Lipogenesis
De Novo Synthesis of Fatty Acids
Lipogenesis
Definition: The process by which fatty acids are synthesized from acetyl-CoA and other substrates.
Lipogenic Tissues: Only a few tissues are primarily involved in lipogenesis:
Liver: The main site of de novo fatty acid synthesis.
Adipose Tissue: Plays a role in fat storage and synthesis.
Lactating Mammary Glands: Involved in synthesize fatty acids for milk.
Acetyl-CoA and its Role in Fatty Acid Synthesis
Building Block: Acetyl-CoA serves as the fundamental building block in fatty acid synthesis.
Acetyl-CoA is in the mitochondria, not the cytosol, but fatty acid synthesis is in the cytosol.
Location: Fatty acid synthesis enzymes are located in the cytosol.
Transport Mechanism:
Citrate: Acts as a vehicle for transporting acetyl units from the mitochondria to the cytosol for fatty acid (FA) and cholesterol synthesis.
Citrate Synthesis: High levels of pyruvate production from glucose promote citrate synthesis in mitochondria by serving both as a source of acetyl-CoA and as a precursor methoxyacetate.
Fatty Acid Oxidation: Generates FADH2 and NADH
Fatty Acid Synthesis: Requires NADPH
NADPH is generated from the pentose phosphate pathway and by the conversion of malate to pyruvate through malic enzyme
What are the roles of these enzymes in fatty acid synthesis?
ATP Citrate Lyase: Converts citrate into acetyl-CoA and oxaloacetate
Acyl-CoA carboxylase: Catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA
Key regulator step in fatty acid synthesis
+ Citrate (allosteric), + Insulin (dephosphorylation), - Acyl-CoA (allosteric), - AMPK phosphorylation)
AMPK: AMP Activated Protein Kinase
Biotin is a co-factor for most carboxylation enzymes
ACC1: Acetyl-CoA Carboxylase 1, which catalyzes the first committed step in lipogenesis by converting Acetyl-CoA to Malonyl-CoA, is regulated by both hormonal signals and the energy status of the cell.
Found mostly in liver and white adipose tissue, so lipogenic tissues
ACC2: Acetyl-CoA Carboxylase 2, which also plays a critical role in fatty acid synthesis but is primarily found in skeletal muscle and heart, is less sensitive to hormonal regulation compared to ACC1.
Regulatory purpose
Fatty Acid Synthase: A multi-enzyme complex that catalyzes the synthesis of fatty acids from malonyl-CoA and acetyl-CoA through a series of elongation and reduction reactions. Produces palmitic acid.
Malate Dehydrogenase: Enzyme involved in the citric acid cycle, catalyzing the conversion of oxaloacetate to malate, which is an essential step for the regeneration of NADH and the continuation of energy production through aerobic respiration.
Malic Enzyme: An enzyme that catalyzes the conversion of malate to pyruvate while reducing NADP+ to NADPH, contributing to both the lipogenesis process and the cellular redox balance.
Pyruvate Carboxylase: An enzyme that converts pyruvate into oxaloacetate, playing a crucial role in gluconeogenesis and providing the necessary substrates for fatty acid synthesis as it links carbohydrate metabolism to lipogenesis.
Citrate Synthase: Enzyme that catalyzes the condensation of acetyl-CoA and oxaloacetate to form citrate, serving as the starting substrate for the citric acid cycle and linking glycolysis and lipogenesis by providing acetyl-CoA for fatty acid synthesis.
Pyruvate Dehydrogenase Complex: A multi-enzyme complex that converts pyruvate into acetyl-CoA, thereby linking glycolysis to the citric acid cycle and providing a crucial substrate for lipogenesis, as it ensures an adequate supply of acetyl-CoA for fatty acid biosynthesis.
Metabolic Pathways
Diagram: Understanding the flow from pyruvate to fatty acid synthesis:
Pyruvate is converted to Acetyl-CoA in the mitochondrial matrix via the enzyme pyruvate dehydrogenase, producing CO2 and NADH.
Citrate Synthase converts Acetyl-CoA and Oxaloacetate into citrate.
Citrate Transporter moves citrate into the cytosol, where it is then cleaved back into Acetyl-CoA and Oxaloacetate by ATP Citrate Lyase.
Malate Dehydrogenase and Pyruvate Carboxylase are involved in regenerating oxaloacetate and feeding back into the cycle.
Fatty Acid Synthesis - Key Enzymes and Processes
Acetyl-CoA Carboxylase (ACC):
Function: Transforms Acetyl-CoA into Malonyl-CoA (the donor of two-carbon moieties for fatty acid synthesis).
Regulation: Malonyl-CoA also regulates the activity of CAT1 (Carnitine Acyltransferase 1).
Cofactor: Biotin is crucial for enzymatic carboxylation reactions.
Citrate is a positive allosteric regulator.
Isozymes:
ACC1 and ACC2: These isozymes derived from ACACA and ACACB genes, respectively, play different roles in lipid metabolism:
ACC1: Predominant in lipogenic tissues (liver, white adipose tissue).
ACC2: Found in oxidative tissues (skeletal and cardiac muscle).
Hypothesis: Malonyl-CoA from ACC1 facilitates fatty acid synthesis while ACC2 regulates fatty acid oxidation, although recent findings suggest overlapping functions in human tissues.
Mechanism of Fatty Acid Synthase (FAS)
Structure and Function:
The fatty acid synthase complex comprises multiple domains, facilitating various activities.
