chem 45 biochemistry: stoker chapter 25 lipid metabolism

Chapter 25

Lipid Metabolism

Chapter 25

Table of Contents

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25.1Digestion and Absorption of Lipids

25.2Triacylglycerol Storage and Mobilization

25.3 Glycerol Metabolism

25.4 Oxidation of Fatty Acids

25.5 ATP Production from Fatty Acid Oxidation

25.6 Ketone Bodies

25.7 Biosynthesis of Fatty Acids: Lipogenesis

25.8 Relationship Between Lipogenesis and Citric Acid Cycle Intermediates

25.9 Fate of Fatty-Acid Generated Acetyl CoA

25.10 Relationships Between Lipid and Carbohydrate Metabolism

25.11B Vitamins and Lipid Metabolism

Digestion and Absorption of Lipids

Section 25.1


• Dietary Lipids: 98% triacylglycerols (TAGs): Fats and oils• Salivary enzymes (water soluble) in the mouth have no effect on lipids (TAGs) which

are water insoluble• In Stomach: most, not all, of TAGs change physically to small globules or droplets --

called chyme which floats above other material:


Section 25.1


• Lipid digestion starts in the stomach:– Gastric lipase hydrolyzes ester bonds -- 2 fatty acids and one

monoacylglycerol --About 10% of TAGS are hydrolyzed• High fat foods stay in stomach for longer time -- high fat meal gives

you a feeling of being full for longer time

• Chyme enters into small intestine and is emulsified with bile salts• Pancreatic lipase hydrolyzes ester bonds to form fatty acids and glycerol

– Normally 2 out of 3 fatty acids are hydrolyzed• Fatty acids, monoacyglycerols and bile salts make small droplets: called micelles --

hydrophobic chain in the interior• Micelles consist of monoacyglycerols and free fatty acids:

– Small enough to absorb through intestinal cells


Section 25.1


• In the intestinal cells monoacylglycerols and free fatty acids are repackaged to form TAGs

• These new TAGs combine with membrane lipids (phospholipids and cholesterol) and lipoproteins to form chylomicrons

• Chylomicrons transport TAGs from intestinal cells to the bloodstream though the lymphatic system

• From the lymphatics the fats flow through the thoracic duct into the bloodstream and then to the liver

• In the liver some of the fats are changed to phospholipids, so the blood leaving the liver contains both fats and phospholipids

• These phospholipids, such as sphingomyelin and lecithin are necessary for the formation of nerve and brain tissues

• Lecithins are also involved in the transport of fat to the tissues

• Cephalin, another phospholipid, is involved in the normal blood clotting

• From the liver, some fat goes to the cells through the bloodstream


Section 25.1


• In the bloodstream TAGs are completely hydrolyzed by lipase enzymes

• Fatty acids and glycerol are absorbed by the cell and are either broken down to the acetyl Co-A for energy or repacked to store as lipids

• The fat in excess of what the cells need is stored in specialized cells called adipocytes (the largest cell in the body) in the adipose tissue– Located primarily beneath the skin especially in abdominal region and

vital organs– Adipose tissue also serves as a protection against the heat loss and

mechanical shock

• Triacylglycerol energy reserves (fat reserves) are the human body’s major source of stored energy: – Energy reserves associated with protein, glycogen, and glucose are

small to very small when compared to fat reserves

Section 25.3

Glycerol Metabolism


• Taken to liver or kidney by blood -- converted to dihydroxyacetone phosphate

• Recall that DHAP is part of the glycolysis pathway• This compound may be converted to lactic acid or to glycogen in the liver or

muscle tissue or to pyruvic acid, which enters the TCA cycle

• Thus, the glycerol part of a fat is metabolized through the carbohydrate sequence

Section 25.4

Oxidation of Fatty Acids


• There are three parts to the process by which fatty acids are broken down to obtain energy.

