BCHEM 202: Lipid Metabolism

• This module covers lipid metabolism taught in the BCHEM 202 course, worth 3 credit hours.

Learning Objectives

• Understand lipid digestion processes and lipoprotein roles in lipid transport in the bloodstream.
• Describe beta-oxidation steps in fatty acids and their usage for energy production.
• Explain the key enzymes and regulatory pathways in fatty acid synthesis.

Introduction to Fatty Acids

• Fatty acids function as building blocks for phospholipids and glycolipids.
• They target proteins to membranes.
• Fatty acids are a high-energy fuel source.
• Fatty acid derivatives act as hormones and intracellular messengers.

Lipid Metabolism

• Lipid metabolism includes lipogenesis, lipolysis, β-oxidation, ketogenesis and cholesterol synthesis.

Oxidation and Reduction

• Oxidation is adding oxygen or removing hydrogen from a substance, involving electron loss.
• Reduction is adding hydrogen or removing oxygen, the opposite of oxidation.
• Oxidation requires a corresponding reduction reaction.

Reactions

• Hydration is a chemical reaction where a substance combines with water.
• Dehydration involves eliminating a water molecule from a reactant.
• Bond cleavage (bond fission) splits chemical bonds, cleaving a molecule into fragments.
• Condensation combines two molecules, often eliminating water with a catalyst.

Lipogenesis

• Is the synthesis of fatty acids from acetyl CoA, occurring in the cytosol.
• Lipogenesis uses reduced coenzyme NADPH (NADH with a phosphate group) and requires an acyl carrier protein (ACP).

Malonyl CoA Formation

• In lipogenesis, acetyl CoA combines with bicarbonate to form malonyl CoA.
• ATP hydrolysis provides the energy for this process.

Acetyl and Malonyl ACP

• Acetyl CoA and malonyl CoA combine with acyl carrier protein (ACP) to form acetyl-ACP and malonyl-ACP.

Condensation and Reduction in Fatty Acid Synthesis

• Condensation by a synthase combines acetyl-ACP with malonyl-ACP to form acetoacetyl-ACP (4C), releasing CO₂ in reaction 1.
• Reduction converts a ketone to an alcohol using NADPH in reaction 2.

Dehydration and Reduction in Fatty Acid Synthesis

• Dehydration forms a trans double bond in reaction 3.
• Reduction converts the double bond to a single bond using NADPH in reaction 4.

Lipogenesis Cycle Repetition

• Malonyl-ACP combines with four-carbon butyryl-ACP to form six-carbon hexanoyl-ACP.
• The carbon chain lengthens by two carbons in each cycle.

Lipogenesis Cycle Completion

• Fatty acid synthesis completes when palmitoyl-ACP reacts with water, yielding palmitate (C16) and free ACP.

Lipolysis

• Is a metabolic process where triacylglycerols (TAGs) break down via hydrolysis into glycerol and free fatty acids (FFAs).

Body Fat as Energy Source

• Adipose tissue is comprised of fat cells called adipocytes.
• A typical 70 kg person stores 135,000 kcal as fat, 24,000 kcal as protein, 720 kcal as glycogen, and 80 kcal as blood glucose.
• About 85% of total body energy is available from stored fats.

Digestion of Triacylglycerols

• Bile salts break fat globules into micelles in the small intestine.
• Pancreatic lipases hydrolyze ester bonds, forming monoacylglycerols and fatty acids that recombine in the intestinal lining.
• Lipoproteins transport triacylglycerols to cells of the heart, muscle, and adipose tissues.
• Brain and red blood cells cannot use fatty acids; glucose and glycogen are the only energy source for the brain and red blood cells.

Triacylglycerol Digestion

• Dietary triacylglycerols must be broken down for absorption.
• Bile salts act as detergents to solubilize triacylglycerols.

Fat Mobilization

• Fat mobilization breaks down triacylglycerols in adipose tissue into fatty acids and glycerol.
• Hormones glucagon and epinephrine trigger the process.
• Fatty acids are initially hydrolyzed from C1 or C3 of the fat.
• The reaction is Triacylglycerols + 3H₂O → Glycerol + 3 Fatty acids.

Glycerol Metabolism

• Enzymes in the liver convert glycerol to dihydroxyacetone phosphate in two steps.
• First, glycerol is phosphorylated using ATP to yield glycerol-3-phosphate.
• Second, the hydroxyl group is oxidized to yield dihydroxyacetone phosphate.
• The overall reaction is : Glycerol + ATP + NAD⁺ → Dihydroxyacetone phosphate + ADP + NADH + H⁺.

