Fatty acids are long-chain hydrocarbon molecules that serve as a major source of energy for cells. They can be obtained through the diet or synthesized endogenously. The metabolism of fatty acids involves several interconnected pathways, including fatty acid oxidation (beta-oxidation), fatty acid synthesis (lipogenesis), and the synthesis and degradation of complex lipids such as triglycerides and phospholipids.
(a) Fatty acid chains. (b) Lipid molecules. (Halimet al., 2012)
Select Services
Fatty Acid Oxidation
Activation and Transport: In the cytoplasm, fatty acids are activated by conjugating with coenzyme A (CoA) to generate fatty acyl-CoA. Carnitine and the enzyme carnitine palmitoyltransferase I (CPT1) then help transport the fatty acyl-CoA through the mitochondrial membrane.
Beta-Oxidation Steps: Once inside the mitochondria, fatty acyl-CoA undergoes a series of four enzymatic reactions, collectively known as beta-oxidation. In each cycle of beta-oxidation, two carbon units are sequentially removed from the fatty acyl-CoA molecule. These steps include oxidation, hydration, oxidation, and thiolysis, resulting in the generation of acetyl-CoA, NADH, and FADH2.
Acetyl-CoA Utilization: Acetyl-CoA generated during beta-oxidation enters the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, where it undergoes further oxidation to produce additional NADH, FADH2, and ATP. The NADH and FADH2 molecules subsequently participate in the electron transport chain (ETC) to generate ATP through oxidative phosphorylation.
Regulation: Fatty acid oxidation is tightly regulated by various factors to ensure a balanced energy supply. The key regulatory enzyme, carnitine palmitoyltransferase I (CPT1), controls the entry of fatty acids into the mitochondria. Hormones such as glucagon and epinephrine stimulate fatty acid oxidation, whereas insulin inhibits it, favoring other metabolic pathways.
Fatty Acid Synthesis
Fatty acid synthesis, or lipogenesis, is the process by which excess carbohydrates are converted into fatty acids. It predominantly occurs in the cytoplasm and involves several enzymatic steps.
Acetyl-CoA Carboxylation: The first committed step in fatty acid synthesis is the conversion of acetyl-CoA to malonyl-CoA. This reaction is catalyzed by the enzyme acetyl-CoA carboxylase (ACC), which adds a bicarbonate molecule to acetyl-CoA in the presence of ATP and biotin as a cofactor. Malonyl-CoA is the building block for fatty acid synthesis.
Fatty Acid Synthase (FAS) Complex: Fatty acid synthase is a large, multifunctional enzyme complex responsible for the synthesis of long-chain fatty acids. The FAS complex consists of multiple enzymatic domains, including acyl carrier protein (ACP), ketoacyl synthase (KS), ketoacyl reductase (KR), and enoyl reductase (ER).
Fatty Acid Elongation: The FAS complex catalyzes a series of reactions to sequentially add two-carbon units from malonyl-CoA to the growing fatty acid chain. These reactions include condensation, reduction, dehydration, and reduction again, leading to the formation of a saturated fatty acid chain.
Desaturation: If unsaturated fatty acids are required, additional enzymatic steps are involved. Desaturases introduce double bonds into the fatty acid chain at specific positions. These enzymes are responsible for the synthesis of important polyunsaturated fatty acids, such as omega-3 and omega-6 fatty acids, which cannot be synthesized by the human body and must be obtained from the diet.
Regulation of Fatty Acid Metabolism
Fatty acid metabolism is tightly regulated to maintain energy homeostasis and adapt to different nutritional conditions. Various enzymes, signaling pathways, and hormones play critical roles in controlling fatty acid oxidation and synthesis.
Hormonal Regulation: Insulin, which is released in response to high blood glucose levels, increases lipogenesis by activating important fatty acid synthesis enzymes such as ACC and FAS. Insulin also inhibits fatty acid oxidation by reducing the activity of beta-oxidation enzymes.
Glucagon, on the other hand, increases fatty acid oxidation when released during fasting or low blood glucose levels. It inhibits lipogenesis by inactivating ACC and FAS and stimulates beta-oxidation enzymes, boosting fatty acid breakdown for energy production.
Leptin is a hormone produced by adipose tissue that controls hunger and energy expenditure. It regulates food intake and modulates fatty acid metabolism via acting on the hypothalamus.
