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5.2: Lipolysis, β-oxidation, and ketogenesis

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    The processes of lipolysis, \(\beta\)-oxidation, and ketogenesis work in concert within the cell but should be considered distinct pathways.

    Lipolysis

    Lipolysis is the release of fatty acids from adipose tissue where they are stored as triacylglycerols (TAGs). This process is mediated by increasing levels of glucagon and epinephrine, which bind G-protein coupled receptors on the adipose tissue and activate lipolysis This cell-signaling cascade phosphorylates and activates hormone-sensitive lipase, the regulatory enzyme for lipolysis. Once phosphorylated (through hormone-mediated increase in cAMP) this enzyme will hydrolyze TAGs to three long-chain fatty acids (LCFAs) and glycerol. The LCFAs are released into the bloodstream and will circulate bound to albumin (fatty acids are hydrophobic and require a protein carrier). LCFAs will be taken up and oxidized by peripheral tissues and the liver under fasted conditions. The glycerol will also be released and used as a substrate for hepatic gluconeogenesis (section 5.1) (figure 5.6).

    Fasted state has low insulin/high glucagon to activate G-protein coupled receptors. In the adipose cell, lipase (inactive) arrow hormone-sensitive lipase (active). Triglyceride arrow with hormone-sensitive lipase to fatty acids, fatty acids, fatty acids, and glycerol which move outside of the cell to the blood

    Figure 5.8: Process of lipolysis.

    β-oxidation (oxidation of free fatty acids)

    Fatty acid oxidation is a high energy yielding process. It can support the cellular energy needs during fasting and under conditions when excess energy is needed (exercise). After uptake from circulation, the LCFAs must be transferred into the mitochondria where \(\beta\)-oxidation occurs. Initially, the LCFAs are activated to acyl-CoA derivatives in the cytosol by acyl-CoA synthetase. The fatty acyl-CoA can then be transferred across the mitochondrial membranes using a series of transport proteins: carnitine palmitoyltransferase 1 and 2 (CPT1 and CPT2) (figure 5.9).

    Lysine dotted arrow carnitine arrow touching CPT1 to fatty-acyl carnitine arrow going through translocase and CPT2 to carnitine. Fatty acyl-CoA arrow touching CPT1 to CoA. CoA arrow going through translocase and CPT2 to fatty acyl-CoA arrow with enzyme acyl-CoA dehydrogenase to trans-enoyl-CoA arrow with enzyme hydratase to β-hydroxyacyl-CoA arrow with enzyme hydroxyacyl-CoA dehydrogenase to β-ketoacyl-CoA arrow acetyl-CoA. β-ketoacyl-CoA arrow (n-2) fatty acyl-CoA dotted arrow that says many cycles to fatty acyl-CoA. CoA arrow touching arrow between β-ketoacyl-CoA and acetyl-CoA that says odd chain fatty acids only to propionyl-CoA arrow with enzyme propionyl-CoA carboxylase to methylmalonyl-CoA arrow with enzyme methylmalonyl-CoA mutase to succinyl-CoA dotted arrow TCA

    Figure 5.9: Overview of LCFA transport into the mitochondria and β-oxidation.

    CPT1 sits on the outer mitochondrial membrane and transfers the fatty acyl-CoA to carnitine. Fatty acyl carnitine is transferred into the mitochondrial matrix through CPT2, and the carnitine is released and recycled. Only long-chain fatty acyl-CoAs require carnitine as a carrier; short- and medium-chain fatty acids can move into the mitochondria without the assistance of these transporters. Once in the matrix, the fatty acyl-CoA is now ready to undergo \(\beta\)-oxidation (figure 5.9).

    \(\beta\)-oxidation is an iterative process that involves a series of enzymes that preferentially oxidize different length fatty acids (long, medium, and short). The full \(\beta\)-oxidation spiral consists of four steps that result in the generation of acetyl-CoA, NADH, and FADH\(_2\) for each cycle (figure 5.9). The NADH and FADH\(_2\) generated will be oxidized in the ETC to produce ATP. The acetyl-CoA can be oxidized in the TCA cycle, but more likely it will be used in ketogenesis. Oxidation of odd chain fatty acids will result in the generation of propionyl-CoA as the final carbon unit, which can also be oxidized in the TCA cycle. The acetyl-CoA from \(\beta\)-oxidation also plays a key role in the allosteric activation of pyruvate carboxylase, which is necessary for gluconeogenesis to occur (section 5.1).

    Regulation of β-oxidation

    \(\beta\)-oxidation is regulated primarily at the level of transport of LCFAs across the mitochondrial membrane. Malonyl-CoA will inhibit CPT1 therefore ensuring that \(\beta\)-oxidation is not occurring at the same time as fatty acid synthesis (figure 5.10; section 4.4). Additionally, the rate of ATP production (ATP/ADP ratio) will also regulate the rate of NADH and FADH\(_2\) produced through β-oxidation (figure 5.10).

