Fat Metabolism
Chapter Overview
Fat metabolism represents one of the most important energy storage and utilization systems in living organisms. Fatty acids serve as both structural components of cellular membranes and as highly efficient energy storage molecules. This chapter explores the intricate biochemical pathways involved in fatty acid synthesis (lipogenesis) and breakdown (lipolysis and β-oxidation), examining their regulation, physiological significance, and clinical implications.
Introduction to Fatty Acids
Fatty acids are carboxylic acids with long hydrocarbon chains, typically containing 4-36 carbon atoms. The most common fatty acids in mammals contain 14-20 carbons and can be classified as saturated (no double bonds) or unsaturated (containing one or more double bonds). These molecules play crucial roles in energy storage, membrane structure, and signaling pathways.
The human body can synthesize most fatty acids de novo, but certain polyunsaturated fatty acids, termed essential fatty acids, must be obtained from the diet. The two primary essential fatty acids are linoleic acid (18:2) and α-linolenic acid (18:3).
Part I: Fatty Acid Synthesis (Lipogenesis)
Overview of Fatty Acid Synthesis
Fatty acid synthesis is an anabolic process that occurs primarily in the liver, adipose tissue, mammary glands, and brain. This process requires significant energy investment, consuming ATP and NADPH, and typically occurs during periods of nutritional abundance when carbohydrate intake exceeds immediate energy needs.
Acetyl-CoA: The Building Block
The fundamental building block for fatty acid synthesis is acetyl-CoA, a two-carbon unit derived primarily from glucose metabolism through glycolysis and the citrate-pyruvate cycle. Since fatty acid synthesis occurs in the cytoplasm while acetyl-CoA is produced in the mitochondria, a transport system is required.
The Citrate-Malate Cycle
The citrate-malate cycle, also known as the citrate-pyruvate cycle, serves as the primary mechanism for transporting acetyl units from mitochondria to the cytoplasm:
The Fatty Acid Synthase Complex
Fatty acid synthesis in mammals is catalyzed by fatty acid synthase (FAS), a large multifunctional enzyme complex containing seven distinct catalytic activities and an acyl carrier protein (ACP) domain.
Structure and Organization
The mammalian fatty acid synthase is a homodimer with each subunit containing:
- Acetyl-CoA carboxylase (ACC) binding domain
- Malonyl-CoA binding domain
- Acyl carrier protein (ACP)
- β-ketoacyl synthase (condensing enzyme)
- β-ketoacyl reductase
- β-hydroxyacyl dehydratase
- Enoyl reductase
- Thioesterase
The Synthesis Cycle
Fatty acid synthesis occurs through repeated cycles of four-step reactions:
Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA using ATP and biotin as cofactor. Acetyl-CoA and malonyl-CoA are loaded onto the ACP domain.
β-ketoacyl synthase catalyzes the condensation of acetyl-ACP with malonyl-ACP. This reaction involves decarboxylation of malonyl-ACP, providing energy for carbon-carbon bond formation.
Product: acetoacetyl-ACP (4-carbon unit)
β-ketoacyl reductase reduces the ketone group to a hydroxyl group using NADPH.
Product: β-hydroxybutyryl-ACP
β-hydroxyacyl dehydratase removes water to form a double bond.
Product: crotonyl-ACP (trans-Δ²-butenoyl-ACP)
Enoyl reductase reduces the double bond using NADPH.
Product: butyryl-ACP
This cycle repeats seven times, with each cycle adding a two-carbon unit from malonyl-CoA, ultimately producing palmitic acid (16:0) as the primary product.
Regulation of Fatty Acid Synthesis
Allosteric Regulation
Acetyl-CoA Carboxylase (ACC) Regulation:
- Activators: Citrate promotes ACC activity by causing enzyme polymerization
- Inhibitors: Palmitoyl-CoA (end-product inhibition) and AMP kinase phosphorylation inhibit ACC
Hormonal Regulation
Insulin:
- Promotes fatty acid synthesis by activating ACC through dephosphorylation
- Increases transcription of lipogenic enzymes
- Enhances glucose uptake and glycolysis, providing substrates
Glucagon and Epinephrine:
- Inhibit fatty acid synthesis by activating AMP kinase
- Promote ACC phosphorylation and inactivation
- Reduce transcription of lipogenic enzymes
Transcriptional Control
The sterol regulatory element-binding protein 1c (SREBP-1c) serves as the master transcriptional regulator of lipogenesis, controlling expression of acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase, and other lipogenic enzymes.
Part II: Fatty Acid Breakdown (β-Oxidation)
Overview of Fatty Acid Oxidation
Fatty acid oxidation, primarily through β-oxidation, represents the major pathway for fatty acid catabolism. This process occurs mainly in mitochondria and produces acetyl-CoA units that can enter the citric acid cycle for energy production or serve as precursors for ketone body synthesis.
Fatty Acid Activation
Before oxidation can occur, fatty acids must be activated to their CoA derivatives, a process requiring ATP:
This reaction occurs on the outer mitochondrial membrane and effectively commits the fatty acid to oxidation.
