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Questions and Answers
What is the principal storage form of energy in the body?
Which component is predominantly found in chylomicrons?
What is the role of apolipoproteins in lipoproteins?
Which lipoprotein is secreted into the lymphatic circulation after fat absorption?
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What type of enzymes do chylomicrons encounter in the blood?
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What are the predominant forms of absorbed fat after digestion?
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How are triglycerides transported in the body?
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Which statement about lipoproteins is true?
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Where is LPL primarily synthesized and secreted?
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What amino acid does LPL bind to on chylomicrons to become activated?
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In the fasting state, which cells preferentially take up TGs for energy?
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What is the main metabolic pathway responsible for breaking down TGs into glycerol and free fatty acids?
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Which enzyme is primarily involved in the hydrolysis of the first and second fatty acids from glycerol during lipolysis?
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What molecule is formed by the combination of free fatty acids and glycerol?
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Which enzyme complex catalyzes the process of lipogenesis?
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How does HSL activity change when phosphorylated?
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What are the major dietary fats found in food?
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Which of the following statements is true regarding triglycerides?
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What role does beta-oxidation play in lipid metabolism?
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Which statement best describes the function of brown adipose tissue?
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What happens to triglycerides during lipolysis?
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What is the primary substrate for ketogenesis?
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In the post-absorption state, what is the fate of fatty acids?
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What condition is characterized by Medium-chain Acyl-CoA Dehydrogenase Deficiency?
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Which hormone primarily inhibits lipolysis during the fed state?
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What is the function of hormone-sensitive lipase (HSL) during fasting or exercise?
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What is the process through which fatty acids are broken down to generate energy?
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Which statement about the process of β-oxidation is true?
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Where does the β-oxidation of fatty acids primarily occur?
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Which of the following hormones enhances the effects of catecholamines during lipolysis?
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Which molecule is formed during the activation of fatty acids?
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In which stage of β-oxidation are fatty acids transported into the mitochondrion?
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What is the main function of the Carnitine Shuttle in fatty acid metabolism?
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Which enzyme is responsible for the first step in the beta-oxidation process?
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What occurs during each cycle of beta-oxidation?
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Which factor primarily inhibits the entry of fatty acids into the mitochondrion?
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What are the three ketone bodies produced during ketogenesis?
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What triggers the synthesis of ketone bodies in the liver?
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What role does Acyl-Carnitine Translocase play in fatty acid transport?
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How does the availability of plasma free fatty acids affect their metabolism?
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What is the primary function of brown adipose tissue?
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Which fatty acids are primarily utilized in the post-absorption phase?
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What role do lipase enzymes play in the digestion of dietary fats?
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When is ketogenesis primarily stimulated in the body?
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What is the end product of beta-oxidation of fatty acids?
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What condition is associated with a deficiency in Medium-chain Acyl-CoA Dehydrogenase?
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What is the primary mechanism by which fats contribute to energy reserve in the body?
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What distinguishes unsaturated fats from saturated fats in dietary terms?
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What happens to acetyl CoA when oxaloacetate is depleted?
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During ketogenesis triggered by prolonged fasting, which organ primarily converts acetyl CoA into ketone bodies?
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What primarily regulates the rate of β-oxidation in the mitochondria?
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Which enzyme resubstitutes CoA for carnitine after transport into the mitochondrial matrix?
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Which condition is characterized by high levels of ketone bodies leading to acidemia?
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What is a common symptom of diabetic ketoacidosis?
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What is the primary function of ketone bodies in the body?
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Which of the following molecules is formed as a byproduct of the decarboxylation of acetoacetate?
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Which factor can contribute to the onset of diabetic ketoacidosis?
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What characterizes the primary function of brown adipose tissue compared to white adipose tissue?
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How does malonyl-CoA influence fatty acid metabolism?
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What is the metabolic pathway that uses oxaloacetate in the absence of glucose?
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What initiates the process of β-oxidation in the mitochondrial matrix?
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During each cycle of β-oxidation, how many carbon atoms are removed from the fatty acid chain?
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What is the substrate for ketogenesis in the liver?
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Which of the following statements accurately describes the role of lipoprotein lipase (LPL) in fat metabolism?
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How does insulin influence lipoprotein lipase (LPL) expression in adipocytes?
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Which enzyme is responsible for converting acetyl CoA into fatty acids during lipogenesis?
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What is the primary function of glycerol in lipid metabolism?
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During lipolysis, how is hormone-sensitive lipase (HSL) activated?
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In which scenario are triglycerides preferentially utilized by muscle cells for energy?
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What does lipolysis primarily achieve in the body?
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What are the end products of the enzymatic action during lipolysis in adipocytes?
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Which characteristic distinguishes brown adipose tissue (BAT) from white adipose tissue (WAT)?
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What is the primary mechanism through which BAT generates heat?
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Which clinical sign is NOT associated with Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)?
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What is the effect of low ATP synthase levels in brown adipose tissue?
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What is the major complication arising from Medium Chain Acyl-CoA Dehydrogenase deficiency?
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What role does UCP1 play in brown adipose tissue?
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What is the recommended preventive measure for individuals with Medium Chain Acyl-CoA Dehydrogenase Deficiency?
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What is a defining feature of brown adipose tissue in terms of its cellular composition?
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What is the primary function of lipoprotein lipase (LPL) in chylomicron metabolism?
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Which process occurs when acetyl CoA is diverted from the TCA cycle?
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What hormone primarily activates hormone-sensitive lipase (HSL)?
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Which enzymatic step is responsible for the removal of the first fatty acid from glycerol during lipolysis?
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What is the fate of glycerol released during lipolysis?
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How does insulin affect lipoprotein lipase (LPL) expression in adipocytes?
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What component binds to LPL, facilitating its activation?
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What process is primarily stimulated during fasting to provide energy from stored triglycerides?
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What is the primary consequence of oxaloacetate depletion in the metabolism of acetyl CoA?
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Under what conditions is ketogenesis predominantly triggered?
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What symptom is NOT commonly associated with ketoacidosis?
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What is a key function of brown adipose tissue (BAT) in response to cold?
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How can diabetic ketoacidosis develop in patients with diabetes mellitus?
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Which condition describes the combination of high ketone levels and acidosis?
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What is NOT an important energy source when ketones become elevated?
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Which of the following is a contributing factor to the onset of diabetic ketoacidosis?
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What is the primary role of brown adipose tissue in energy metabolism?
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Which condition is characterized by the inability to metabolize medium-chain fatty acids?
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During lipolysis, which process results in the breakdown of triglycerides?
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What is the correct sequence of events during the fasting state regarding triglyceride utilization?
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Which of the following best describes the composition of triglycerides?
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How does beta-oxidation contribute to energy production?
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What represents the correct relationship between dietary fats and their categories?
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Which metabolic scenario predominantly stimulates the synthesis of ketone bodies?
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What is the main effect of insulin on hormone-sensitive lipase (HSL)?
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In what state are catecholamines and glucagon primarily released to promote lipolysis?
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What occurs during the activation of fatty acids in the cytosol?
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What is the primary mechanism through which fatty acids are transported into mitochondria?
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Which hormone enhances the effects of catecholamines during lipolysis by increasing HSL expression?
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What is the primary end product of β-oxidation of fatty acids?
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During which step of fatty acid catabolism does the breakdown of fatty acid chains occur?
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What role does HSL serve in the context of fasting or exercise?
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What is the significance of free fatty acids in the metabolism of fatty acids by tissues?
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What role does Malonyl-CoA play in the transport of fatty acids into the mitochondrion?
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In terms of energy production, what is produced for every cycle of beta-oxidation?
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What is the specific function of Carnitine Palmitoyl Transferase II (CPT II) in fatty acid metabolism?
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What initiates the cyclic reaction of beta-oxidation in the mitochondrial matrix?
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What is the primary trigger for ketogenesis in the liver?
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Which ketone body is produced in the smallest amounts during ketogenesis?
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What crucial role does the Carnitine Shuttle perform in lipid metabolism?
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Study Notes
Dietary Fat
- Three major types of dietary fats: saturated, trans, and unsaturated.
- Most dietary fats share a chemical structure: three fatty acids attached to a glycerol backbone (triglyceride).
- Digested by lipase enzymes in the small intestine.
- Functions: Energy reserve, temperature control, protection of internal organs, absorption of fat-soluble vitamins.
Fast Fed Cycle
- Fed state: Nutrient rich; absorption and transport of fats; triglyceride synthesis.
- Fasting state: Nutrient poor; lipolysis; use of stored energy; ketone bodies.
Lipid Digestion and Absorption
- Triacylglycerides are stored in adipocytes and are the primary storage form of energy.
- Contain twice the energy per gram compared to carbohydrates.
Triglyceride Transport
- Triglycerides are large and hydrophobic molecules, transported by incorporation into lipoprotein particles.
- Lipoproteins consist of a core containing triglycerides and cholesterol surrounded by an outer shell of phospholipids and apolipoproteins.
- Apolipoproteins stabilize the complex and have roles in guiding the formation of lipoproteins, acting as ligands for lipoprotein receptors, and regulating enzymes involved in lipoprotein metabolism.
- There are several classes of lipoproteins classified by size, lipid composition, and apolipoproteins.
- Size decreases, and density increases as triglycerides are removed.
Post-absorption Transport of Triglyceride
- Fat is absorbed as 2-monoacylglycerol and free fatty acids.
- Triglycerides are resynthesized in the endoplasmic reticulum.
- Triglycerides are incorporated into chylomicrons in the Golgi apparatus, along with cholesterol esters and fat-soluble vitamins.
- Important apolipoproteins in chylomicrons include Apo B, Apo C, and Apo E.
- Chylomicrons are secreted into the lymphatic circulation and enter the blood via the thoracic duct.
Lipoprotein Lipase and Lipogenesis
- Chylomicrons circulate in the blood until they encounter organs expressing lipoprotein lipase (LPL).
- LPL is synthesized in adipose, muscle, and heart tissue and secreted to the endothelium of capillaries (not expressed in the liver or brain).
- LPL is activated when it binds to ApoC II on chylomicrons.
- LPL hydrolyses triglycerides in chylomicrons into free fatty acids and monoacylglycerol.
- These products diffuse into adipocytes and are reassembled into triglycerides for storage in the fed state.
- In the fasting state, triglycerides are preferentially taken up by muscle cells for energy generation.
- Triglyceride synthesis can occur in the liver and adipose tissue.
- Following a meal high in carbohydrates, excess glucose is used to make triglycerides.
- Glucose is metabolized by glycolysis to acetyl-CoA, which is diverted from the TCA cycle into lipogenesis to form fatty acids.
- Fatty acids combine with glycerol to form triglycerides in the endoplasmic reticulum.
- Triglycerides are packaged into very-low-density lipoproteins (VLDLs) and secreted into the blood.
Lipolysis
- Lipolysis breaks down triglycerides into glycerol and free fatty acids.
- Involves three enzymes: adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL).
- HSL hydrolyzes the first and second fatty acids from glycerol.
- HSL activity is controlled by phosphorylation, with phosphorylation activating the enzyme and dephosphorylation inactivating it.
Hormonal Regulation of Lipolysis
- Key hormonal target for lipolysis regulation is HSL activity.
- Insulin inhibits HSL phosphorylation in the fed state, thus inhibiting lipolysis.
- Catecholamines and glucagon promote HSL phosphorylation in the fasted/exercise states, promoting lipolysis.
- Other lipolytic hormones (e.g., glucocorticoids, growth hormone, and thyroid hormone) increase the expression of HSL.
- Insulin inhibits lipolysis, while glucagon and catecholamines promote lipolysis.
Summary
- Fed state (high insulin): Triglycerides transported in chylomicrons to adipose tissue; chylomicrons bind to LPL via ApoC; LPL breaks down triglycerides into monoacylglycerol and free fatty acids; these diffuse into adipocytes and are reassembled into triglycerides for storage.
- Fasting state/exercise (low insulin, high glucagon/catecholamines): HSL and other lipases are activated; triglycerides are metabolized into free fatty acids and glycerol; fatty acids bind to albumin and travel to target tissues for metabolism; glycerol travels to the liver for further metabolism (glycolysis or gluconeogenesis).
Extraction of Energy from Fatty Acids
- Occurs through a process called β-oxidation.
- β-oxidation breaks down fatty acids to generate energy.
- Occurs in most cell types (except erythrocytes and neurons).
- Enzymes for β-oxidation are found in the mitochondria.
- Involves three stages: activation of fatty acids in the cytosol; transport into the mitochondrion; β-oxidation in the mitochondrial matrix.
- Overall process breaks down fatty acid chains into acetyl-CoA, which enters the TCA cycle for energy production.
Step 1: Activation of Fatty Acids
- Fatty acids enter the cytosol and are activated to acyl-CoA by acyl-CoA synthase (thiokinase).
- Short-chain fatty acyl-CoA can diffuse into the mitochondrion.
- Long-chain fatty acids need the carnitine shuttle for transport.
Step 2: Transport to the Mitochondrion
- Carnitine palmitoyl transferase I (CPT I) substitutes carnitine for CoA on the fatty acid.
- Acyl-carnitine crosses the inner mitochondrial membrane (IMM) via acyl-carnitine translocase.
- Carnitine palmitoyl transferase II (CPT II) resubstitutes CoA for carnitine.
- Carnitine exits the matrix through the translocase.
Step 3: β-oxidation in the Mitochondrial Matrix
- Cyclic four-step reaction initiated by acyl-CoA dehydrogenase.
- Three isoforms of acyl-CoA dehydrogenase exist: short-chain, medium-chain, and long-chain.
- With each cycle, two carbons are removed from the fatty acid as acetyl-CoA.
- Each cycle produces: acetyl-CoA, NADH, and FADH2.
Regulation of β-oxidation
- Rate of β-oxidation is regulated by:
- Levels of free fatty acids: Metabolism of fatty acids is proportional to plasma free fatty acid levels, which is dependent on HSL activity and levels of insulin (inhibitory) and glucagon/catecholamines (stimulatory).
- Levels of cytosolic malonyl-CoA (fatty acid biosynthesis): Malonyl-CoA inhibits CPT1, preventing fatty acids from entering the mitochondria. This ensures that fatty acid biosynthesis and breakdown don't occur simultaneously.
Ketone Bodies
- Ketone bodies serve as a reserve fuel in the body, especially for the brain.
- Three types of ketone bodies: acetoacetate, β-hydroxybutyric acid, and acetone.
- They are only synthesized in the liver from acetyl-CoA.
Ketogenesis
- Synthesis occurs only in response to an unavailability of blood glucose (e.g., fasting).
- Blood glucose levels decrease, and glycogen is depleted.
Dietary Fats
- Three major dietary fats: saturated, trans fats, and unsaturated.
- Most dietary fats have a similar chemical structure: three fatty acids attached to a glycerol backbone, known as triglyceride or triacylglycerol.
- Digested by lipase enzymes and absorbed in the small intestine.
- Functions: energy reserve, temperature control, protection of internal organs, and absorption of fat-soluble nutrients like vitamins.
Fed and Fast Cycles
- Fed State: During nutrient rich conditions the body builds up stores
- The body absorbs and transports lipids, then synthesizes triglycerides (TGs) for storage.
- Fasting State: Nutrient poor conditions use stored energy.
- TGs are broken down by lipolysis into free fatty acids (FFAs) and glycerol.
- The liver uses FFAs to generate ketone bodies.
Lipoprotein Lipase (LPL)
- Primarily synthesized in adipose, muscle, and heart tissue and secreted to the endothelium of adjacent capillaries.
- Not expressed in the liver or brain.
- LPL is activated by binding to ApoC II on chylomicrons.
- Its primary function is to hydrolyze TGs in chylomicrons into FFAs and monoacylglycerol for diffusion into adipocytes and reassembly into TGs.
- LPL expression is upregulated by insulin in adipocytes and is constitutively active in muscle cells.
- During the fed state, TGs are taken up by adipocytes.
- During fasting, TGs are preferentially taken up by muscle cells for energy generation.
Triglyceride Synthesis
- After a meal, most FFAs used for TG synthesis in adipose tissue come from chylomicrons.
- FFAs can also be synthesized from glucose by glycolysis to Acetyl-CoA.
- Acetyl CoA is diverted from the TCA cycle into lipogenesis to form FAs.
- This process is catalyzed by the enzyme complex Fatty Acid Synthase.
- FAs combine with glycerol to form TGs in the endoplasmic reticulum.
- TGs are packaged into VLDLs and secreted into the blood.
Lipolysis
- The metabolic pathway where TGs are hydrolyzed into glycerol and FFAs.
- Primary function: mobilization of stored energy during fasting or exercise.
- Three enzymes involved: Adipose Triglyceride Lipase (ATGL), Hormone Sensitive Lipase (HSL), and Monoacylglycerol Lipase (MGL).
- These enzymes successively remove FFAs from the glycerol backbone.
- FFAs diffuse out of the cell and are distributed throughout the body in the blood bound to albumin.
- Glycerol travels to the liver and can enter glycolysis or gluconeogenesis.
Hormonal Regulation of Lipolysis
- Key target for hormonal regulation is the activity of HSL, which hydrolyses the first and second FFAs from glycerol.
- HSL activity is controlled by its phosphorylation state.
- Phosphorylation activates HSL (mediated by protein kinase A).
- Dephosphorylation inactivates HSL (mediated by phosphatase).
Beta-oxidation: Step 1: Activation of Fatty Acid
- Fatty acids are activated by the addition of Coenzyme A (CoA) to form acyl-CoA.
- This reaction is catalyzed by acyl-CoA synthetase, requiring ATP hydrolysis.
- Short-chain fatty acyl-CoA can diffuse into the mitochondria.
- Long-chain FAs cannot enter by diffusion and must use the carnitine shuttle.
Beta-oxidation: Step 2: Transport to the Mitochondrion
- Carnitine Shuttle
- Carnitine Palmitoyl Transferase I (CPT I) substitutes carnitine for CoA on the FA.
- Acyl-carnitine crosses the inner mitochondrial membrane (IMM) into the matrix via Acyl-Carnitine Translocase.
- Carnitine Palmitoyl Transferase II (CPT II) resubstitutes CoA for carnitine to regenerate the acyl-CoA.
- Carnitine exits the matrix through the translocase into the intermembrane space.
Beta-oxidation: Step 3: Beta-oxidation in the Mitochondrial Matrix
- A cyclic four-step reaction initiated by Acyl-CoA dehydrogenase.
- Three isoforms of Acyl-CoA dehydrogenase exist: short chain, medium chain, and long chain.
- Each cycle removes two carbons from the FA as Acetyl-CoA, producing:
- Acetyl CoA → TCA cycle/ETC → ATP
- 1 NADH → ETC→ ATP
- 1 FADH2
Regulation of Beta-oxidation
- Rate of beta-oxidation is largely regulated by:
- Levels of free FFAs: metabolism of FAs by tissues is proportional to levels of plasma free FFAs dependent on the activity of HSL in adipose tissue and levels of insulin, glucagon, and catecholamines.
- Levels of cytosolic malonyl-CoA (Fatty Acid biosynthesis): The first step in FA biosynthesis is the generation of malonyl Co-A in the cytoplasm. Malonyl Co-A inhibits CPT1, preventing FAs from entering the mitochondria, ensuring that FA biosynthesis and FA breakdown do not occur simultaneously.
Ketone Bodies
- Primarily function as a reserve fuel in the body, especially for the brain.
- Three ketone bodies: acetoacetate, beta-hydroxybutyric acid (formed from acetoacetate), and acetone (formed in small amounts by decarboxylation of acetoacetate).
- Only synthesized in the liver from acetyl Co-A.
Ketogenesis
- Synthesis occurs during periods of unavailable blood glucose (e.g., fasting).
- Blood glucose levels decrease, and glycogen is depleted, causing the body to switch to lipid metabolism.
- Acetyl CoA enters the TCA cycle to produce energy, requiring oxaloacetate.
- When glucose levels are low, the body also switches to gluconeogenesis, depleting oxaloacetate.
- When oxaloacetate is depleted, acetyl CoA cannot enter the TCA cycle and forms ketone bodies instead (Ketogenesis).
- Ketogenesis also occurs in Diabetes Mellitus as cells cannot metabolize glucose.
Ketogenesis: The Process
- Occurs when glucose is unavailable and oxaloacetate is depleted (e.g., fasting or diabetes).
- Acetyl CoA enters ketogenesis in the liver.
- Ketone bodies are released into the blood.
- They are taken up by target tissues (brain, heart, muscle) and reconverted into acetyl CoA to enter the TCA cycle.
Ketoacidosis
- Under conditions of poorly managed diabetes or prolonged starvation, glucose becomes unavailable and ketones become an important energy source.
- If levels in the blood become too high, ketoacidosis can occur as both acetoacetate and b-hydroxybutyrate are acids. .
- Can occur due to missed insulin treatments, malfunctioning pumps, or illnesses that release hormones that reduce insulin secretion (e.g., pneumonia, infection).
- Symptoms: thirst, increased urination, abdominal pain, nausea, vomiting, dehydration and confusion.
- Can be fatal if not managed.
- Treatment: insulin, fluids, and electrolytes.
Brown Adipose Tissue (BAT)
- White adipose tissue (WAT) comprises most of the body’s fat stores and functions to store and release fatty acids for energy generation.
- BAT is distinct from WAT and is activated in response to cold temperatures.
- Its primary function is to produce heat (thermogenesis) to maintain body temperature.
- Abundant in newborns and hibernating animals.
- BAT is characterized by:
- Multiple lipid droplets, densely packed with mitochondria rich in iron (brown color), and highly vascularized for good oxygen supply for oxidative phosphorylation.
- BAT expresses low levels of ATP synthase, meaning the electron transport chain (ETC) is not coupled to ATP production.
- Instead, BAT expresses Uncoupling protein 1 (aka.thermogenin), which uncouples oxidative phosphorylation from ATP synthesis, releasing the energy as heat.
Brown Adipose Tissue - Summary
- ATP synthases expression is low.
- Oxidative phosphorylation is uncoupled from ATP synthase.
- UCP1 expression is high.
- Heat is generated.
Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
- Disorder of beta-oxidation that impairs the breakdown of medium-chain FAs into acetyl-CoA.
- A rare genetic defect in Medium Chain Acyl Co-A Dehydrogenase (the first step in beta-oxidation of FAs in the mitochondria).
- Clinical signs: Intolerance to prolonged fasting, hypoglycemia, impaired ketogenesis, and acidosis due to FA accumulation in the blood.
- Treatment is preventive: Avoid fasting and situations where the body relies on beta-oxidation for energy. Glucose supplements are helpful.
Dietary Fat
- Three major dietary fats: saturated, trans, and unsaturated
- Most dietary fats have a similar structure: three fatty acids attached to a glycerol backbone (triglyceride or triacylglycerol)
- Digested by lipase enzymes and absorbed in the small intestine
- Functions: energy reserve, temperature control, protection of internal organs, absorption of fat-soluble nutrients (vitamins)
Fed State
- Nutrient-rich state
- Lipids are absorbed and transported
- Triglyceride synthesis occurs in adipose tissue
Fasting State
- Nutrient-poor state
- Lipolysis (breakdown of triglyceride) occurs in adipocytes
- Free fatty acids and glycerol are released
- Free fatty acids are transported in the blood bound to albumin
- Glycerol travels to the liver
Lipoprotein Lipase (LPL)
- Enzyme responsible for hydrolysing triglycerides in chylomicrons
- Synthesized in adipose, muscle, and heart tissue
- Attached to the endothelium of adjacent capillaries
- Activated by binding to ApoC II on chylomicrons
- Expression is upregulated by insulin in adipocytes
- Constitutively active in muscle cells
- In the fed state, triglycerides are taken up by adipocytes for storage
- In the fasting state, triglycerides are preferentially taken up by muscle cells
Triglyceride Synthesis
- After a meal, most fatty acids used for triglyceride synthesis in adipose tissue come from chylomicrons
- Fatty acids can also be synthesized in the liver and adipose tissue
- Occurs following a meal high in carbohydrates when glycogen stores are filled and excess glucose is used to make triglycerides
- Glucose is metabolized by glycolysis to acetyl CoA
- Acetyl CoA is diverted from the TCA cycle into lipogenesis (catalyzed by fatty acid synthase)
- Fatty acids combine with glycerol to form triglycerides in the endoplasmic reticulum
- Triglycerides are packaged into very-low-density lipoproteins (VLDLs) and secreted into the blood
Lipolysis
- The metabolic pathway where triglycerides are hydrolyzed into glycerol and free fatty acids
- Primary function is to mobilize stored energy during fasting or exercise
- Three enzymes involved in adipocytes: adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL)
- Free fatty acids diffuse from cells and are distributed throughout the body bound to albumin
- Glycerol travels to the liver and can enter glycolysis or gluconeogenesis
Hormonal Regulation of Lipolysis
- Key target for hormonal regulation is the activity of hormone-sensitive lipase (HSL)
- HSL activity is controlled by its phosphorylation state
- Phosphorylated = Active (mediated by protein kinase A)
- Dephosphorylated = Inactive (mediated by phosphatase)
- Primary hormones regulating lipolysis:
- Insulin: released in the fed state, inhibits HSL phosphorylation and lipolysis
- Catecholamines & Glucagon: released in the fasted/exercise state, elevate cAMP levels, activate protein kinase A, promote HSL phosphorylation and lipolysis
- Other lipolytic hormones (glucocorticoids, growth hormone, thyroid hormone) enhance the effects of catecholamines & glucagon
Summary
- Fed state (high insulin): triglycerides are transported in chylomicrons to adipose tissue, chylomicrons bind via ApoC to LPL, LPL breaks down triglycerides into monoacylglycerol and free fatty acids, these diffuse into adipocytes and are reassembled into triglycerides, stored in fat droplets
- Fasting state/exercise (low insulin, high glucagon/catecholamines): HSL and other lipases become phosphorylated and activated, triglycerides are metabolized into free fatty acids and glycerol, free fatty acids bind albumin and travel to target tissues for further metabolism, glycerol travels to the liver for further metabolism (glycolysis or gluconeogenesis)
Extraction of Energy from Fatty Acids
- Occurs by a process called β-oxidation
- β-oxidation is the catabolic process where fatty acids are broken down to generate energy
- Occurs in almost all cell types except erythrocytes and neurons
- Enzymes required for β-oxidation are found in the mitochondria
- Three stages:
- Activation of fatty acids in the cytosol
- Transport into the mitochondrion
- β-oxidation in the mitochondrial matrix
- The overall process involves breaking down fatty acid chains into acetyl-CoA, which then enters the TCA cycle to produce energy (ATP)
Step 1: Activation of Fatty Acids
- Fatty acids are activated to acyl-CoA by acyl CoA synthase (thiokinase)
- Short-chain fatty acyl-CoA can diffuse into the mitochondrion
- Long-chain fatty acids cannot diffuse and must use the carnitine shuttle
Step 2: Transport to the Mitochondrion (Carnitine Shuttle)
- Carnitine palmitoyl transferase I (CPT I) substitutes carnitine for CoA on the fatty acid
- Acyl-carnitine crosses the inner mitochondrial membrane (IMM) into the matrix via acyl-carnitine translocase
- Carnitine palmitoyl transferase II (CPT II) resubstitutes CoA for carnitine to regenerate the acyl-CoA
- Carnitine exits the matrix through the translocase into the intermembrane space
Step 3: β-oxidation in the Mitochondrial Matrix
- A cyclic four-step reaction
- Initiated by acyl-CoA dehydrogenase
- Three isoforms of acyl-CoA dehydrogenase exist: short-chain, medium-chain, and long-chain
- With each cycle, two carbons are removed from the fatty acid as acetyl-CoA
- Each cycle produces acetyl CoA, which enters the TCA cycle/ETC to produce ATP.
Regulation of β-oxidation
- Rate of β-oxidation is largely regulated by levels of free fatty acids and cytosolic malonyl-CoA
- Levels of free fatty acids are dependent on the activity of HSL in adipose tissue and levels of insulin (inhibitory) and glucagon/catecholamines (stimulatory)
- Malonyl-CoA is the first step in fatty acid biosynthesis and inhibits CPT1, ensuring that fatty acid biosynthesis and breakdown don't occur simultaneously.
Ketone Bodies
- Primary function is to serve as a reserve fuel in the body, especially for the brain.
- Three types of ketone bodies: acetoacetate, β-hydroxybutyric acid, and acetone
- Synthesized only in the liver from acetyl CoA
Ketogenesis
- Synthesis occurs in response to unavailability of blood glucose
- Blood glucose levels decrease and glycogen is depleted
- The body switches to lipid metabolism
- Acetyl CoA enters the TCA cycle to produce energy.
- Oxaloacetate is required for the cycle (but depleted during gluconeogenesis)
- When oxaloacetate is depleted, acetyl CoA cannot enter the TCA cycle and is used to form ketone bodies (ketogenesis)
- Ketogenesis also occurs in diabetes mellitus, as cells cannot metabolize glucose
Ketoacidosis
- Under conditions of poorly managed diabetes or prolonged starvation, glucose is unavailable, and ketones become an important energy source
- If blood ketone levels become too high, ketoacidosis can occur (both acetoacetate and β-hydroxybutyrate are acids)
- Diabetic ketoacidosis can occur due to missed insulin treatments, malfunctioning pump, or illnesses that release hormones reducing insulin secretion (e.g., pneumonia, infection)
- Symptoms: thirst, increased urination, abdominal pain, nausea, vomiting, dehydration, confusion.
- Can be fatal if not managed
- Treatment: insulin, fluids, and electrolytes
Brown Adipose Tissue
- White adipose tissue (WAT) stores and releases fatty acids for energy
- Brown adipose tissue (BAT) is distinct from WAT and is activated by cold temperatures
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Description
This quiz explores the different types of dietary fats, their roles in the body, and the processes involved in lipid digestion and absorption. Understand the cycles of fed and fasting states, and how triglycerides are transported in the body. Test your knowledge on the essential functions of fats and their importance in nutrition.
