LIPID CHEMISTRY AND METABOLISM

Contents
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Lipid Chemistry Lipid Classes Lipid Synthesis Metabolism Lipid Disorders Lipid and Lipoprotein Analyses

Lipid Chemistry
Introduction

Composed of mostly carbons-hydrogen (C-H) bonds Classification of Medically Important lipids: 1. Fatty acids 2. Triglycerides 3. Cholesterol 4. Phospholipids Transported by lipoproteins (VLDL, LDL, HDL)

Classes of lipids in General

Classes of Lipids By Function By Structures

torage

Messenger Membrane

Simple

Sterol Compound

Derived Miscellaneous

Fats/Oil

Waxes Phospholipids Glycolipids

Lipid Chemistry
1. Fatty Acids
Linear chains of C-H bonds that terminated with -COOH Classifications: a. unesterified bound to albumin b. esterified constituent of triglycerides/phospholipids g. saturated no double bonds h. monosaturated one double bond i. polyunsaturated double bonds

Lipid Chemistry
1. Fatty Acids
Linear chains of C-H bonds that terminated with -COOH

Lipid Chemistry
2. Triglyceride
a. Contain 3 FA attached to one molecule of glycerol fattyor acids or unsaturated b. Contain saturated FAs unsaturated f=FAs fatty acids c. No charged groups, water insoluble, neutral lipid

Lipid Chemistry
3. Phospholipids
a. Contain 2 FAs attached to one molecule of glycerol b. Third position contain phospholipid head groups c. Amphipathic

Lipid Chemistry
3. Phospholipids
a. Contain 2 FAs attached to one molecule of glycerol b. Third position contain phospholipid head groups c. Amphipathic
Lecithin

Lipid Chemistry
4. Cholesterol
a. Unsaturated steroid alcohol contain four rings b. Amphipathic c. Classifications: i. unesterified free cholesterol (amphipathic) ii. esterified cholesteryl ester (neutral lipid)

Lipid Chemistry
4. Cholesterol
Converted to: a. Bile salts b. Steroid hormones c. Vitamin D and Cell membrane

Lipid Chemistry
Chemical Structure of Lipids

Lipoprotein Structure
COMPONENTS Lipids and proteins Composition: a. Free cholesterol and phospholipids are on the surface b. Triglycerides and cholesteryl esters are in the core regions

Lipoprotein Structure
Characteristics of the Major Human Apolipoproteins
Apolipoprotein Apo A-I Apo A-II Major LPP Location HDL HDL Function LCAT activator, ABCA1 lipid acceptor inactivates LCAT LDL receptor ligand Remnant receptor ligand LPL cofactor LPL inhibitor LDL receptor Ligand plasminogen inhibitor

Apo A-IV
Apo B-100 Apo B-48

Chylos, VLDL, HDL

LDL, VLDL Chylos

Apo C-I
Apo C-II Apo C-III Apo E Apo(a)

Chylos, VLDL, HDL

Chylos, VLDL, HDL Chylos, VLDL, HDL VLDL, HDL Lp(a)

Lipoprotein Structure
MAJOR TYPES
1. 2. 3. 4. Chylomicrons VLDL LDL HDL

Lipoprotein Structure
Characteristics of the Major Human Lipoproteins
Characteristics Density (g/mL) Diameter (nm) Total lipid (%) Triglyceride (%) Cholesterol (%) Major Protein Chylo. <0.93 80-1,200 98 84 7 Apo B-48 VLDL 0.93-1.006 30-80 89-96 44-60 16-22 Apo B-100 LDL 1.019-1.063 18-30 77 11 62 Apo B-100 HDL 1.063-1.21 5-12 50 3 19 Apo A-1

Lipoprotein Structure
MAJOR TYPES 1. Chylomicrons Largest and least dense Produced in the intestine Delivery of dietary lipids to hepatic and peripheral cells

Tube of turbid plasma left overnight in a refrigerator at 4OC

Lipoprotein Structure
MAJOR TYPES 2. Very Low Density Lipoproteins Pre-- lipoprotein Produced in the Liver Transfer triglycerides from the liver to peripheral tissue
Tube of turbid plasma left overnight in a refrigerator at 4OC

Lipoprotein Structure
MAJOR TYPES 3. Low Density Lipoproteins (LDL) -lipoprotein or bad cholesterol Formed from lypolysis of VLDL to IDL then to LDL Transfer dietery cholesterol to peripheral tissues

Lipoprotein Structure
MAJOR TYPES 4. High Density Lipoproteins (HDL) -LPP or good cholesterol Produced in the Liver and the Intestine Transfer cholesterol from peripheral cells back to the liver

Lipoprotein Structure
MINOR TYPES 5. Lipoprotein(a) LDL lipoprotein like particle Confers increased risk for premature coronary heart disease and stroke.