1. Activation of the fatty acid by binding to Coenzyme-A - product is called acyl Co-A

2. Transport of acyl Co-A to mitochondrial matrix

3. Repeated oxidation (fatty acid spiral) to produce acetyl Co-A, FADH2 and NADH

• Note: the difference between the designations acyl CoA and acetyl CoA is that acyl refers to a random-length fatty acid carbon chain that is covalently bonded to coenzyme A, whereas acetyl refers to a two-carbon chain covalently bonded to coenzyme A.

Section 25.4



Fatty Acid Activation and Transport• Activation of fatty acid takes place

in outer mitochondrial membrane• FA reacts with coenzyme A at the

expense of 2 moles ATP to produce high energy acyl CoA

• acyl CoA is too large to pass through the inner mitochondrial membrane to the mitochondrial matrix, where the enzymes needed for fatty acid oxidation are located; it is converted to acyl carnitine

• a shuttle mechanism involving the molecule carnitine effects the transport of acyl CoA into the mitochondrial matrix.

Section 25.4



Reactions of the Beta-Oxidation Pathway

• Repeated oxidation of fatty acid, cycling through a series of four reactions to produce acetyl CoA, FADH2, and NADH.

• the oxidation of fatty acids follow the β-oxidation theory that involves the oxidation of the 2nd carbon atom from the acid end of the saturated fatty acid molecule, the β-carbon atom.

• in this process, β-oxidation removes two carbon atoms at a time from the fatty acid chain; i.e., an 18-carbon fatty acid is oxidized to a 16-carbon fatty acid, then to 14-carbon fatty acid, and so on until the oxidation process is complete

• the process is also known as fatty acid spiral because the fatty acid goes through the cycle again and again until it is finally degraded to acetyl CoA.

• the fatty acid spiral is a repetitive series of four reactions (dehydrogenation, hydration, dehydrogenation, release of acetyl CoA) in which each sequence produces acetyl CoA, FADH2, NADH, and an acyl CoA that is shorter than the previous acyl CoA by two carbon atoms.

Section 25.4



Four Steps of the Beta-Oxidation Pathway• Step 1: Oxidation (dehydrogenation):

– FAD is the oxidizing agent, and a FADH2

molecule is a product.• Step 2: Hydration:

– A molecule of water is added across the trans double bond, producing a secondary alcohol at the beta-carbon position

• Step 3: Oxidation (dehydrogenation): – The beta-hydroxyl group is oxidized to a

keto functional group with NAD+ serving as the oxidizing agent.

• Step 4: Chain Cleavage: – The fatty acid chain is broken between

the alpha and beta carbons by reaction with a coenzyme A molecule.

– The result is an acetyl CoA molecule and a new acyl CoA molecule that is shorter by two carbon atoms than its predecessor

Section 25.4


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Section 25.4



• The acetyl CoA produced enters the citric acid cycle and the new molecule of active fatty acid (active acyl CoA) goes through the same sequence again, each time losing two carbon atoms until the entire molecule has been oxidized

• The sequence presupposes the presence of fatty acids containing an even number of carbon atoms, a condition usually encountered in nature

• If fatty acid containing odd number of carbon atoms are oxidized they follow the same steps except that the final products are acetyl CoA and propionyl CoA. The propionyl CoA is changed in a series of steps to succinyl CoA, which enters the citric acid cycle, as does the acetyl CoA; these reactions require the presence of cobamide and biotin

• The unsaturated fatty acids are metabolized slowly; they must first be reduced by some of the dehydrogenases found in the cells, then they can follow the fatty acid spiral for oxidation

• The FADH2 and the NADH + H+ enter the respiratory chain

Section 25.5

ATP Production From Fatty Acid Oxidation


Fatty Acid vs. Glucose Oxidation: A Comparison• the oxidation of 1 g of fat produces

more than twice as much energy as the oxidation of 1 g of carbohydrate

-oxidation of 18:0 fatty acid (stearic acid) produces a net of 120 ATP molecules

• 2 ATP molecules are needed for activation of fatty acids so net ATP produced is 120 molecules

• 1 Glucose molecule (6 carbon atoms) produces 30 ATP molecules

• Three molecules of glucose (18 Carbon atoms) produce 90 ATP

• Stearic acid produces 2.5 time more energy than glucose

Section 25.6

Ketone Bodies


• Ordinarily, most of the acetyl CoA produced from the fatty acid spiral is further processed through the Krebs cycle.

• Therefore an adequate balance in carbohydrate and lipid metabolism is required

• The first step of the Krebs cycle involves the reaction between oxaloacetate and acetyl CoA; Sufficient oxaloacetate must be present for the acetyl CoA to react with.

• Oxaloacetate concentration depends on pyruvate produced from glycolysis; pyruvate can be converted to oxaloacetate by pyruvate carboxylase.

• Certain body conditions upset the lipid-carbohydrate balance required for the acetyl CoA generated by fatty acids to be processed by the TCA cycle: (under these conditions, the problem of inadequate oxaloacetate arises) – Dietary intakes high in fat and low in carbohydrates– Diabetic conditions -- glucose not used properly– Prolonged fasting conditions

• When oxaloacetate supplies are too low for all acetyl CoA to be processed through the TCA cycle, ketogenesis takes place where excess acetyl CoA is converted to ketone bodies

Section 25.6

Ketone Bodies


• Synthesis of ketone bodies from acetyl CoA is primarily in liver mitochondria

• the three ketone bodies produced are: acetoacetic acid, β-hydroxybutyric acid, and acetone; they are carried by the blood to the muscles and tissues where they are converted back to acetoacetyl CoA and then oxidized normally.

• during diabetes, however, the production of ketone bodies by the liver exceeds the ability of the muscles and tissues to oxidize them so that they accumulate in the blood

• ketosis is the overall accumulation of ketone bodies in the blood (ketonemia) and in the urine (ketonuria)

Section 25.6

Ketone Bodies


• during ketosis acetone may be detected on the patient’s breath because it is a volatile compound and is easily excreted through the lungs

• ketosis may occur with diabetes mellitus, in starvation, or severe liver damage, or on a diet high in fats and low in carbohydrates

• during diabetes mellitus, the body is unable to oxidize carbohydrates and instead oxidizes fats, leading to an accumulation of ketone bodies in the blood and the urine; the ketone bodies are acidic and tend to decrease the pH of the blood leading to acidosis which may lead to a fatal coma.

• during acidosis, an increased amount of water intake is needed to eliminate the products of metabolism. Unless the water intake of a diabetic is increased, dehydration will occur. Dehydration of diabetics may also be caused by polyuria due to an increased amount of glucose in the urine.

• likewise, during prolonged starvation or on a high-fat, low-carbohydrate diet, the body tends to burn fat instead of carbohydrates, leading to ketosis and acidosis.

• in severe liver damage, the liver cannot store glycogen in the required amounts so that the carbohydrates are not available for the normal oxidation of fats, leading to ketosis

•

Section 25.7

Biosynthesis of Fatty Acids: Lipogenesis


Lipogenesis vs. Fatty Acid Degradation

Lipogenesis Degradation of a fatty acids

Takes place in cell cytosol Takes place in mitochondrial matrix

A multi-enzyme complex called fatty acid synthase catalyzes reactions

Enzymes are not complexed and the steps are independent

Intermediates bonded to acyl carrier protein (ACP)

The carrier for fatty acid spiral is CoA

Depends upon reducing agent NADPH

Dependent upon oxidizing agents FAD and NAD+

Section 25.7



The Citrate–Malate Shuttle System

• Acetyl CoA is the starting material for lipogenesis.

• Acetyl CoA needed for lipogenesis is generated in mitochondria, therefore it must first be transported to the cytosol.

• Citrate-malate transport system helps transport acetyl CoA to cytosol indirectly.

Section 25.7



• Cytoplasmic acetyl CoA is converted to malonyl CoA in a carboxylation reaction that involves CO2 and ATP.

• The reaction occurs only when cellular ATP levels are high catalyzed by acetyl CoA carboxylase complex, which requires both Mn2+ and biotin for its activity.

• ACP (Acyl Carrier Protein) Complex Formation:

– All intermediates in fatty acid synthesis are linked to carrier proteins (ACP-SH)

– ACP-SH can be regarded as a “giant CoA-SH molecule”

Section 25.7



Chain Elongation

• Four reactions constitute the steps of chain elongation process– Condensation: Acetyl-ACP and

malonyl-ACP condense together to form acetoacetyl-ACP

– Hydrogenation: The keto group of the acetoacetyl complex is reduced to alcohol by NADPH

– Dehydration: Water is removed from alcohol to form an alkene

– Hydrogenation: Hydrogen is added to alkene 3 to form saturated butyryl ACP from NADPH

Section 25.7



Section 25.7



Chain Elongation

• In the first “turn” of the fatty acid biosynthetic pathway, acetyl ACP is converted to butyryl ACP. In the next cycle, the butyryl ACP reacts with another malonyl ACP to produce a 6-carbon acid. Continued cycles produce acids with 8, 10, 12, 14, and 16 carbon atoms

• elongation of the acyl group chain through this procedure, which is tied to the fatty acid synthase complex, stops upon formation of the C16 acyl group (palmitic acid)

Section 25.7



Unsaturated Fatty Acid Biosynthesis and Essential FattyAcids• different enzyme systems and different cellular locations are

required for elongation of the chain beyond C16 and for introduction of double bonds into the acyl group (unsaturated fatty acids)

• production or unsaturated fatty acids (insertion of double bonds) requires oxidation by molecular oxygen (O2), which combines with the hydrogen that is removed to form water

• in humans and animals, enzymes can introduce double bonds only between C4 and C5 and between C9 and C10.

• thus the important unsaturated fatty acids linoleic (C18 with C9 and C12 double bonds) and linolenic (C18 with C9, C12, and C15 double bonds) cannot be biosynthesized.

• They must be obtained from the diet. Plants have the necessary enzymes to synthesize these acids.

Section 25.9

Fate of Fatty-Acid Generated Acetyl CoA


• Acetyl-CoA formed from fatty acids is further channeled in various different routes:– Oxidation in the citric acid cycle: both lipids and

carbohydrates supply acetyl CoA– Ketone body formation: Very important when imbalance

between carbohydrate and lipid metabolism– Fatty acid biosynthesis: the buildup of excess acetyl CoA

when dietary intake exceeds energy needs energy needs leads to accelerated fatty acid biosynthesis

– Cholesterol biosynthesis: It occurs when the body is in an acetyl CoA- rich state

Section 25.9



Cholesterol• Secondary component of cell membrane• Precursor for bile salts, sex hormones and adrenal hormone• Body synthesizes 1.5 - 2.0 g of cholesterol everyday from acetyl CoA units

– Average daily dietary intake is ~ 0.3 g

• Synthesis of cholesterol, a C27 molecule, occur in liver and requires at least 15 acetyl CoAs and involves at least 27 separate enzymatic steps

• once cholesterol has been formed, biosynthetic pathways are available to convert it to each of the five major classes of steroid hormones: progestins, androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as bile salts and vitamin D.

Section 25.9



Overview of fat and sugar synthesis and

breakdown pathways

Section 25.10

Relationships Between Lipid and Carbohydrate Metabolism


• Acetyl Co-A is the primary link between these two metabolic pathways– Acetyl Co-A is the

starting material for the biosynthesis of fatty acids, cholesterol and ketone bodies

– Acetyl CoA is the product of oxidation of glucose, glycerol and fatty acids

Section 25.11

B Vitamins and Carbohydrate Metabolism


• Structurally modified B-vitamins function as coenzymes in lipid metabolism

• 6 B-Vitamins participate in various pathways of lipid metabolism:– Niacin – NAD+ and NADH;

NADP + and NADPH– Riboflavin – as FAD,

FADH2

– Pantothenic acid - as CoA– Biotin

• Without these B-vitamins body would be unable to utilize lipids as energy sources.

chem 45 biochemistry: stoker chapter 25 lipid metabolism

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