Transport into Mitochondria: The Carnitine Shuttle
Long-chain fatty acyl-CoA molecules cannot cross the inner mitochondrial membrane directly. The carnitine shuttle system facilitates this transport:
The β-Oxidation Cycle
β-oxidation proceeds through four sequential reactions that remove two-carbon units as acetyl-CoA:
Acyl-CoA dehydrogenase introduces a double bond between C2 and C3. FAD serves as electron acceptor, producing FADH₂.
Product: trans-Δ²-enoyl-CoA
Enoyl-CoA hydratase adds water across the double bond.
Product: L-3-hydroxyacyl-CoA
3-hydroxyacyl-CoA dehydrogenase oxidizes the hydroxyl group to a ketone. NAD⁺ serves as electron acceptor, producing NADH.
Product: 3-ketoacyl-CoA
Thiolase cleaves the C2-C3 bond using CoA.
Products: acetyl-CoA + acyl-CoA (shortened by 2 carbons)
This cycle continues until the fatty acid is completely oxidized to acetyl-CoA units.
Energetics of β-Oxidation
Complete oxidation of palmitic acid (16:0):
• 7 cycles of β-oxidation producing: 7 FADH₂, 7 NADH, 8 acetyl-CoA
• 8 acetyl-CoA through citric acid cycle producing: 8 GTP, 24 NADH, 8 FADH₂
• Total ATP yield: approximately 129 ATP molecules
(accounting for 2 ATP equivalents consumed in activation)
Regulation of β-Oxidation
Key Regulatory Points
Carnitine Palmitoyltransferase I (CPT-1):
- Rate-limiting enzyme for β-oxidation
- Inhibited by malonyl-CoA (product of ACC)
- Provides coordinate regulation with fatty acid synthesis
Hormonal Control
- Glucagon/Epinephrine: Promote β-oxidation by reducing malonyl-CoA levels
- Insulin: Inhibits β-oxidation by increasing malonyl-CoA production
Clinical Significance and Metabolic Disorders
Fatty Acid Oxidation Disorders
Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)
- Most common fatty acid oxidation disorder
- Causes hypoglycemia, lethargy, and potentially fatal metabolic crisis
- Diagnosed through newborn screening
Carnitine Deficiency
- Can be primary (genetic) or secondary (dietary/medication-induced)
- Results in impaired fatty acid oxidation and muscle weakness
Metabolic Syndrome and Fatty Acid Metabolism
Disrupted fatty acid metabolism contributes to various components of metabolic syndrome including insulin resistance, non-alcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease. Understanding fatty acid metabolism is crucial for developing therapeutic interventions for these conditions.
Integration with Other Metabolic Pathways
Glucose-Fatty Acid Cycle (Randle Cycle)
The glucose-fatty acid cycle describes the metabolic competition between glucose and fatty acid oxidation:
- High fatty acid oxidation inhibits glucose utilization
- High glucose utilization inhibits fatty acid oxidation
- This metabolic flexibility allows efficient fuel selection based on availability
Ketone Body Synthesis
During prolonged fasting or carbohydrate restriction, excessive acetyl-CoA from β-oxidation is converted to ketone bodies in the liver:
- Acetoacetate
- β-hydroxybutyrate
- Acetone
Ketone bodies serve as alternative fuel sources for brain and other tissues when glucose availability is limited.
Summary and Key Concepts
Fat metabolism encompasses the complex, highly regulated processes of fatty acid synthesis and breakdown. These pathways are essential for energy storage, membrane synthesis, and metabolic flexibility. Key concepts include:
- Fatty acid synthesis occurs in the cytoplasm using acetyl-CoA and malonyl-CoA as substrates, requiring significant energy input in the form of ATP and NADPH
- β-oxidation breaks down fatty acids in mitochondria, producing acetyl-CoA, NADH, and FADH₂ for energy generation
- Regulation occurs at multiple levels, ensuring coordinate control of synthesis and breakdown to prevent wasteful futile cycling
- Integration with other metabolic pathways provides metabolic flexibility and efficient energy utilization
- Clinical relevance extends to understanding metabolic disorders, drug targets, and therapeutic interventions
Understanding these processes is fundamental to biochemistry, metabolism, and clinical medicine, providing the foundation for addressing metabolic diseases and developing targeted therapies.
Study Questions
- Explain why fatty acid synthesis and β-oxidation occur in different cellular compartments and how this compartmentalization contributes to metabolic regulation.
- Calculate the net ATP yield from complete oxidation of stearic acid (18:0) and compare it to glucose oxidation on a per-carbon basis.
- Describe the role of malonyl-CoA in coordinating fatty acid synthesis and oxidation, and explain how hormonal signals affect this regulation.
- Compare and contrast the enzyme complexes involved in fatty acid synthesis versus β-oxidation, highlighting key structural and functional differences.
- Discuss the clinical implications of carnitine deficiency and explain why medium-chain triglycerides might be used therapeutically in certain fatty acid oxidation disorders.
