Fatty Acid Metabolism and Disorders

Lipid Metabolism

• Lipids are a diverse group of molecules that are essential for various bodily functions, including energy storage, hormone production, and cell membrane structure.
• The digestion and absorption of lipids are complex processes that involve several enzymes and hormones.
• Lipid metabolism comprises multiple stages, including digestion, absorption, transport, and utilization.

Digestion and Absorption of Lipids

• Lingual lipase in the mouth initiates lipid digestion, primarily targeting short and medium-chain fatty acids in milk fat. Its activity is highest in newborns and declines with age.
• Gastric lipase in the stomach continues lipid digestion, requiring emulsification by substances like polysaccharides, phospholipids, and digested proteins.
• Bile salts aid emulsification of lipids in the small intestine, increasing the surface area for enzyme action.
• Pancreatic lipase, activated by calcium and colipase, further degrades dietary triacylglycerols (TAGs) into fatty acids and 2-monoacylglycerol.
• Cholesteryl esterase breaks down cholesterol esters into cholesterol and free fatty acids, whose activity is enhanced by bile salts.
• Phospholipases, such as A₂ and A₁, break down phospholipids, releasing fatty acids.

Absorption of Lipids

• In the small intestine, free fatty acids, 2-monoacylglycerol, and other components form micelles, aiding their absorption across the intestinal mucosal cells.
• Micelles facilitate the absorption of nonpolar fatty acids, cholesterol, and fat-soluble vitamins.
• Inside the enterocytes, fatty acids and monoglycerides are re-esterified to form triacylglycerol (TAG).
• Chylomicrons, lipoprotein particles, are formed in the epithelial cells of the small intestine, packaging TAG, cholesterol, and fat-soluble vitamins for transport into the lymphatic system and into the bloodstream.

Lipid Metabolism and Hormonal Regulation

• Hormones like cholecystokinin (CCK), secretin, and gastric inhibitory peptide (GIP) regulate various stages of lipid digestion and absorption in response to food intake.
• The presence of fat in the stomach stimulates the release of hormones like CCK to regulate secretions from the pancreas and gallbladder. This facilitates the digestion process.
• Other hormones play a part in the mobilization and utilization of lipids.

Lipid Malabsorption

• Steatorrhea, characterized by the presence of excessive fat in stool, indicates malabsorption of lipids.
• This can result from defects in lipid digestion or absorption, potentially due to issues with pancreatic enzyme production, bile secretion, or intestinal absorption.

Metabolism of Chylomicrons and VLDL

• Nascent chylomicrons are synthesized in the intestines, acquiring apolipoproteins C and E from HDL.
• Lipoprotein lipase degrades the triacylglycerols in chylomicrons, releasing fatty acids and glycerol into tissues.
• VLDL, synthesized in the liver, transports endogenous triacylglycerols and cholesterol to tissues.
• Chylomicrons and remnants are taken up by the liver through apolipoprotein E.
• Catabolism of remnant chylomicrons and VLDL follows similar mechanisms.

Metabolism of LDL

• LDL carries cholesterol to peripheral tissues.
• The liver and many extrahepatic tissues express LDL (apo B-100, E) receptors, which are essential for LDL uptake.
• The LDL receptor is subject to regulation and is crucial for cholesterol homeostasis.
• Degradation of LDL plays a crucial role in overall cholesterol balance.

Metabolism of HDL

• HDL is synthesized and secreted from both liver and intestine, with apolipoproteins C and E being transferred to HDL when it enters the plasma.
• HDL functions as a repository for apolipoproteins.
• LCAT and the LCAT activator apo A-I bind to the nascent HDL, converting free cholesterol to cholesteryl esters for uptake by peripheral tissues or the liver.

Fate of Dietary Lipids by Tissues

• Fatty acids are oxidized by various tissues for energy production.
• Glycerol is used by the liver to form glycerol 3-phosphate, which enters glycolysis or gluconeogenesis.
• The oxidation of fatty acids involves three primary stages, with acetyl-CoA, FADH2, and NADH being produced.

Oxidation of Fatty Acids

• Fatty acid oxidation provides energy for cellular metabolic work.
• The process occurs via β-oxidation and is highly active in tissues with high metabolic activity, such as skeletal and heart muscles.
• Oxidation of fatty acids occurs in various physiological conditions, including fasting, heavy exercise, and diets with reduced carbohydrate intake.
• Specific physiological conditions contribute to fatty acid oxidation.
• Fatty acid oxidation is also a source of heat, especially with the help of thermogenin function in brown fat tissue.
• Fatty acids also yield metabolic intermediates that can be used in synthetic processes, including phospholipids and eicosanoids (like prostaglandins).
• The transport of long-chain fatty acids inside the mitochondria involves the carnitine shuttle.
• Specific enzymes are involved in the process inside mitochondria, which are regulated.
• The products from β-oxidation, acetyl-CoA and NADH, are crucial for generating ATP.

Oxidation of Unsaturated Fatty Acids

• Unsaturated fatty acids undergo similar β-oxidation but involve additional enzymes.
• The number of double bonds impacts the oxidation process.
• The presence of a double bond affects the rate of β-oxidation.
• Several enzymes act to modify the form of unsaturated fatty acids, aiding β-oxidation processing; such as isomerases or reductases.
• There are also specific oxidation processes associated with these fatty acids (such as α-oxidation and ω-oxidation).
• There are three main types of fatty acyl-CoA dehydrogenase, which differ based on the chain length involved in the process.

