Lipid Metabolism Overview

Lipid Metabolism Overview

• Lipid oxidation is a primary energy source in many organisms, providing about one-third of human energy needs from dietary triglycerides. Mammalian heart and liver rely heavily on fatty acid oxidation, accounting for up to 80% of their energy demands. Hibernating animals, like grizzly bears, primarily depend on fats for energy during extended periods of inactivity.

Fats as Efficient Fuel Storage

• Fats are a superior long-term energy storage form compared to polysaccharides (like glycogen). Fatty acids store more energy per carbon due to their high reduction state and carry less water, making them a compact energy reserve. Glucose and glycogen provide quicker energy release than fats.

Fatty Acid Composition

• Animal fats usually contain more saturated fatty acids than vegetable oils. Generally, vegetable oils are good sources of polyunsaturated fatty acids (PUFAs). Coconut oil stands out as a notable exception containing high proportions of saturated fatty acids from vegetable oils.
• Natural fatty acids are primarily even-numbered. A typical length for fatty acid is C16 and C18 chains.

Lipid Function and Metabolism Summary

• Lipids are ingested, digested, and absorbed.
• Stored as adipose tissue providing insulation, support for vital organs, and generating heat.
• Circulate in the blood as lipoproteins. Lipoproteins transport lipids and are a key component of lipid transport in blood. Different lipoproteins contribute diverse functions including VLDL, LDL, HDL, and Chylomicrons.
• They're either oxidized for energy or converted into other types of molecules used by the body—like components of nerve tissue. Excreted as waste in feces

Dietary Fatty Acid Absorption

• Dietary fatty acids are absorbed in the small intestine.
• Chylomicrons are formed and transported via the bloodstream to target tissues.
• The liver plays a role in converting excess fatty acids to triglycerides and packaging them into VLDL for transport. The liver is critical in converting unused fats into usable forms for transportation and storage.

Lipids in Blood as Lipoproteins

• Complex structures formed by lipids and apolipoproteins.
• Vary in density, from very low density lipoproteins (VLDL) to high-density lipoproteins (HDL). Lipoproteins such as VLDL, LDL, HDL, and chylomicrons have specialized roles in transporting lipids through the blood.

Plasma Lipoproteins

• Composed of a core of triglycerides and cholesteryl esters surrounded by phospholipids and apolipoproteins. The structure of lipoproteins is crucial for lipid transport in the blood.
• In a constant state of synthesis and breakdown.
• Essential for maintaining lipid solubility in plasma, facilitating transport, and delivering lipids to tissues.
• Crucial in preventing buildup in arteries like atherosclerosis.

Hormonal Trigger of Stored Triglycerols

• Lipases, enzymes, catalyze the breakdown of stored triglycerides (TAGs) into fatty acids (FFAs), diacylglycerol (DAG), and monoacylglycerol (MAG) and glycerol.
• Hormones, like glucagon and epinephrine, regulate the activity of lipases. These hormones are signal molecules for the breakdown of stored triglycerides.
• The hormone epinephrine signals the necessity of using energy and glucagon signifies a lack of glucose.

Glycerol from Fats

• Glycerol, a byproduct of fat breakdown, enters glycolysis.
• Glycerol kinase converts glycerol to glycerol-3-phosphate, requiring ATP.
• Subsequent reactions further process glycerol-3-phosphate, recovering more ATP. Glycerol can directly enter glycolysis, providing the body with energy through this important pathway, in contrast with the more indirect route of fats.

Fatty Acid Transport into Mitochondria

• Fatty acids are broken down into fatty acids and glycerol in the cytoplasm.
• Small fatty acids diffuse directly across mitochondrial membranes.
• Larger fatty acids require the carnitine shuttle for transport across mitochondrial membranes into the interior of cells for further metabolic processes.

Stages of Fatty Acid Oxidation

• Three stages including beta-oxidation (Stage 1), entry into the citric acid cycle (Stage 2) and electron transfer chain (ETC) (Stage 3). These stages ensure efficient breakdown and release of energy from fatty acids.

ẞ-Oxidation Pathway

• Each cycle removes two carbons from the fatty acyl-CoA chain in the form of acetyl-CoA.
• Processes occur in the mitochondria, generating the energy carriers NADH and FADH2, essential for energy production.
• Multiple steps are involved in the process.

Fatty Acid Catabolism for Energy

• Repeating ẞ-oxidation cycles to completely degrade fatty acids.
• Products like FADH2 and NADH enter the electron transport chain, generating ATP.
• Fatty acid oxidation yields significant ATP and high-energy molecules.

NADH and FADH2

• These energy carriers store energy from fatty acid oxidation.
• They contribute to the generation of ATP through the electron transport chain. These molecules are critical for the transfer of energy throughout the cell.

Formation of Ketone Bodies

• When oxaloacetate levels are low, acetyl-CoA is converted to ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate).
• These bodies serve as an alternative energy source for tissues when glucose is limited. Ketone bodies are an important energy source especially during times of starvation.

Release of Free Coenzyme A

• Crucial for continuing the breakdown of fatty acids into ketone bodies. Coenzyme A is critical to continuing the process of lipid metabolism.

