Fat Metabolism Notes

Fat Metabolism

Fatty Acid Synthesis
Key Substrates:

  • Acetyl CoA: Primary building block derived from glucose and amino acid metabolism; transported from mitochondria to the cytoplasm for fatty acid synthesis.

  • ATP, Biotin, HCO3, Mn+2: Essential for Acetyl CoA carboxylase (ACC) activity, which synthesizes Malonyl CoA. Requires ATP for energy, Biotin as a cofactor, HCO3 for carboxylation, and Mn+2 as a metal ion activator.

  • NADPH: Reducing agent supplied mainly by the pentose phosphate pathway and malic enzyme; crucial for the reduction steps in fatty acid synthesis.

De Novo Cholesterol Synthesis

  • All carbon atoms are NOT derived from citrate. This statement is false. Cholesterol is synthesized from Acetyl CoA, which can be derived from various sources including citrate, but not exclusively.

DHAP in TAG Synthesis

  • DHAP (Dihydroxyacetone phosphate) can be used for the synthesis of Triacylglycerols (TAG). This statement is true. DHAP, an intermediate in glycolysis, can be converted to glycerol-3-phosphate, a precursor for TAG synthesis.

Thioesterase

  • Thioesterase is the enzyme responsible for releasing the newly synthesized fatty acid (typically palmitate) from the fatty acid synthase complex. Also known as palmitoyl-CoA thioesterase.

Fatty Acid Synthase

  • A multi-enzyme complex: A large, complex enzyme that catalyzes the synthesis of fatty acids from acetyl-CoA and malonyl-CoA.

  • It is a homodimer; each monomer has 7 protein domains: The functional enzyme consists of two identical subunits, each containing all the necessary enzymatic activities.

  • The acyl carrier protein (ACP) domain is where the nascent fatty acid attaches until it reaches 16 carbons, at which point it is hydrolyzed by Thioesterase (TE). ACP contains a phosphopantetheine group derived from vitamin B5 (pantothenic acid), which tethers the growing fatty acid chain to the enzyme complex.

Fatty Acid Synthase Domains

  • KS (Beta-ketoacyl synthase): Contains a cysteine residue to which nascent fatty acid chains are covalently attached. Condenses the growing fatty acid chain with malonyl-CoA.

  • AT (Acyl transferase): Transfers acetyl groups from acetyl-CoA to the ACP domain and malonyl groups from malonyl-CoA to the ACP domain.

  • DH (Dehydratase): Removes water from β-hydroxyacyl-ACP, forming a double bond.

  • ER (Enoyl reductase): Reduces the double bond formed by DH, using NADPH as a reducing agent.

  • KR (Ketoacyl reductase): Reduces a β-ketoacyl group to a β-hydroxyacyl group, using NADPH.

  • ACP (Acyl carrier protein): It has a pantothenic acid residue, which is the attachment site for incoming malonyl CoA. Delivers acyl groups to different enzymatic sites within the fatty acid synthase complex.

  • TE (Thioesterase): Cleaves the completed fatty acid (palmitate) from the ACP domain.

Acetyl CoA Carboxylase

  • Acetyl CoA carboxylase is the key regulatory enzyme in fatty acid synthesis. Catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, the committed step in fatty acid synthesis. Activated by insulin and citrate; inhibited by glucagon and palmitoyl-CoA.

Elongation of Fatty Acids

  • The Smooth Endoplasmic Reticulum (SER) elongates saturated and unsaturated fatty acyl-CoAs by two carbons, using Malonyl CoA. Elongation systems in the ER can add carbons to palmitate to produce longer-chain fatty acids (e.g., stearate).

Lipogenesis and Fructose

  • Lipogenesis increases when fructose is ingested instead of glucose because fructose bypasses the phosphofructokinase control point in glycolysis, flooding the pathway. Fructose is metabolized primarily in the liver, where it is rapidly converted to fatty acid precursors.

Fructose Metabolism

  • Fructose unregulated entry into glycolysis provides more substrates for fatty acid synthesis. This leads to increased production of acetyl-CoA, the building block for fatty acids.

