9.2 Fatty acid synthesis and degradation

Fatty acids play a crucial role in energy storage and metabolism. This section explores how our bodies make and break down these important molecules. We'll look at the complex processes of fatty acid synthesis and degradation, which are key to maintaining energy balance.

Understanding these pathways is essential for grasping how our bodies handle fats. We'll dive into the enzymes involved, the step-by-step reactions, and how these processes are regulated. This knowledge forms the foundation for comprehending lipid metabolism and its impact on health.

Fatty Acid Synthesis

Fatty Acid Synthase Complex

• Fatty acid synthase is a multi-enzyme complex that catalyzes the synthesis of fatty acids, primarily palmitate, from acetyl-CoA and malonyl-CoA
• Consists of two identical monomers, each containing seven distinct enzymatic activities and an acyl carrier protein (ACP)
• The ACP is post-translationally modified with a phosphopantetheine group, which serves as a flexible arm to transport the growing fatty acid chain between the active sites of the enzymes
• The synthesis process is initiated by the transfer of an acetyl group from acetyl-CoA to the ACP, followed by the transfer of a malonyl group from malonyl-CoA to the ACP
• The malonyl group undergoes decarboxylation, and the resulting carbon-carbon bond formation leads to the elongation of the fatty acid chain by two carbon units
• This cycle of elongation is repeated seven times, resulting in the formation of a 16-carbon saturated fatty acid, palmitate (most common product)

Acetyl-CoA Carboxylase and Malonyl-CoA Formation

• Acetyl-CoA carboxylase is the rate-limiting enzyme in fatty acid synthesis catalyzes the irreversible carboxylation of acetyl-CoA to form malonyl-CoA
• This reaction requires biotin as a coenzyme and consumes ATP
• Malonyl-CoA is an essential substrate for fatty acid synthase and provides the two-carbon units for the elongation of the fatty acid chain
• Acetyl-CoA carboxylase is highly regulated by various factors, including hormones (insulin and glucagon), allosteric effectors (citrate and long-chain fatty acyl-CoA), and phosphorylation/dephosphorylation (inhibited by phosphorylation)

Elongation and Desaturation of Fatty Acids

• Fatty acids can be further elongated by elongase enzymes located in the endoplasmic reticulum (ER) membrane
• Elongases add two-carbon units derived from malonyl-CoA to the carboxyl end of the fatty acid chain, resulting in the formation of longer-chain fatty acids (18, 20, 22, or 24 carbons)
• Desaturation of fatty acids introduces double bonds at specific positions in the hydrocarbon chain catalyzed by desaturase enzymes, also located in the ER membrane
• Desaturases require molecular oxygen and NADH or NADPH as cofactors
• In humans, desaturases can introduce double bonds at the Δ9, Δ6, and Δ5 positions (counting from the carboxyl end) examples include stearoyl-CoA desaturase (Δ9) and fatty acid desaturase 1 (FADS1, Δ5) and 2 (FADS2, Δ6)
• Essential fatty acids, such as linoleic acid (omega-6) and α-linolenic acid (omega-3), cannot be synthesized by humans due to the lack of Δ12 and Δ15 desaturases and must be obtained from the diet

Fatty Acid Degradation

Beta-Oxidation Pathway

• Beta-oxidation is the primary pathway for the catabolism of fatty acids occurs in the mitochondrial matrix
• Fatty acids are activated by conversion to fatty acyl-CoA thioesters in the cytosol by acyl-CoA synthetases before being transported into the mitochondria
• The activated fatty acyl-CoA undergoes four enzymatic reactions in each cycle of beta-oxidation:

1. Dehydrogenation by acyl-CoA dehydrogenase (FAD-dependent)
2. Hydration by enoyl-CoA hydratase
3. Dehydrogenation by 3-hydroxyacyl-CoA dehydrogenase (NAD+-dependent)
4. Thiolytic cleavage by β-ketoacyl-CoA thiolase

