Fatty Acid Metabolism Notes
Fatty Acid Physiological Roles
Fatty acids have four major physiological roles:
Fuel molecules (primary source of energy for moderate exercise and rest).
Building blocks of phospholipids and glycolipids.
Modify proteins by covalent attachment, targeting them to membrane locations.
Derivatives serve as hormones and intracellular messengers.
Triacylglycerols as Energy Stores
Triacylglycerols (triglycerides) are uncharged esters of fatty acids with glycerol.
Mainly stored in adipose tissue and muscle.
Triacylglycerols are highly concentrated stores of metabolic energy because they are reduced and contain no water.
Complete oxidation of fatty acids yields , compared to for carbohydrates and proteins.
A gram of anhydrous fat stores 6.75 times as much energy as a gram of hydrated glycogen.
Adipose Tissue and Adipocytes
Adipose tissue is a fuel-rich, white tissue beneath the skin (subcutaneous fat) and surrounding internal organs (visceral fat).
Adipocytes are fat cells that make up adipose tissue.
Major site of triacylglycerol accumulation.
Specialized for triacylglycerol synthesis, storage, and mobilization into fuel.
Lipid droplets are large globules formed by the coalescence of triacylglycerols.
Digestion of Dietary Lipids
Lipases are intestinal enzymes that degrade triacylglycerols to free fatty acids and monoacylglycerol, secreted by the pancreas.
Bile Acids and Colipase
Lipids exit the stomach as an emulsion (particles with a triacylglycerol core surrounded by cholesterol and cholesterol esters).
Bile acids are amphipathic molecules that facilitate lipid digestion by lipases.
Synthesized from cholesterol in the liver and secreted from the gallbladder.
Orient ester bonds to make them more accessible to lipases in aqueous solution.
Colipase is a protein that binds lipase to the particle to permit lipid degradation, secreted by the pancreas.
Transport of Dietary Lipids
In the intestine, triacylglycerols are reformed and packaged into lipoprotein particles called chylomicrons.
Chylomicrons enter the blood so that the triacylglycerols can be absorbed by tissues.
Free fatty acids and monoacylglycerols are transported in micelles to the plasma membrane of intestinal epithelial cells.
FATPs (fatty-acid transport proteins) transport free fatty acids and monoacylglycerols inside the membrane.
FABPs (fatty-acid binding proteins) ferry free fatty acids and monoacylglycerols to the cytosolic face of the smooth ER for resynthesis of triacylglycerols.
Chylomicron Formation and Degradation
Chylomicrons are lipoprotein transport particles composed of newly synthesized triacylglycerols, with proteins, phospholipids, and cholesterol on the surface.
Released into the blood and degraded by membrane-bound lipases at adipose tissue and muscles.
Stages of Using Fatty Acids as Fuel
Stage 1 (mobilization): Triacylglycerol degradation to fatty acids and glycerol, release from adipose tissue, and transport to the energy-requiring tissues.
Stage 2 (activation and transport): Activation of the fatty acids and transport into the mitochondria.
Stage 3 (breakdown into acetyl CoA): Degradation of fatty acids to acetyl CoA for processing in the citric acid cycle.
Mobilization of Triacylglycerols
Hormonally controlled lipases catalyze the hydrolysis of triacylglycerols to fatty acids.
Glucagon and epinephrine act through 7TM receptors, leading to phosphorylation of two proteins by PKA:
Perilipin, a fat-droplet-associated protein.
Hormone-sensitive lipase.
Completion of Fatty Acid Mobilization
Hormone-sensitive lipase converts diacylglycerol into a free fatty acid and monoacylglycerol.
Monoacylglycerol lipase converts monoacylglycerol into a free fatty acid and glycerol, completing fatty acid mobilization.
Ethanol can inhibit the signaling pathway, leading to fatty liver disease.
Release of Free Fatty Acids and Glycerol into the Blood
Albumin transports fatty acids in the blood and has seven binding sites for fatty acids of varying affinity.
Glycerol is absorbed by the liver, phosphorylated, oxidized to dihydroxyacetone phosphate, and isomerized to glyceraldehyde 3-phosphate.
Lipolysis
Lipolysis generates fatty acids and glycerol.
Depending on metabolic needs, the liver processes glycerol by the glycolytic or gluconeogenic pathway.
Activation of Fatty Acids
Fatty acids enter intestinal cells through FATPs and are transported within the cell by FABPs.
Acyl CoA synthetase catalyzes the activation of fatty acids through the formation of a thioester linkage to coenzyme A, requiring ATP, and takes place on the outer mitochondrial membrane.
Transport of Fatty Acids into Mitochondria
Carnitine is an alcohol with both a positive and a negative charge (a zwitterion).
Fatty acids must be conjugated to carnitine to be transported across the inner mitochondrial membrane.