Fatty Acid Activation

• Fatty acid activation allows fatty acids in the cytosol to enter the mitochondria for oxidation.
• It combines a fatty acid with CoA, yielding fatty acyl CoA that combines with carnitine.

Transport into Mitochondrial Matrix

• Carnitine carries activated long-chain fatty acids into the mitochondrial matrix.
• The first acyl group is transferred from cytosolic coenzyme A to carnitine by acyltransferase-1.
• Acylcarnitine is transported to the mitochondrial matrix and carnitine shuttle is inhibited by malonyl CoA.

Fatty Acid Activation and Transport

• Fatty acyl-carnitine transports the fatty acid into the matrix.
• The fatty acid acyl group recombines with CoA for oxidation.
• Fatty acid activation regulates degradation and synthesis.

Beta Oxidation

• Is reaction 1, removes H atoms from the alpha and beta carbons.
• Forms a trans C=C bond called trans-enoyl CoA.
• Reduces FAD to FADH₂.

Beta Oxidation Reaction 2

• Involves hydration which is adding water across the trans C=C bond.
• Forms a hydroxyl group (-OH) on the beta carbon.

Beta Oxidation Reaction 3

• A second oxidation occurs to oxidize the hydroxyl group
• A keto group forms on the beta carbon.

Beta Oxidation Reaction 4

• Acetyl CoA is cleaved by splitting the bond between the alpha and beta carbons.
• A shortened fatty acyl CoA repeats steps 1 - 4, as part of beta-oxidation.

Beta Oxidation of Myristic Acid

• Reaction 1 involves oxidation (dehydrogenation).
• Reaction 2 involves hydration.
• Reaction 3 involves oxidation (dehydrogenation).
• Reaction 4 involves cleavage.

Beta Oxidation of Myristic Acid Continued

• The cycles repeats 6 times
• Produces 7 Acetyl CoA

Cycles of Beta Oxidation

• The length of a fatty acid determines the amount of oxidations.
• Number of Carbons | Acetyl CoA (C/2) | β-Oxidation Cycles (C/2 -1)
• 12 = 6 = 5
• 14 = 7 = 6
• 16 = 8 = 7
• 18 = 9 = 8

-Oxidation and ATP

• 2 ATP are required for activation of a fatty acid.
• Each cycle of oxidation produces 3 ATP from 1 NADH and 2 ATP from 1 FADH₂.
• Acetyl CoA entering the citric acid cycle produces 12 ATP.

ATP for Lauric Acid C12

• Requires -2 ATP for activation
• Occurs 6 Acetyl CoA
• There are 6 acetyl CoA x 12 ATP/acetyl CoA produces 72 ATP.
• Requires 5 Oxidation cycles which is 5 NADH x 3ATP/NADH produces 15 АТР
• And 5 FADH₂ x 2ATP/FADH₂ produces 10 АТР
• Total АТР Produced is 95 АТР

Oxidation of Unsaturated Fatty Acids

• Oxidation of monounsaturated fatty acyl-CoA needs additional reaction performed with the help of enzyme isomerase.
• Double bonds in unsaturated fatty acids are in cis configuration and cannot be acted upon by enoyl-CoA hydratase.
• Enoyl-CoA isomerase repositions the double bond, converting the cis isomer to trans isomer.

Oxidation of Polyunsaturated Fatty Acids

• Requires two additional reactions and a second enzyme, reductase, in addition to isomerase.
• NADPH-dependent 2,4-dienoyl-CoA reductase converts trans-2, cis-4-dienoyl-CoA intermediate to trans-2-enoyl-CoA substrate.

Oxidation of Odd-Chain Fatty Acids

• Odd-carbon fatty acids oxidize same way as even-carbon acids until three-carbon propionyl-CoA results.
• Three reactions involving three enzymes are needed afterwards.
• Propionyl-CoA carboxylated by propionyl-CoA carboxylase (cofactor biotin) creates D stereoisomer methylmalonyl-CoA.
• The reaction to for the carboxybiotin intermediate requires energy from ATP.
• D-methylmalonyl-CoA changes in L-methylmalonyl-CoA by methylmalonyl-CoA epimerase.
• L-methylmalonyl-CoA rearranges into succinyl-CoA, which enters citric acid cycle.
• This is catalyzed by methylmalonyl-CoA mutase, using coenzyme B12 (from vitamin B12 / cobalamin).