  • The pancreas lacks a GLUT5 transporter; therefore, fructose does not significantly increase insulin release. Unlike glucose, fructose does not stimulate insulin secretion to the same extent.

Apo C II

  • Apo C II is an activator of Lipoprotein lipase. A protein component of VLDL and chylomicrons that activates lipoprotein lipase in capillaries, facilitating the breakdown of triglycerides.

Thiokinase

  • Thiokinase (Acyl-CoA Synthase): Catalyzes the activation of fatty acids by attaching them to CoA, forming fatty acyl-CoA. This is a necessary step for fatty acid metabolism, including both synthesis and degradation.

NADPH Source

  • The pentose phosphate pathway serves as the primary source of NADPH required for fatty acid synthesis. Specifically, the reactions catalyzed by glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in the pentose phosphate pathway generate NADPH.

Malonyl-CoA

  • Malonyl-CoA is a direct inhibitor of CAT1 (Carnitine-acyltransferase I). CAT1 is located in the outer mitochondrial membrane and is essential for transporting fatty acids into the mitochondria for beta-oxidation. Inhibition by malonyl-CoA prevents the simultaneous synthesis and breakdown of fatty acids.

Functional Ketone Bodies

  • Acetoacetate

  • Beta-hydroxybutyrate

  • Acetone (produced by spontaneous decarboxylation of acetoacetate, although not directly used as a fuel).

HMG CoA Reductase

  • HMG CoA reductase is the key regulatory enzyme of cholesterol synthesis. Catalyzes the conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol synthesis. Target of statin drugs, which inhibit cholesterol synthesis.

Palmitate Oxidation

  • The yield of ATP (and/or GTP) from the oxidation of 1 molecule of palmitate (C16:0) to CO2 and H2O is 106.

ATP Yield Calculation:

  • Each cycle of B-oxidation yields 1 FADH2 (= 1.5 ATP) and 1 NADH (= 2.5 ATP) plus 1 Acetyl CoA, totaling 4 ATP per cycle.

  • Palmitate (C16) undergoes 7 cycles (n/2 - 1) of B-oxidation, yielding 28 ATP.

  • The first cycle costs 2 ATP to form fatty acyl CoA, resulting in a net of 26 ATP from B-oxidation.

  • 8 Acetyl CoA (n/2) yield an additional 80 ATP and/or GTP.

  • Total yield: 106 ATP and/or GTP per molecule of palmitate.

Ketone Body Catabolism

  • Occurs in extra-hepatic mitochondria: Tissues such as the brain, heart, and muscle can use ketone bodies as fuel, especially during prolonged fasting or starvation.

Enzymes Involved

  • D-ß-hydroxybutyrate dehydrogenase: Converts β-hydroxybutyrate to acetoacetate.

  • Acetoacetate:succinyl CoA transferase (Thiophorase): Transfers CoA from succinyl CoA to acetoacetate, forming acetoacetyl-CoA. Absent in the liver.

  • Thiolase: Cleaves acetoacetyl-CoA into two molecules of acetyl-CoA.

Process

  1. D-B-hydroxybutyrate is converted to Acetoacetate.

  2. Acetoacetate is converted to Acetoacetyl CoA

  3. Acetoacetyl CoA is converted to 2 Acetyl CoA via Thiolase.

  • Ketone bodies act as an alternative fuel to glucose. Important during prolonged fasting, starvation, or in conditions like uncontrolled diabetes.

  • The liver does not have Thiophorase: The liver produces ketone bodies but cannot utilize them, thus exporting them to other tissues.

Acetoacetate Oxidation

  • The yield of ATP (and/or GTP) from the oxidation of 1 molecule of acetoacetate to CO2 and H2O is 19.

ATP Yield Calculation:

  • Each molecule of acetoacetate yields 2 acetyl CoA, which yield 20 ATP and / or GTP in the citric acid cycle.

  • The formation of acetoacetyl CoA from acetoacetate uses succinyl CoA to yield succinate; this normally would provide 1 molecule of ATP or GTP in the citric acid cycle.

B-hydroxybutyrate Oxidation

  • The yield of ATP (and/or GTP) from the oxidation of 1 molecule of B-hydroxybutyrate to CO2 and H2O is 21.5.