Breakdown of Fatty Acids: β-Oxidation
The β-oxidation pathway consists of four steps that are repeated:
Step 1: Oxidation by FAD
Step 2: Hydration
Step 3: Oxidation by NAD+
Step 4: Thiolysis by coenzyme A
Each repetition shortens the fatty acid chain by two carbons. Oxidation occurs at the β-carbon atom.
Ketone Bodies as Fuel
Acetyl CoA formed in fatty acid oxidation enters the citric acid cycle if fat and carbohydrate degradation are balanced.
Acetyl CoA combines with oxaloacetate in the first step of the citric acid cycle, where oxaloacetate availability depends on carbohydrate availability.
Ketone Body Formation
In fasting or diabetes:
Oxaloacetate is consumed to form glucose in the gluconeogenic pathway.
Acetyl CoA is diverted to form acetoacetate and D-3-hydroxybutyrate.
Ketone bodies are acetoacetate, D-3-hydroxybutyrate, and acetone, which are water-soluble, transportable forms of acetyl units.
Abnormally high levels of ketone bodies are present in the blood of untreated diabetics.
Ketone Bodies Utilization
The liver is the major site of production of acetoacetate and 3-hydroxybutyrate.
Acetoacetate and 3-hydroxybutyrate are carried from the liver mitochondria into the blood by transport proteins for delivery to other tissues (e.g., heart, kidney).
The brain adapts to the utilization of acetoacetate during starvation and diabetes.
Fatty Acid Synthesis
Fatty acid synthase is a complex of enzymes that synthesize fatty acids.
Many tissues, such as liver and adipose tissue, are capable of synthesizing fatty acids.
Most humans get enough fatty acids from the diet, but fatty acid synthesis is required under certain physiological conditions, like embryonic development and lactation in mammary glands.
Comparison of Fatty Acid Degradation and Synthesis
Fatty acid degradation involves oxidation, hydration, oxidation, and cleavage.
Fatty acid synthesis involves condensation, reduction, dehydration, and reduction.
Differences Between Fatty Acid Synthesis and Degradation
Synthesis occurs in the cytoplasm, whereas degradation occurs in the mitochondrial matrix.
Intermediates in synthesis are covalently linked to the sulfhydryl groups of an acyl carrier protein (ACP), whereas intermediates in degradation are covalently attached to the sulfhydryl group of coenzyme A.
The activated donor of two-carbon units in synthesis is malonyl ACP, whereas degradation releases acetyl CoA.
The reductant in synthesis is NADPH, whereas the oxidants in degradation are NAD+ and FAD.
The isomeric form of the hydroxyacyl intermediate in synthesis is D, whereas the form is L in degradation.
Transport of Acetyl Groups for Fatty Acid Synthesis
Acetyl CoA must be transferred from mitochondria to the cytoplasm for fatty acid synthesis, since mitochondria are not readily permeable to acetyl CoA.
Citrate is formed from acetyl CoA and oxaloacetate in the mitochondrial matrix and can be transported to the cytoplasm.
ATP-citrate lyase cleaves citrate into acetyl CoA and oxaloacetate:
Regulation of Fatty Acid Metabolism
Fatty acid metabolism is controlled so synthesis and degradation are responsive to physiological needs.
ACC1 and ACC2 catalyze the committed step in fatty acid synthesis: the production of malonyl CoA.
ACC1 and ACC2 play essential roles in regulating fatty acid synthesis and degradation.
Regulation of Acetyl CoA Carboxylase (ACC1)
ACC1 is inhibited when phosphorylated by AMP-dependent kinase (AMPK).
ACC1 is activated when dephosphorylated by protein phosphatase 2A.
ACC1 is allosterically stimulated by citrate and inhibited by palmitoyl CoA.
AMPK is activated by AMP and inhibited by ATP.
Regulation of Acetyl CoA Carboxylase (ACC2)
ACC2, a mitochondrial enzyme, is phosphorylated and inhibited by AMPK.
The product of ACC2, malonyl CoA, inhibits carnitine acyltransferase I, preventing the entry of fatty acyl CoAs into the mitochondrial matrix.
Hormone Control of Acetyl CoA Carboxylase
Glucagon and epinephrine inhibit ACC by augmenting AMPK activity, ultimately inhibiting fatty acid synthesis.
Insulin activates ACC by enhancing phosphorylation and inactivation of AMPK by protein kinase B, ultimately stimulating fatty acid synthesis.
Insulin also promotes the activity of a protein phosphatase that dephosphorylates and activates ACC.
AMP-Activated Protein Kinase (AMPK) as a Key Regulator
AMPK inhibits fatty acid synthesis and stimulates fatty acid oxidation.
This trimeric protein () exists in several isozymic forms.
AMPK:
Activates ATP-generating pathways.
Inhibits ATP-requiring pathways.
Moderates the inflammatory response.
Helps initiate nonshivering thermogenesis.
Is required in early embryo development.