BCM 223: Metabolism of Macromolecules, University Notes

Digestion, Absorption, Transportation of Lipids

The major form of energy: triacylglycerol/fat/triglycerides

• 90% of dietary lipid
• 6 times more energy/weight of glycogen
• water insoluble
• emulsified by bile salts/bile acids in small intestine
• digestion at lipid/water interface

Digestion of lipids: Bile acids have detergent character and they help to solubilize and absorb lipids in the gut, and secreted as glycine or taurine conjugates into the gallbladder for storage, from gallbladder secreted into small intestine, where lipid digestion and absorption mainly takes place.

Lipid absorption by enterocytes: They are absorbed as micelles with bile salts and (lecithin) Or lipid-protein complexes.

Transport of Lipids: They are transported as Lipoproteins, in form of lipid/protein complexes, lipoproteins. The protein wraps around a lipid droplet and thereby makes it soluble.

Lipid Metabolism Overview

Lipid metabolism refers to the process of how the body breaks down fats (lipids) for energy and storage. This process involves multiple steps and enzymes that are tightly regulated. Here are some of the key steps involved in lipid metabolism:

Biosynthesis of Triacylglycerols (Lipogenesis)

Most of the fatty acids synthesized or ingested by an organism have one of two fates:

• incorporation into triacylglycerols for the storage of metabolic energy or
• incorporation into the phospholipid components of membranes.

During rapid growth, synthesis of new membranes requires the production of membrane phospholipids; when an organism has a plentiful food supply but is not actively growing, it shunts most of its fatty acids into storage fats.

Triacylglycerols and glycerophospholipids such as phosphatidylethanolamine share two precursors, fatty acyl-CoA and L- glycerol 3-phosphate, and several biosynthetic steps. The vast majority of the glycerol 3-phosphate is derived from the glycolytic intermediate dihydroxyacetone phosphate (DHAP) by the action of the cytosolic NAD linked glycerol 3-phosphate dehydrogenase; in liver and kidney, a small amount of glycerol 3- phosphate is also formed from glycerol by the action of glycerol kinase. The other precursors of triacylglycerols are fatty acyl-CoAs, formed from fatty acids by acyl-CoA synthetases, the same enzymes responsible for the activation of fatty acids for ß oxidation.

Steps in Triacylglycerol Biosynthesis

Steps:

• The first stage in the biosynthesis of triacylglycerols is acylation of the two free hydroxyl groups of L-glycerol 3-phosphate by two molecules of fatty acyl-CoA to yield diacylglycerol 3-phosphate, more commonly called phosphatidic acid, or phosphatidate (see fig.). Phosphatidic acid is present in only trace amounts in cells but is a central intermediate in lipid biosynthesis; it can be converted either to a triacylglycerol or to a glycerophospholipid.
• In the pathway to triacylglycerols, phosphatidic acid is hydrolyzed by phosphatidic acid phosphatase (also called lipin) to form a 1,2-diacylglycerol (Fig. 5).
• Diacylglycerols are then converted to triacylglycerols by transesterification with a third fatty acyl-CoA.Glucose

1 glycolysis H2COH H2COH C=O O - H2C-O-P-O- HCOH - H2COH Dihydroxyacetone 5- Glycerol phosphate NADH + H+ ATP glycerol 3-phosphate dehydrogenase glycerol kinase NAD+ H2COH HO-C-H H2C-O- -0- L-Glycerol 3-phosphate R1-COO- CoA-SH ATP acyl-CoA synthetase O AMP + PP¡ S-CoA acyl transferase CoA-SH R2-COO- CoA-SH ATP acyl-CoA synthetase R2-c=0 AMP + PP¡ S-CoA acyl transferase CoA-SH 0=0 O H2C-O- C-R1 R2-C-O-C-H -O- H2C-O- 0=2-0 Phosphatidic acid Figure 1- Biosynthesis of phosphatidic acid. 0=2-0 ADPO H2C-0-C-R1 O II HC-0-C-R2 Phosphatidic acid O IL H2C-O-P-O- 0- phosphatidic acid phosphatase (lipin) O attachment of head group (serine, choline, ethanolamine, etc.) H2C-O-C-R1 O O ǁ HC-O-C-R2 H2C-O-C-R1 | H2C-OH O 1,2-Diacylglycerol HC-0-C-R2 O II I O Head group CoA-SH O Glycerophospholipid H2C-0-C-R1 O HC-0-C-R2 II O H2C-0-C-R3 Triacylglycerol Fig. 2- Phosphatidic acid in lipid biosynthesis. Phosphatidic acid is the precursor of both triacylglycerols and glycerophospholipids. O=0 R3-C acyl transferase H2C-O-P-O S-CoA

Lipolysis Process

Lipolysis: This is the process by which stored fat in adipose tissue is broken down into free fatty acids and glycerol. This process is regulated by the hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). Fatty acids are fuel molecules. They are stored as triacylglycerols (also called neutral fats or triglycerides), which are uncharged esters of fatty acids with glycerol. Fatty acids mobilized from triacylglycerols (lipolysis) are oxidized to meet the energy needs of a cell or organism.

Fatty acid degradation and synthesis are relatively simple processes that are essentially the reverse of each other. The process of degradation converts an aliphatic compound into a set of activated acetyl units (acetyl CoA) that can be processed by the citric acid cycle. The repetitive four-step process by which fatty acids are converted into acetyl-CoA is called ß oxidation.

Triacylglycerols are highly concentrated stores of metabolic energy because they are reduced and anhydrous. Most of the triacylglycerols in animals are stored in adipose tissue. The yield from the complete oxidation of fatty acids is about 9 kcal g-1 (38 kJ g-1), in contrast with about 4 kcal g-1 (17 kJ g-1) for carbohydrates and proteins.