AMP-Activated Protein Kinase (AMPK): AMPK acts as a sensor of cellular energy status and is activated under conditions of low energy availability, such as during fasting or exercise. AMPK phosphorylates and inhibits ACC, the key enzyme in fatty acid synthesis, reducing malonyl-CoA levels and inhibiting lipogenesis. Simultaneously, AMPK activates enzymes involved in fatty acid oxidation, enhancing energy production from fatty acids.
Transcriptional Regulation: A number of transcription factors are important in regulating fatty acid metabolism. Peroxisome proliferator-activated receptors (PPARs), for example, are ligand-activated transcription factors that regulate the expression of fatty acid oxidation genes. Sterol regulatory element-binding proteins (SREBPs) regulate gene expression in fatty acid production and absorption.
Applications of Fatty Acid Metabolism
Fatty acid metabolism has important implications in various aspects of human health and disease. Here are some notable applications:
Obesity and Weight Management: Understanding the regulation of fatty acid metabolism is crucial for developing strategies to manage obesity and promote weight loss. Targeting enzymes and signaling pathways involved in fatty acid synthesis and oxidation can potentially modulate energy balance and promote fat utilization.
Diabetes and Metabolic Syndrome: Dysregulation of fatty acid metabolism is closely linked to insulin resistance and the development of type 2 diabetes. Studying the intricate mechanisms of fatty acid metabolism can help identify therapeutic targets for managing glucose and lipid metabolism and improving insulin sensitivity.
Cardiovascular Diseases: Abnormal fatty acid metabolism contributes to the development of cardiovascular diseases, including atherosclerosis and coronary artery disease. Understanding the underlying mechanisms can aid in identifying novel therapeutic approaches to prevent or treat these conditions.
Cancer Metabolism: Altered fatty acid metabolism is a hallmark of many cancer types. Cancer cells often exhibit enhanced lipogenesis and increased fatty acid uptake to meet their high energy demands. Targeting specific enzymes and transporters involved in fatty acid metabolism holds promise for developing novel anticancer therapies.
Fatty acid metabolism in the TME of ovarian cancer (Yoon et al., 2022).
Detection of Fatty Acid Metabolism
The detection and quantification of fatty acid metabolism rely heavily on mass spectrometry (MS). It has a high sensitivity, specificity, and can evaluate a wide variety of fatty acid species. Here are some examples of mass spectrometry-based approaches used to study fatty acid metabolism:
Lipidomics: MS-based lipidomics enables the identification and quantification of individual fatty acid species, including saturated, monounsaturated, and polyunsaturated fatty acids. Various MS techniques, such as electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI), coupled with different mass analyzers, are employed for lipidomic analysis.
Stable Isotope Tracer Experiments: Stable isotope-labeled fatty acids combined with mass spectrometry allow for the investigation of fatty acid metabolism in vivo and in vitro. By administering labeled fatty acids and analyzing their incorporation into lipid pools or metabolic intermediates, researchers can track fatty acid uptake, oxidation, and synthesis. Isotope labeling combined with MS can provide quantitative insights into the kinetics and fluxes of fatty acid metabolism.
Metabolomics: MS-based metabolomics techniques, such as liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS), enable the profiling and quantification of fatty acid-related metabolites, such as acylcarnitines, acyl-CoAs, and other lipid-derived molecules. These metabolites serve as important indicators of fatty acid metabolism and its dysregulation in various diseases.
Imaging Mass Spectrometry: Imaging mass spectrometry (IMS) allows for the spatial visualization of fatty acids and their metabolites within tissue sections. Techniques such as MALDI imaging mass spectrometry (MALDI-IMS) enable the direct analysis and mapping of lipid distributions in biological samples. This approach provides valuable insights into the localization and changes in lipid metabolism in specific tissues or regions of interest.
Select Service
Learn more
References
- Halim, Ronald, Michael K. Danquah, and Paul A. Webley. "Extraction of oil from microalgae for biodiesel production: A review." Biotechnology advances 30.3 (2012): 709-732.
- Yoon, Hyunho, and Sanghoon Lee. "Fatty acid metabolism in ovarian cancer: Therapeutic implications." International Journal of Molecular Sciences 23.4 (2022): 2170.
You may be interested in:
