Biochemistry: Lipid Metabolism Quiz

Fatty Acid Catabolism

• Fatty acid catabolism is a central energy-yielding pathway in many organisms and tissues
• Long-chain fatty acids provide up to 80% of energetic needs in mammalian heart and liver
• Fatty acid oxidation contributes to over 40% of daily energy requirements in mammals
• Electrons released during fatty acid oxidation travel through the respiratory chain, driving ATP synthesis
• Acetyl-CoA produced from fatty acids can be completely oxidized to CO2 in the citric acid cycle

β Oxidation

• β oxidation is the oxidation of the fatty acyl group at the C-3 position (hence the name)
• It occurs after the carboxyl group at C-1 is activated by attachment to coenzyme A

Principles of Fatty Acid Catabolism

• Principle 1: Diverse metabolites funnel into few central pathways, whereby fatty acid catabolism and glycolysis convert distinct starting materials into a common product (acetyl-CoA). Associated electrons from oxidative pathways and the citric acid cycle are then carried by cofactors (NAD and FAD) to the mitochondrial respiratory chain, which leads to oxygen, ultimately producing ATP through oxidative phosphorylation.
• Principle 2: Evolution prioritizes chemical mechanisms that enhance energy efficiency. In fatty acid breakdown, the conversion of carboxylic acids into thioesters, such as acetyl-CoA, within the citric acid cycle is a key mechanism. This process breaks the relatively inert C-C bonds in long fatty acid chains by creating a carbonyl group adjacent to the CH2 group.
• Principle 3: Allosteric mechanisms and post-translational regulation (e.g., protein phosphorylation) coordinate metabolic processes within a cell. Hormones and growth factors control metabolic activity among tissues and organs. Reciprocal control of catabolic and anabolic pathways prevent futile cycling.
• Principle 4: Loss of essential components like enzymes, cofactors, or regulatory agents disrupt homeostasis and manifest across a spectrum of severity, leading to diseases. Fatty acid breakdown defects exemplify this principle.
• Principle 5: The liver plays a critical role in whole-body metabolism. When glucose is not available the liver produces glucose via gluconeogenesis and distributes it to tissues (including the brain). During starvation, the liver converts fatty acids to ketone bodies, which, unlike fatty acids, can cross the blood-brain barrier and fuel the brain.

Digestion, Mobilization, and Transport of Fats

• Dietary fats are absorbed in the small intestine, where bile salts emulsify them, forming mixed micelles.
• Intestinal lipases then degrade triacylglycerols (TAGs) into fatty acids (FAs) and other breakdown products.
• These products are taken up by the intestinal mucosa, reconverted to triacylglycerols, and packaged into chylomicrons.
• Chylomicrons are lipoprotein aggregates that transport lipids and lipoprotein lipase converts the TAGs in the chylomicrons into fatty acids and monoacylglycerols. These are then used by myocytes or adipocytes for oxidation as fuel or reesterfication for storage.

Sources of Fatty Acid Fuels

• Fats originate from four sources: dietary fats, stored fats in lipid droplets, fats synthesized in one organ for transport to another, and fats obtained via autophagy

Chylomicron Formation

• Apolipoproteins are lipid-free proteins that bind lipids to form lipoproteins
• Chylomicrons = particles consisting of triacylglycerols, cholesterol, and apolipoproteins
• These are essential for the transport of lipids between organs.

Lipoprotein Particles

• Spherical aggregates of apolipoproteins and lipids
• Hydrophobic lipids are at the core, while hydrophilic lipids and protein components reside on the surface
• Vary in density based on the mix of lipids and protein
• Range from chylomicrons to HDL

Apolipoprotein B-48 (apoB-48) and Apolipoprotein C-II (apoC-II)

• apoB-48 = major protein component of chylomicrons
• apoC-II = protein found in the blood and is picked up by chylomicrons from HDL (high-density lipoprotein) particles

Lipoprotein Lipase

• Extracellular enzyme in capillaries of muscle and adipose tissue.
• Hydrolyzes triacylglycerols into free fatty acids and monoacylglycerols.
• The enzyme is activated by apoC-II

Fatty Acyl-CoA Synthetase

• Present in the outer mitochondrial membrane
• Activates fatty acids through conversion into fatty acyl-CoA thioesters
• Fatty acid + CoA + ATP produce fatty acyl-CoA + AMP + PP;

Carnitine

• A compound that transports fatty acyl-CoAs across the inner mitochondrial membrane for oxidation.