Stages of Lipid Energy Mobilization

Peripheral tissues gain access to the lipid energy reserves stored in adipose tissue through three stages of processing.

• First, the lipids must be mobilized, in this process, TAGs are degraded to fatty acids and glycerol, which are released from the adipose tissue and transported to the energy- requiring tissues. The hydrolysis of triacylglycerols by lipases, an event referred to as lipolysis. The lipase of adipose tissue is activated on treatment of these cells with the hormones: epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone. In adipose cells, these hormones trigger receptors that activate adenylate cyclase. The increased level of cyclic AMP then stimulates protein kinase A, which activates the lipases by phosphorylating them. Thus, epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone induce lipolysis. In contrast, insulin inhibits lipolysis.
• Second, the released fatty acids are not soluble in blood plasma, and so, on release, serum albumin binds the fatty acids and serves as a carrier. By these means, free fatty acids are made accessible as a fuel in other tissues and at these tissues, the fatty acids must be activated and transported into mitochondria for degradation.
• Third, the fatty acids are broken down in a step-by-step fashion into acetyl COA, which is then processed in the citric acid cycle.R1

HỌC -H H2C. Triacylglyceride -3 H20 Lipase 3 H+ CHOH HO- Č-H CH20H Glycerol R.1 Rs Fatty acids Figure 3- lipolysis (release of FAs from TAGs in adipose tissues)

Lipid Oxidation and Energy Production

Lipid oxidation: Once released from adipose tissue, free fatty acids are transported to the mitochondria of cells, where they undergo beta-oxidation to produce acetyl-CoA, which is used by the cell for energy production.

Stages of Fatty Acid Oxidation

oxidation of fatty acids takes place in three stages.

• In the first stage-ß oxidation-fatty acids undergo oxidative removal of successive two- carbon units in the form of acetyl- CoA, starting from the carboxyl end of the fatty acyl chain.
• In the second stage of fatty acid oxidation, the acetyl groups of acetyl- CoA are oxidized to CO2 in the citric acid cycle, which also takes place in the mitochondrial matrix. Acetyl-CoA derived from fatty acids thus enters a final common pathway of oxidation with the acetyl-CoA derived from glucose via glycolysis and pyruvate oxidation. The first two stages of fatty acid oxidation produce the reduced electron carriers NADH and FADH2.
• Electrons derived from the oxidations of stages 1 and 2 pass to 02 via the mitochondrial respiratory chain, providing the energy for ATP synthesis by oxidative phosphorylation. The energy released by fatty acid oxidation is thus conserved as ATP.Stage 1

Stage 2 CH3 CH2 ß Oxidation CH2 8 Acetyl-CoA `CH2 CH2 `CH2 CH2 1 `CH2 CH2 CH2 wwww Citric acid cycle CH2 CH2 CH2 CH2 64e- 16CO2 CH2 C=0 -C 28e- Stage 3 NADH, FADH2 e- 2H+ + 1/202 Respiratory (electron-transfer) chain H2O ADP + Pi ATP Figure 13- Stages of fatty acid oxidation.

Ketone Bodies

Ketogenesis Process

Ketogenesis: In times of low carbohydrate availability, excess fatty acids are converted into ketone bodies, such as acetoacetate, -hydroxybutyrate, and acetone. This process occurs in the liver and is regulated by enzymes such as ß-ketoacyl-CoA transferase and ß-hydroxybutyrate dehydrogenase.

Ketone bodies are produced in the liver when the supply of carbohydrates is low and the body needs to use fat as its primary fuel source. This process, called ketogenesis, involves the conversion of fatty acids to ketone bodies, specifically acetoacetate, ß-hydroxybutyrate, and acetone.

In humans and most other mammals, acetyl-CoA formed in the liver during oxidation of fatty acids can either enter the citric acid cycle or undergo conversion to the "ketone bodies," acetone, acetoacetate, and D-B-hydroxybutyrate, for export to other tissues.CH3-C-CH3 Ö Acetone O CH3-C-CH2-C = O Acetoacetate OH CH3-C-CH2-C 1 H / O D-B-Hydroxybutyrate

Acetone, produced in smaller quantities than the other ketone bodies, is exhaled. Acetoacetate and D-B-hydroxybutyrate are transported by the blood to tissues other than the liver (extrahepatic tissues), where they are converted to acetyl-CoA and oxidized in the citric acid cycle, providing much of the energy required by tissues such as skeletal and heart muscle and the renal cortex.

The brain, which preferentially uses glucose as fuel, can adapt to the use of acetoacetate and D-B-hydroxybutyrate under starvation conditions, when glucose is unavailable. In this situation, the brain cannot use fatty acids as fuel, because they do not cross the blood brain barrier. The production and export of ketone bodies from the liver to extrahepatic tissues allows continued oxidation of fatty acids in the liver when acetyl-CoA is not being oxidized in the citric acid cycle.

Enzymatic Reactions in Ketogenesis

Ketogenesis: The excess acetyl-CoA is converted into ketone bodies by a series of enzymatic reactions in the liver mitochondria. The initial step involves the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA, which is then converted to acetoacetate by the enzyme B-ketoacyl-CoA transferase (also known as thiophorase or succinyl-CoA:3-ketoacid CoA transferase). Acetoacetate can then be reduced to ß-hydroxybutyrate by the enzyme ß- hydroxybutyrate dehydrogenase.

Release of Ketone Bodies

Release of ketone bodies: Once produced, the ketone bodies are released into the bloodstream and transported to other tissues, such as the brain and skeletal muscle, where they can be used as an alternative fuel source.

Overall, the formation of ketone bodies provides an important mechanism for the body to maintain energy homeostasis during times of low carbohydrate availability.