β-Oxidation in Peroxisomes

• Very-long-chain fatty acids (VLCFAs) are initially oxidized in peroxisomes, generating H2O2.
• H2O2 produced during oxidation is a toxic product, metabolized by catalase.
• The process of β-oxidation inside peroxisomes generates acetyl-CoA which ultimately provides energy for the cells.
• Peroxisomes utilize specific enzymes during β-oxidation.

Degradation of Odd-Chain Fatty Acids

• Odd-chain fatty acids yield propionyl-CoA as a product of β-oxidation, which undergoes further conversion.
• A biotin-dependent enzyme, propionyl-CoA carboxylase, converts propionyl-CoA into methylmalonyl-CoA.
• This molecule is further converted to succinyl-CoA through a vitamin B12-dependent process, a crucial step in energy production and metabolic pathways.
• Defects in these enzymes can cause metabolic disorders (e.g., propionic acidemia, methylmalonic acidemia).

Degradation of α-hydroxy fatty acids

• α-oxidation processes lead to the removal of individual carbon atoms (one at a time) from the carboxyl end of the fatty acid chain.
• The process of α-oxidation produces hydroxy fatty acids, to finally obtain 2-keto acid products for further processing.
• Special enzymes are involved in all steps of this reaction.
• A major example of a substrate of this reaction is phytanic acid, a very-long-chain fatty acid.
• The absence of enzymes in these processes causes metabolic disturbances.

Omega-Oxidation of Fatty Acids

• Omega-oxidation occurs in the endoplasmic reticulum and involves oxidizing the terminal (ω-) carbon.
• Through a similar process, fatty acids may undergo omega-oxidation, where oxidation takes place at the terminal carbon atom of the fatty acid chain.
• Dicarboxylic acids serve as products of this oxidation.
• They are important as they enter further catabolic pathways and are easily excreted.

Regulation of β-oxidation

• Fatty acid oxidation primarily depends on fatty acid availability and the presence of sufficient CoA and NAD+.
• Malonyl-CoA, a product of fatty acid synthesis, acts as an inhibitor of transport of the fatty acids to the mitochondria for degradation, hence, effectively inhibiting β-oxidation.

Regulation of Ketogenesis

• Ketogenesis is a metabolic pathway that contributes to energy production, particularly during periods of low carbohydrate availability.
• Lipolysis or fat breakdown is crucial for ketogenesis, which takes place in the liver.
• The main regulation points are in the stages associated with lipolysis and conversion of fatty acids to ketone bodies, as well as the subsequent utilization of these ketone bodies by tissues.
• Insulin and glucagon play key roles in regulating ketogenesis via their effect on enzymes associated with the metabolic process.

Regulation of Acetyl-CoA Carboxylase

• Acetyl-CoA carboxylase is the primary regulatory point in fatty acid synthesis, the rate-controlling step.
• Allosteric mechanisms and covalent modifcation regulate its activity.
• Citrate activates, while palmitoyl-CoA inhibits the enzyme to maintain metabolic balance.
• Hormonal regulation plays a part in regulating the activity of the acetyl-CoA carboxylase.

Regulation of Cholesterol Synthesis

• HMG-CoA reductase enzyme activity is the primary regulator for cholesterol synthesis.
• The balance between synthesis and uptake of cholesterol is important for regulating homeostasis.
• Hormonal regulation and the feedback effects of different molecules influence cholesterol synthesis and availability.

Lipid Synthesis and Storage in Liver and Adipocytes

• In the liver, newly synthesized TAGs and other lipids are packaged into lipoproteins (like VLDL) for transport to other tissues.
• Adipocytes primarily store TAGs, which can be mobilized during fasting or energy demands.

Synthesis of Phospholipids

• Different phospholipids are synthesized through a series of enzymatic reactions involving CDP-diacylglycerols, inositol, and other components.
• The synthesis of specific phospholipids occurs in the endoplasmic reticulum and Golgi complex.
• Various cells, except mature red blood cells, produce various types of phospholipids.

Degradation of Sphingolipids

• Specific lysosomal enzymes are involved in the degradation of sphingolipids
• Individual enzymes degrade different sphingolipids, removing components like the phospho-choline group(e.g. sphingomyelin).
• The degradation of sphingolipids serves as a crucial part of cellular homeostasis for different processes, as well as lipid homeostasis.

Sphingolipidoses

• Sphingolipidoses comprise a group of inherited metabolic disorders resulting from the accumulation of sphingolipids in lysosomes due to defects in specific enzyme activities required for degradation of sphingolipids.
• Different types of sphingolipidoses are categorized by affected enzymes and the sphingolipids that accumulate as a result of these defects.
• Accumulation of specific sphingolipids leads to progressive involvement of the nervous system, and other organs.

Physiological Actions of Eicosanoids

• Eicosanoids exert various biological effects at extremely low concentrations by stimulating specific receptors. Their short half-lives and local actions define their effects.
• They regulate pain and fever, blood pressure, and blood clotting, and also play a role in inflammation, labor, and other bodily processes.

Mechanisms of Action of Eicosanoids

• Eicosanoids, like hormones, use G protein-coupled receptors and other signal transduction pathways for mediating their diverse biological effects.
• Different Eicosanoid types use slightly different mechanisms of action.

Test your knowledge on fatty acid metabolism, focusing on peroxisomal beta-oxidation and related metabolic disorders. This quiz covers key enzymes, products of oxidation, and the implications of conditions like Zellweger syndrome. Challenge yourself to understand the biochemical pathways involved in fatty acid metabolism.