Formation of Ketone Bodies

• Acetoacetate and Beta-hydroxybutarate are essential.
• Untreated diabetes creates high levels, which lowers blood pH. These conditions can arise under starvation, and some diseases and lead to ketoacidosis.

Ketone Bodies as Fuel

• Ketone bodies—specifically acetoacetate and beta-hydroxybutyrate—can be used as fuel sources in extrahepatic tissues, essentially all tissues aside from the liver.
• The liver produces ketone bodies
• They act as alternative energy sources in cases of low glucose availability, like starvation or untreated diabetes.

Liver as Source of Ketone bodies

• The liver produces ketone bodies when glucose levels are low.
• The liver releases ketone bodies into the bloodstream.
• Other body tissues can utilize ketone bodies as an energy source under conditions of limited glucose availability.

Catabolism and Anabolism of Fatty Acids

• Catabolism breaks down fatty acids into acetyl-CoA, releasing energy.
• Anabolism uses acetyl-CoA and malonyl-CoA to synthesize fatty acids, requiring energy. These pathways are necessary for all living organisms.

Overview of Fatty Acid Synthesis

• Fatty acids are built by sequentially adding acetate units.
• This process starts with activating malonate in the form of malonyl-CoA.
• Each step involves reducing a carbonyl group to a methylene group.

Malonyl-CoA

• Formed from acetyl-CoA and bicarbonate, catalyzed by acetyl-CoA carboxylase (ACC).
• A key intermediate in fatty acid synthesis.

Synthesis of Fatty Acids

• Catalyzed by fatty acid synthase (FAS).
• Repeating four-step reaction cycles to elongate the fatty acid chain.
• Requires electrons provided by NADPH, an essential reducing agent in biosynthesis.

Fatty Acid Synthesis

• The overall goal of fatty acid synthesis is to attach two-carbon acetate units to a growing fatty acid chain, beginning with activating malonyl-CoA.
• Crucial steps include condensation, reduction of one carbonyl group to form another hydroxyl group (alcohol). Then there are dehydration steps.
• The growing chain is transferred between enzymes via thioester linkage on acyl carrier proteins(ACPs).

Steps of FAS I Reaction

• Crucial steps for fatty acid biosynthesis, forming an intermediate with a beta keto group.

Steps 2-4 of the FAS I reaction

• These steps involve reduction, dehydration, and further reduction reactions catalyzed by the fatty acid synthase.

Overall Palmitate Synthesis

• Multiple steps and cycles to form palmitate (a 16-carbon saturated fatty acid).
• Requires and uses multiple energy carriers.

Stoichiometry of Palmitate Synthesis

• Detailed accounting of molecules used and produced during palmitate synthesis.
• ATP, NADPH (reduction agent) and CO2 are essential for the entire synthesis process. These precise balances are used in biological systems for precise measurements and to ensure smooth metabolic functioning

Acetyl-CoA

• Transport of Acetyl-CoA into the cytosol to be used for fatty acid synthesis, at some cost to the organism in energy terms.

Regulation of Fatty Acid Synthesis and Breakdown

• Regulation mechanisms ensure appropriate fatty acid metabolism in response to nutrient availability.
• Specific hormones (glucagon, insulin) play a key role in regulating the process.

Clinical Significance

• ACC deficiency impacts fatty acid metabolism, leading to difficulties in regulating the processes involved in fatty metabolism.

Palmitate Lengthening

• Systems in the endoplasmic reticulum and mitochondria for creating various fatty acid chains.

Phospholipids Transport

• Phospholipids synthesis in the smooth endoplasmic reticulum and transportation to other membranes throughout the cell.

Cholesterol Synthesis

• A series of enzymatic steps starting with the condensation of three acetyl coenzyme A molecules producing a 6-C precursor called mevalonate.
• The synthesis of the 5-C isoprene building blocks, the polymerization of six isoprenes to generate squalene, the cyclization of squalene to form the characteristic four-ring structure of cholesterol.

Statin Drugs

• Competitive inhibitors of HMG-CoA reductase, an enzyme crucial for cholesterol synthesis.
• Effectively lower cholesterol levels in the body, and are vital to reducing cholesterol in the body. This reduces plaque in the arteries, and lowers the likelihood of cardiovascular disease..

Conversion of Squalene to Cholesterol

• A series of multistep enzymatic reactions that create cholesterol.
• The key reactions involve the use of enzymes and include NADPH.

Fate of Cholesterol

• After synthesis, cholesterol is often exported from the liver as bile acids or cholesteryl esters.
• Other tissues use cholesterol as a precursor for steroid hormones.

Bile Acids

• Aids in emulsifying fats, increasing the surface area for lipase action, essential components of digestion.

Cholesterol Esters

• More nonpolar than cholesterol due to their esterified fatty acid.
• Transported in lipoproteins.

Cholesterol Regulation

• Multiple mechanisms (covalent modification, gene regulation) for regulating cholesterol synthesis and transport.

HMG-CoA Reductase

• This enzyme is crucial to cholesterol synthesis.
• Is primarily regulated by the phosphorylation status of the enzyme, indicating important regulation at the step of cholesterol production.