Carnitine Acyltransferase 1 (CAT1/CPT1)

• Catalyzes the transesterification reaction to attach fatty acyl-CoA to the hydroxyl group of carnitine creating fatty acyl carnitine, a necessary step for fatty acid entry into the inner mitochondrial membrane.

Acyl-carnitine/carnitine cotransporter

• Allows passive transport of fatty acyl-carnitine esters across the inner mitochondrial membrane
• Moves one carnitine into the intermembrane space while the other fatty acyl-carnitine moves into the matrix.

Carnitine Acyltransferase 2 (CAT2/CPT2)

• Transfers the fatty acyl group from carnitine back to coenzyme A, then regenerates fatty acyl-CoA and free carnitine
• Located on the inner face of the mitochondrial membrane.

Stage 1 of Fatty Acid Oxidation

• Fatty acids undergo oxidative removal of successive two-carbon units in the form of acetyl-CoA

Stage 2 of Fatty Acid Oxidation

• Acetyl-CoA groups are oxidized to carbon dioxide (CO2) in the mitochondrial matrix's citric acid cycle, producing NADH, FADH2 and GTP

Stage 3 of Fatty Acid Oxidation

• Electron transfer chain and oxidative phosphorylation generate ATP from NADH and FADH2.

Fatty Acid Oxidation - Additional Information

• The four enzymes of mitochondrial β oxidation are acyl-CoA dehydrogenase, enoyl-CoA hydratase, β-hydroxyacyl-CoA dehydrogenase, and acyl-CoA acetyltransferase (thiolase).
• The trifunctional protein (TFP) is a multienzyme complex associated with the inner mitochondrial membrane that catalyzes steps 2–4 of the β-oxidation pathway for fatty acyl chains of 12+ carbons; this allows efficient substrate channeling through the process.
• Oxidation of unsaturated fatty acids requires two additional enzymes: enoyl-CoA isomerase (converts cis double bonds to trans bonds) and 2,4-dienoyl-CoA reductase (reduces cis double bonds).
• Oxidation of odd-number fatty acids requires three further reactions: propionyl-CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase.
• The liver lacks ß-ketoacyl-CoA transferase
• The enzymes that catalyze the synthesis of ketone bodies are predominantly found in the cytosol of hepatocytes.
• NADH is produced during the catabolism of D-β-hydroxybutyrate.
• Conversion of 2 acetyl-CoAs to acetoacetyl-CoA is accompanied by the hydrolysis of ATP to AMP and PPi.

Regulation and Defects

• Malonyl-CoA, the first intermediate in fatty acid synthesis, inhibits carnitine acyltransferase 1 (CAT1), preventing simultaneous synthesis and degradation of fatty acids.
• PPARα (peroxisome proliferator-activated receptor alpha) is a nuclear transcription factor that enhances the expression of genes for β-oxidation enzymes which aids regulation of fatty acid oxidation/metabolism when energetic demand is high.
• Genetic defects in fatty acyl-CoA dehydrogenases or other enzymes involved can lead to serious diseases like medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, causing problems with fatty acid oxidation and potentially life-threatening consequences.
• Zellweger and X-linked adrenoleukodystrophy also result from defects in peroxisome function/pathways and result in impaired fatty acid metabolism.

Peroxisomal β-oxidation

• Peroxisomes contain the flavoprotein acyl-CoA oxidase which produces H2O2
• The enzyme catalase cleaves H2O2.
• Peroxisomal oxidation is more active for very-long-chain fatty acids and branched-chain fatty acids.
• Phytanic acid undergoes a-oxidation and not β-oxidation due to its methyl group on the β carbon.

Test your knowledge on lipid metabolism with this quiz focused on the oxidation of palmitoyl-CoA and related metabolic pathways. Explore concepts such as ATP yield, enzyme functions, and the role of lipoproteins and ketone bodies. Perfect for biochemistry students looking to reinforce their understanding of fat metabolism.