LIPID-METABOLISM
Digestion and Absorption of Lipids
Dietary lipids contain 98% triacylglycerols (TAGs), which include fats and oils.
Salivary enzymes in the mouth have no effect on lipids (TAGs), which are water insoluble.
In the stomach, most TAGs change physically to small globules or droplets called chyme.
Gastric lipase enzymes hydrolyze TAG ester bonds in the stomach.
About 10% of TAGs are hydrolyzed in the stomach.
Chyme enters into the small intestine and is emulsified with bile salts.
Pancreatic lipase hydrolyzes ester bond linkages between fatty acid units and glycerol in the small intestine.
Fatty acids, monoacylglycerols, and bile salts combine into small droplets called micelles.
Micelles are small enough to be absorbed through intestinal cell membranes.
In the intestinal cells, monoacylglycerols and free fatty acids are repackaged into TAGs.
These new TAGs combine with membrane lipids and water-soluble proteins to form chylomicrons.
Chylomicrons transport TAGs from intestinal cells to the bloodstream.
Triacylglycerol Storage and Mobilization
TAGs are stored in specialized cells called adipocytes found in adipose tissue.
Adipose tissue serves as an insulator against heat loss and protection against physical shock.
Several hormones trigger the hydrolysis of TAGs, releasing glycerol and fatty acids into the bloodstream.
Triacylglycerol energy reserves are the body's major source of stored energy.
Glycerol is taken to the liver or kidney and converted to dihydroxyacetone phosphate.
Fatty acids are oxidized to produce energy or repacked and stored as lipids.
Hydrolysis of TAGs
TAG hydrolysis is triggered by hormones and involves the activation of hormone-sensitive lipase (HSL).
Glycerol and fatty acids are released into the bloodstream.
On average, 10% of TAGs are replaced every day.
Oxidation of Fatty Acids
Fatty acids must be activated by binding to coenzyme A.
Fatty acids are transported to the mitochondrial matrix.
Fatty acids are oxidized to produce acetyl CoA, FADH2, and NADH.
The beta-oxidation pathway repeatedly cleaves two carbon units from the acyl CoA molecule.
Four steps of the beta-oxidation pathway: dehydrogenation, hydration, second dehydrogenation, and thiolysis.
Oxidation of unsaturated fatty acids requires additional steps compared to saturated fatty acids.
Fatty acid oxidation produces a net of 120 ATP molecules by oxidation of stearic acid.
Stearic acid produces 2.5 times more energy than glucose.
Ketone Bodies and Ketogenesis
Acetyl CoA formed from the beta-oxidation pathway is further processed by the citric acid cycle.
Adequate balance in carbohydrate and lipid metabolism is required.
Lipid-carbohydrate metabolism can be disrupted by high-fat, low-carbohydrate diets, diabetic conditions, and prolonged fasting conditions.
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Ketone Bodies
Under low supply of oxaloacetate, the acetyl CoA will be in excess (increased concentration).
As a consequence, the excess acetyl CoA is converted to ketone bodies.
Ketogenesis
Involves the synthesis of ketone bodies from acetyl CoA.
Primary site for this process is in the liver mitochondria.
The three ketone bodies produced are:
Acetoacetate
β-hydroxybutyrate
Acetone
Steps Involved in Ketogenesis
Step 1: First Condensation
Two acetyl CoA molecules combine to produce acetoacetyl CoA, a reversal of the last step of the β-oxidation pathway.
Step 2: Second Condensation
Acetoacetyl CoA reacts with a third acetyl CoA and water to produce 3-hydroxyl-3-methylglutaryl CoA (HMG-CoA) and CoA-SH
Step 3: Chain Cleavage
HMG-CoA is cleaved to acetyl CoA and acetoacetate.
Step 4: Hydrogenation
Acetoacetate is reduced to β-hydroxybutyrate.
Summary of Ketogenesis
Biosynthesis of Fatty Acids: Lipogenesis
Lipogenesis vs. Fatty Acid Degradation
The Citrate-Malate Shuttle System
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ACP Complex Formation
All intermediates in fatty acid synthesis are linked to carrier proteins (ACP-SH).
ACP-SH can be regarded as a "giant CoA molecule".
Chain Elongation
Four reactions constitute the first step of the chain elongation process:
Step 1: Condensation – where acetyl ACP and malonyl ACP condense together to form acetoacetyl ACP.
Step 2: Hydrogenation – where the keto group of the acetoacetyl complex is reduced to alcohol by NADPH.
Step 3: Dehydration – where water is removed from alcohol to form an alkene.
Step 4: Hydrogenation – where hydrogen is added to alkene 3 to form saturated butyryl ACP from NADPH.
Unsaturated Fatty Acid Biosynthesis
To produce a double bond, molecular O2 is needed.
In humans and animals, enzymes can only introduce double bonds between C4 and C5 and between C9 and C10.
Consequence – Essential unsaturated fatty acids linoleic (C18 with C9 and C12 double bonds) and linolenic (C18 with C9, C12, and C15 double bonds) cannot be biosynthesized.
Relationships Between Lipogenesis and Citric Acid Cycle Intermediates
The last four intermediates of the citric acid cycle bear a relationship with each other.
The intermediate C4 carbon chains of lipogenesis bear a relationship with each other.
Important Contrasts Between Citric Acid Cycle and Lipogenesis Intermediates
The citric acid intermediates involve C4 diacids, and the lipogenesis intermediates involve C4 monoacids.
The order in which the various acid derivative types are encountered in lipogenesis is the reverse of the order in which they are encountered in the citric acid cycle.
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Fate of Fatty – Acid – Generated Acetyl CoA
Further channeled in different routes:
Further processed to obtain ATP
Ketone body formation
Storage in the form of TAGs
Used as starting material for the production of lipids and other fatty acids
Example: Cholesterol biosynthesis occurs when the body is in an acetyl-CoA-rich state.
Cholesterol
Necessary component of cell membrane.
Precursor for bile salts, sex hormones, and adrenal hormone.
Relationships Between Lipid and Carbohydrate Metabolism
Acetyl CoA is the primary link between lipid and carbohydrate metabolism pathways.
Acetyl CoA is the starting material for the biosynthesis of fatty acids, cholesterol, and ketone bodies.
Acetyl CoA is the degradation product for glucose, glycerol, and fatty acids.
B Vitamins and Lipid Metabolism
Structurally modified B vitamins function as coenzymes in lipid metabolism.
B vitamins that participate in various pathways of lipid metabolism include:
Niacin (as NAD+, NADH, and NADPH)
Riboflavin (as FAD)
Panthothenic acid (as CoA, acetyl CoA, and ACP)
Biotin