Acyl Carrier Protein: Transfers the growing fatty acyl chain between catalytic domains.
Synthesis Steps:
Condensation: Start with Acetyl-CoA (providing the first two carbons) and malonyl-CoA, releasing CO2.
Reduction: Conversion from a ketone group to a hydroxyl group.
Dehydration: Introduction of a double bond in the chain.
Reduction: Saturation of the double bond.
These steps are repeated 6 times, ultimately producing Palmitic Acid (16:0).
Specifics of Fatty Acid Production in Mammary Glands
Thioesterase in the mammary gland cleaves fatty acyl chains from FAS when the chain reaches a length of 6 to 14 carbons.
Fatty Acid Composition in Milk
Positional Distribution of Fatty Acids:
Specific data on fatty acid types and their concentrations in milk:
Butyric Acid (C4): sn-1: 11.8%, sn-2: 0%, sn-3: 0%
Lauric Acid (C12): sn-1: 3.9%, sn-2: 42%, sn-3: 53%
Palmitic Acid (C16): sn-1: 23.9%, sn-2: 47%, sn-3: 45%
Additional data indicates that certain fragments of fatty acids may be derived from de novo or preformed sources.
Elongation and Desaturation of Fatty Acids
Locations: Takes place in the Mitochondria and Endoplasmic Reticulum (ER).
ELOVL (elongation of very-long-chain fatty acids) Enzymes: Engage in elongation of very long-chain fatty acids by condensing acyl-CoA with malonyl-CoA.
Desaturation: Achieved through fatty acyl-CoA desaturases, modifying unsaturation at various positions (C4, C5, C6, C9), with Δ9 -stearoyl-CoA desaturase being rate-limiting for oleic (C18:1) and palmitoleic acids (C16:1).
Regulation: The expression and activity of stearoyl-CoA desaturase (SCD) are regulated by dietary and hormonal status.
Essential Fatty Acids
Significance:
Mammals require consumption of certain fatty acids as they cannot synthesize them:
C18 fatty acid with a double bond at C12 (n-6)
C18 fatty acid with a double bond at C15 (n-3)
Dietary Sources: Linoleic (C18:2n-6) and linolenic acids (C18:3n-3) can be metabolized to longer-chain and more unsaturated fatty acids.
Importance: Essential for both structural and signaling processes within biological membranes.
Dietary Composition:
n-6 fatty acids comprise 17%, 32%, and 55% in plasma TAG (triacylglycerol), PL (phospholipid), and CE (cholesterol esters), respectively.
n-3 fatty acids account for 1-5% across those same lipid fractions.
Fatty Acid Desaturation Mechanism
Enzyme: Stearoyl-CoA desaturase catalyzes fatty acid desaturation.
Reaction:
Substrates: Stearoyl-CoA + O2 → Oleoyl-CoA
Involves redox reactions mediated by cofactors like cyt b5 and NADH.
Prevalence of Polyunsaturated Fatty Acids (PUFAs)
Common PUFAs:
n-6: Linoleic acid (C18:2n–6), and Arachidonic acid (C20:4n–6)
n-3: Alpha-linolenic acid (C18:3n-3), and DHA (C22:6n-3)
Dietary vs. Body Tissue: n–6 are more prevalent in diet and tissue compared to n–3.
Pathways of Triacylglycerol Synthesis
Key Enzymes:
Glycerol 3 -phosphate dehydrogenase: Converts dihydroxyacetone phosphate to glycerol 3-phosphate.
Glycerol Kinase: Converts glycerol to glycerol 3-phosphate using ATP.
The rate limiting step of triacylglycerol synthesis is the conversion of diacylglycerol to triacylglycerol, primarily catalyzed by the enzyme diacylglycerol acyltransferase (DGAT), which is crucial for efficient lipid storage.
High levels of diacylglycerols are associated with insulin resistance
Steps in Pathway:
TAGS Storage: Stored within cells or exported in lipoprotein particles.
Hydrolysis: Can revert to fatty acids and glycerol in cycles that utilize energy but do not yield net TAGs.
Storage in lipid droplets varies by tissue type.
Secretion via lipoproteins (e.g., chylomicrons, VLDLs) and in milk during lactation.
Transcription Factors Affecting Lipogenesis
Key Factors:
SREBP-1c: Sterol regulatory element binding protein involved in lipid regulation.
USF-1: Upstream stimulator factor that modulates lipogenic gene expression.
ChREBP: Carbohydrate response element binding protein, involved in glucose response.
Response Mechanism:
Expression of these factors is augmented by high insulin or glucose levels, targeting genes affecting uptake and metabolism in the liver.
Genes Targeted by Transcription Factors
Lipogenesis Genes:
Include but are not limited to:
Glucokinase
GLUT4 (Glucose transporter)
Liver pyruvate kinase
Glycerol-3-phosphate dehydrogenase
ACC (ACC1 and ACC2)
Fatty Acid Synthase (FAS)
SCD1 (Stearoyl-CoA desaturase)
ELOVL enzymes
Genomic Elements: Genes harbor glucose- or carbohydrate-response elements called ChoRE.
Fructose-Induced De Novo Lipogenesis
Mechanism: Fructose has been noted to acutely and chronically boost intrahepatic de novo lipogenesis, suggesting a direct link between fructose intake and fatty acid synthesis in the liver.
Reference: Tappy L , and Lê K. Physiol Rev 2010;90:23-46.