s energy status. High ATP levels activate ACC, promoting fatty acid synthesis, while energy deficits inhibit it.
Fatty acid synthase (FAS), a dimeric multi-enzyme complex, elongates the fatty acid chain through a series of condensation, reduction, dehydration, and reduction reactions, ultimately forming palmitate. Its modular structure allows for efficient substrate turnover.
ATP-citrate lyase (ACLY) links carbohydrate metabolism to lipogenesis by cleaving citrate into acetyl-CoA and oxaloacetate. Insulin signaling enhances ACLY activity, promoting lipid accumulation in response to nutrient abundance. Dysregulated ACLY activity contributes to metabolic disorders such as obesity and insulin resistance.
Major Intermediates and Their Roles
Fatty acid synthesis progresses through key intermediates that facilitate controlled elongation. Acetyl-CoA provides the initial two-carbon unit, while malonyl-CoA serves as the primary donor for chain extension. Acetyl-CoA carboxylase generates malonyl-CoA, a regulated intermediate that fine-tunes lipogenesis.
Malonyl-CoA undergoes condensation reactions within FAS, adding two-carbon units to the growing chain while releasing carbon dioxide. Intermediates such as acetoacetyl-ACP and β-hydroxybutyryl-ACP undergo reduction and dehydration, remaining tethered to an acyl carrier protein (ACP) for stability and efficient enzyme-substrate interaction.
The final intermediate, palmitoyl-ACP, is hydrolyzed by thioesterase, releasing palmitate. Cells can further elongate or desaturate palmitate in the endoplasmic reticulum to generate diverse lipid species essential for membrane fluidity, signaling, and energy storage.
Regulation by Hormones and Nutrients
Fatty acid synthesis is tightly regulated by hormonal and nutrient signals. Insulin promotes lipogenesis by activating key enzymes and increasing substrate availability. It stimulates ATP-citrate lyase phosphorylation, enhancing citrate conversion to acetyl-CoA. Additionally, insulin upregulates ACC and FAS expression via the sterol regulatory element-binding protein 1c (SREBP-1c) pathway, reinforcing lipid synthesis in response to nutrient abundance.
In contrast, glucagon and epinephrine inhibit lipogenesis, preventing excessive lipid accumulation during fasting or stress. These hormones activate AMPK, which phosphorylates and inactivates ACC, reducing malonyl-CoA production and slowing fatty acid synthesis. AMPK also suppresses SREBP-1c activity, further limiting lipogenic enzyme transcription.
Interplay With Carbohydrate and Protein Metabolism
Fatty acid synthesis is closely linked to carbohydrate and protein metabolism. Acetyl-CoA availability is primarily dictated by carbohydrate metabolism. Glucose oxidation produces pyruvate, which is converted into acetyl-CoA in the mitochondria. Since acetyl-CoA cannot cross the mitochondrial membrane, it is transported as citrate and cleaved in the cytoplasm by ATP-citrate lyase, ensuring excess carbohydrates are efficiently rerouted into lipid storage.
Amino acids also influence fatty acid synthesis. Glucogenic amino acids contribute to citrate production via the tricarboxylic acid (TCA) cycle, while others, like leucine, can be directly converted into acetyl-CoA. Protein metabolism also affects lipid synthesis through hormonal regulation—insulin, stimulated by carbohydrate and protein intake, enhances lipogenic enzyme expression, while glucagon counteracts this effect. This balance ensures macronutrient utilization aligns with dietary composition and metabolic state.
Links to Metabolic Disorders
Dysregulated fatty acid synthesis contributes to metabolic disorders such as obesity, insulin resistance, and dyslipidemia. Excessive lipogenesis, driven by chronic overnutrition and hyperinsulinemia, leads to lipid accumulation in the liver, resulting in non-alcoholic fatty liver disease (NAFLD). This condition, marked by excessive triglyceride storage in hepatocytes, can progress to inflammation, fibrosis, and cirrhosis. Increased expression of lipogenic transcription factors like SREBP-1c further exacerbates hepatic fat deposition.
Aberrant fatty acid metabolism is also linked to insulin resistance, a key feature of type 2 diabetes. Elevated malonyl-CoA levels inhibit carnitine palmitoyltransferase-1 (CPT-1), reducing fatty acid oxidation and promoting ectopic fat accumulation in skeletal muscle and pancreatic β-cells. This impairs glucose uptake and insulin secretion. Additionally, increased circulating free fatty acids contribute to chronic low-grade inflammation, worsening metabolic imbalances.
Targeting lipogenic enzymes, such as ACC inhibitors, has shown promise in preclinical models, offering potential therapeutic strategies for managing metabolic disorders associated with excessive fatty acid synthesis.