    1: Fatty acid down arrow to fatty acyl-CoA arrow fatty acyl carnitine arrow with text β-oxidation to acetyl-CoA. 2: Acetyl-CoA left arrow with enzyme acetyl-CoA carboxylase to malonyl-CoA arrow in between fatty acyl-CoA and fatty acyl carnitine. AMP-PK (muscle, liver) inhibits and insulin (liver) activates acetyl-CoA carboxylase 3: ATP right arrow to electron transport chain arrow NADH arrow fatty acyl carnitine. ADP and FAD(2H) inhibit pathway.

    Figure 5.10: Regulation of β-oxidation.

    Ketogenesis

    As mentioned above, the acetyl-CoA produced by \(\beta\)-oxidation is primarily used for ketogenesis — the synthesis of ketone bodies. Substrates for ketogenesis can also come from the oxidation of ketogenic amino acids. In the fasted state, the process of \(\beta\)-oxidation generates a significant amount of acetyl-CoA, and although some of this substrate can be oxidized in the TCA cycle, we need to consider the other metabolic processes occurring. First, the significant amount of NADH generated through \(\beta\)-oxidation reduces flux through the TCA cycle by decreasing the activity of both \(\alpha\)-ketoglutarate dehydrogenase and isocitrate dehydrogenase. Second, the process of gluconeogenesis is occurring, and intermediates of the TCA cycle, specifically malate, are actively being moved out of the mitochondria. The combination of these two processes reduces the TCA cycle activity allowing for an accumulation of acetyl-CoA. As acetyl-CoA levels elevate in the mitochondria, this will drive the thiolase reaction to generate acetoacetyl-CoA from two acetyl-CoA molecules (figure 5.11).

    Acetyl-CoA bidirectional arrow with enzyme thiolase and loss of CoA to acetoacetyl-CoA arrow with enzyme HMG-CoA synthase (in liver) and acetyl-CoA arrow loss of CoA to β-hydroxy-β-methyl-glutaryl-CoA (HMG-CoA) split arrow to acetyl-CoA and Acetoacetate. Acetoacetate arrow labeled spontaneous and loss of CO2 to acetone. Acetoacetate arrow with enzyme to β-hydroxybutyrate dehydrogenase and bidirectional arrow with NAD+ and NADH to β-hydroxybutyrate.

    Figure 5.11: Overview of ketone body formation.

    This compound is the substrate for HMG-CoA synthase, which generates 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA). HMG-CoA is then accepted by HMG-CoA lyase where an acetyl-CoA group is removed to generate acetoacetate. Acetoacetate can either undergo spontaneous decarboxylation to acetone, which can be exhaled, or it can be reduced to \(\beta\)-hydroxybutyrate using NADH. Acetoacetate and \(\beta\)-hydroxybutyrate are the two primary ketone bodies in circulation, and the ratio of the two is dependent on levels of NADH (figure 5.11). These two ketone bodies can be used as fuel in most tissues with the exception of the liver, which lacks thiophorase, the enzyme needed to metabolize these substrates. Ketone oxidation is not a primary fuel source, as fatty acid oxidation is preferred, but it can supply energy to some peripheral tissues. The brain can also oxidize ketones but only under extreme situations, such as starvation states.

    Summary of pathway regulation

    Table 5.2: Summary of pathway regulation.
    Metabolic pathway Major regulatory enzyme Allosteric effectors Hormonal effects
    Lipolysis Hormone-sensitive lipase None

    Epi ­\(\uparrow\)

    Insulin \(\downarrow\)

    \(\beta\)-oxidation Carnitine palmitoyltransferase (CPT1) Malonyl-CoA (-) None

     

    References and resources

    Text

    Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 10: Gluconeogenesis: Section II, III, IV, Chapter 11: Glycogen Metabolism: Section V, VI, Chapter 16: Fatty Acid Ketone Body and TAG Metabolism: Section III, IV, V, Chapter 19: Removal of Nitrogen from Amino Acids: Section V, VI, Chapter 23: Metabolic Effect of Insulin and Glucagon, Chapter 25: Diabetes Mellitus.

    Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 78, 82, 86, 89–90.

    Lieberman, M., and A. Peet, eds. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 3: The Fasted State, Chapter 19: Basic Concepts in Regulation, Chapter 24: Oxidative Phosphorylation and the ETC, Chapter 26: Formation of Glycogen, Chapter 28: Gluconeogenesis, Chapter 30: Oxidation of Fatty Acids, Chapter 34: Integration of Carbohydrate and Lipid Metabolism, Chapter 36: Fate of Amino Acids Nitrogen: Urea Cycle.

    Figures

    Grey, Kindred, Figure 5.8 Process of lipolysis. 2021. https://archive.org/details/5.6_20210924. CC BY 4.0. Added red blood cells by Lucas Helle from the Noun Project.

    Grey, Kindred, Figure 5.9 Overview of LCFA transport into the mitochondria and β-oxidation. 2021. https://archive.org/details/5.7_20210924_202109. CC BY 4.0.

    Grey, Kindred, Figure 5.10 Regulation of β-oxidation. 2021. https://archive.org/details/5.8_20210924. CC BY 4.0.

    Grey, Kindred, Figure 5.11 Overview of ketone body formation. 2021. https://archive.org/details/5.9-deleted. CC BY 4.0.


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