• Each cycle of beta-oxidation releases one acetyl-CoA molecule (2 carbons) and generates one FADH2 and one NADH
• The remaining fatty acyl-CoA, now shortened by two carbons, re-enters the beta-oxidation cycle until the entire fatty acid is degraded
• Acetyl-CoA can enter the citric acid cycle for further oxidation or be used for ketone body synthesis
• Odd-chain fatty acids yield propionyl-CoA in the final round of beta-oxidation, which is converted to succinyl-CoA (an intermediate of the citric acid cycle) via a three-step process involving biotin and vitamin B12

Carnitine Shuttle System

• The carnitine shuttle system is responsible for the transport of long-chain fatty acyl-CoA molecules from the cytosol into the mitochondrial matrix for beta-oxidation
• Carnitine palmitoyltransferase I (CPT I), located on the outer mitochondrial membrane, catalyzes the transfer of the fatty acyl group from CoA to carnitine, forming fatty acyl-carnitine
• Fatty acyl-carnitine is then transported across the inner mitochondrial membrane by carnitine-acylcarnitine translocase (CACT)
• Inside the mitochondrial matrix, carnitine palmitoyltransferase II (CPT II) transfers the fatty acyl group back to CoA, regenerating fatty acyl-CoA and free carnitine
• The free carnitine is transported back to the cytosol by CACT for another round of fatty acid transport
• CPT I is inhibited by malonyl-CoA (produced during fatty acid synthesis), which helps to regulate the balance between fatty acid synthesis and degradation

Lipolysis and Mobilization of Stored Triacylglycerols

• Lipolysis is the hydrolysis of triacylglycerols (triglycerides) stored in adipose tissue to release free fatty acids and glycerol
• Hormone-sensitive lipase (HSL) is the primary enzyme responsible for the hydrolysis of triacylglycerols
• HSL is regulated by hormones, such as glucagon, epinephrine, and norepinephrine (stimulate lipolysis), and insulin (inhibits lipolysis)
• These hormones act through the cAMP signaling pathway, with increased cAMP levels leading to the phosphorylation and activation of HSL by protein kinase A (PKA)
• Adipose triglyceride lipase (ATGL) and monoacylglycerol lipase (MGL) also contribute to the complete hydrolysis of triacylglycerols
• Released free fatty acids are transported in the bloodstream bound to serum albumin and can be taken up by tissues, such as muscle and liver, for energy production via beta-oxidation

Ketone Body Metabolism

Synthesis and Utilization of Ketone Bodies

• Ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) are water-soluble compounds produced in the liver from acetyl-CoA derived from fatty acid oxidation
• Ketone body synthesis occurs when acetyl-CoA accumulates, such as during fasting, prolonged exercise, or in uncontrolled diabetes mellitus
• Two acetyl-CoA molecules condense to form acetoacetyl-CoA, catalyzed by thiolase
• Acetoacetyl-CoA and another acetyl-CoA molecule form β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), catalyzed by HMG-CoA synthase
• HMG-CoA is cleaved to form acetoacetate and acetyl-CoA by HMG-CoA lyase
• Acetoacetate can be reduced to β-hydroxybutyrate by β-hydroxybutyrate dehydrogenase (NADH-dependent) or spontaneously decarboxylated to form acetone
• Ketone bodies are transported from the liver to extrahepatic tissues, such as the brain, heart, and skeletal muscle, where they serve as an alternative energy source during fasting or carbohydrate restriction
• In these tissues, β-hydroxybutyrate is oxidized back to acetoacetate, which is then activated to acetoacetyl-CoA by succinyl-CoA:3-ketoacid CoA transferase (SCOT)
• Acetoacetyl-CoA is cleaved by thiolase to form two acetyl-CoA molecules that can enter the citric acid cycle for energy production
• The brain normally relies on glucose for energy but can adapt to using ketone bodies during prolonged fasting, as they can cross the blood-brain barrier