ATP Yield Calculation:

  • Each mole of B-hydroxybutyrate yields 1 mole of acetoacetate + 1 NADH, which is equivalent to 2.5 ATP.

  • Oxidation of acetoacetate to CO2 and H2O yields 19 ATP and/or GTP.

Beta Oxidation
Process Overview:

  • Occurs in four reactions involving the β-carbon (carbon 3) that results in shortening the fatty acid chain by two carbons at the carboxylate end. Key pathway for fatty acid degradation in the mitochondria.

Steps:

  1. Oxidation (producing FADH2): Acyl-CoA dehydrogenase introduces a double bond between the α and β carbons.

  2. Hydration: Enoyl-CoA hydratase adds water across the double bond, forming β-hydroxyacyl-CoA.

  3. Second oxidation (producing NADH): β-hydroxyacyl-CoA dehydrogenase oxidizes the β-hydroxyacyl-CoA to β-ketoacyl-CoA.

  4. Thiolytic cleavage (releasing a molecule of acetyl CoA): Thiolase cleaves β-ketoacyl-CoA, releasing acetyl-CoA and a fatty acyl-CoA shortened by two carbons.

  • Each step is catalyzed by enzymes with chain-length specificity. Ensures efficient processing of different fatty acid lengths.

  • These four steps are repeated for saturated fatty acids of even-numbered carbon chains (n/2) - 1 times (where n is the number of carbons), each cycle producing one acetyl CoA plus one NADH and one FADH2.

Visual Representation:

  • Acyl CoA is converted to Enoyl CoA.

  • Enoyl CoA is converted to ß Hydroxy acyl CoA.

  • ß Hydroxy acyl CoA is converted to ß Keto acyl CoA.

  • ß Keto acyl CoA is converted to Acetyl CoA and Acyl CoA (shorter by 2 carbons).

ATP Production from Acetyl CoA:

  • Each acetyl CoA gives 10 ATP by electron transport chain (ETC). Acetyl CoA enters the citric acid cycle, where it is completely oxidized to CO*2, generating NADH and FADH2 that fuel the ETC.

Energy Yield from Fatty Acid Oxidation:

  • High energy yield. Fatty acid oxidation yields more ATP per carbon than glucose oxidation.

  • Example: Oxidation of a 14-carbon fatty acid produces 7 acetyl CoA, 6 NADH, and 6 FADH2. Activation of the fatty acid requires 2 ATP.

Ketosis

  • The rate of ketone body synthesis exceeds their utilization. Occurs when there is a shortage of glucose, forcing the body to use fat as the primary energy source.

Location of Synthesis and Utilization:

  • Ketone bodies are synthesized in the liver and utilized in peripheral tissues. This division of labor allows the liver to spare glucose for other tissues while providing energy to the body.

  • This is due to the absence of thiophorase in the liver. The liver's inability to utilize ketone bodies ensures that they are available for other tissues.

Lipoprotein Lipase

  • Lipoprotein lipase's role is in the metabolism of lipoproteins (specifics not detailed in provided text, but results in 3 Fatty Acids and Glycerol). Lipoprotein lipase hydrolyzes triglycerides in lipoproteins (chylomicrons and VLDL), releasing fatty acids that can be taken up by tissues. The glycerol is then transported to the liver for further metabolism.

LDL vs. HDL
LDL (Bad Cholesterol):

  • Can be oxidized. Oxidation is often mediated by free radicals and reactive oxygen species.

  • Oxidized LDL is not recognized by the LDL receptor. This prevents the normal clearance of LDL from the circulation.

  • Uptake of oxidized LDL by macrophages leads to foam cell formation and infiltration of the arterial lining, contributing to atherogenesis. Foam cells are lipid-laden macrophages that accumulate in the artery walls, leading to plaque formation.

HDL (Good Cholesterol):

  • The main transport of cholesterol from peripheral tissues to the liver (reverse cholesterol transport) for excretion via bile. HDL removes cholesterol from foam cells and other peripheral tissues, reducing plaque formation.

  • The concentration of HDL in serum is inversely related to the incidence of myocardial infarction. Higher HDL levels are associated with a lower risk of heart disease.