Lipoprotein Structure
MAJOR TYPES
1. 2. 3. 4. Chylomicrons VLDL LDL HDL

Lipoprotein Structure
Adult reference ranges for Lipids

Analyte
Total cholesterol HDL cholesterol LDL cholesterol Triglyceride

Reference Range
140-200 mg/dL 40-75 mg/dL 50-130 mg/dL 60-150 mg/dL

Conversion Factor (mmol/L) 0.026

0.011

Overview of Lipid Metabolism

Dietary lipid

Digestion (bile)

Fatty acid + monoglyceride

Absorption

Triglyceride

Chylomicrons

Transport

Liver

Adipose tissues

Skeletal muscle

Ketone bodies Formation

Ketone bodies, also known as ketones, are water-soluble compounds that are produced as by-products of fatty acids oxidation.The The three endogenous ketone bodies are Acetoacetic acid Acetone, Beta-hydroxybutyric acid. Production of these compounds is called ketogenesis. Ketone bodies are synthesized from the Acetyl CoA molecules produced from the -oxidation of fatty acid Glycolysis. Instead of entering the citric acid cycle, some acetyl-CoA is converted to ketone bodies in the liver mitochondria.

Ketone bodies Formation

Ketone bodies are synthesized from acetyl-CoA in liver mitochondria by a short pathway. Step 1: Condensation of two molecules of acetyl-CoA forming acetoacetyl CoA which is catalyzed by the enzyme thiolase. Step2: The acetoacetyl-CoA accepts another acetyl group from acetyl-CoA to form -hydroxy-hydroxymethylglutaryl-CoA (HMG-CoA). The HMG-CoA has two fates: 1.) To be used in cholesterol synthesis or to be converted to another ketone bodies. 2.) The HMG-CoA can undergo cleavage forming acetoacetate and acetyl CoA. Acetoacetate can be reduced to other ketone bodies: hydroxybutyrate and acetone.

Ketone bodies Formation

Step 3: Ketone bodies are transported to other tissues such as brain, muscle and heart where they are converted back to acetyl-CoA to serve as source of energy.
Normally, the brain uses only glucose for energy, but during starvation and high-fat/low carbohydrate diet, the glucose level becomes low. In this condition, ketone bodies can become the main energy source for the brain.
When excess ketone bodies accumulate in the blood, the condition is called ketonemia. This condition decreases the blood pH to acidic levels which could lead to a state called ketoacidosis. T The accumulation of the ketone bodies in the blood which lead to ketonemia and ketoacidosis is generally referred to ketosis. This condition happens most often in untreated Type I diabetes mellitus. A diabetic person has

Metabolic Fate of Ketone Bodies

Ketone bodies are transported from the liver to other tissues such as brain, muscle and heart. The acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce energy via the citric acid cycle. Acetone cannot be converted back to acetyl-CoA, so it is excreted in the urine or exhaled because of its characteristic high vapor pressure. Therefore, acetone is responsible for the characteristic "fruity" odor of the breath of persons in ketoacidosis.

Comparison of Fatty Acid Catabolism and Anabolism

Fatty Acid Catabolism Occurs in mitochondrial matrix Acetyl CoA product Malonyl CoA not involved Biotin not required Oxidative process Requires NAD and FAD Produce ATP Form thioesters with CoA-SH Fatty Acid Anabolism Occurs in the cytoplasm Acetyl CoA - precursor Malonyl CoA source of 2 carbon Biotin required Reductive process Requires NADPH Require ATP Form thioesters with acyl carrier proteins (ACP-SH)

No ordered aggregate of enzymes -hydroxyacyl intermediates have Lconfiguration

With ordered multienzyme complex -hydroxyacyl intermediates have D-configuration

Steps in the biosynthesis of fatty acid

Fatty Acid Anabolism

Fatty acids are synthesized from acetyl CoA. The major source of acetyl CoA is the carbohydrates. Therefore excess intake of carbohydrate can be converted to fats. Acetyl CoA is needed in the synthesis of fatty acid and fatty acid is needed in the synthesis of triglyceride which is the storage form of lipids in the body. This complex process of biosynthesis of fats is referred to as lipogenesis. The reductive synthesis of fatty acids is a cytoplasmic process carried out by a multienzyme complex called the acyl carrier protein (ACP). The reduction-oxidation steps require nicotinamide adenine dinucleotide phosphate (NADPH). There are series of steps: ACP Formation, Condensation, Hydrogemation, Dehydration, and hydrogenation.

Steps in fatty acid biosynthesis

Acp Complex Formation Step 1: Transfer of acetyl group to acyl carrier protein (ACP) with no energy input. The reaction is catalyzed by acetyltransferase and malonyl CoA. .

Step 2: Malonyl CoA is added to the ACP which is catalyzed by malonyltransferase and malonyl ACP is formed..

Steps in fatty acid Biosynthesis

Elongation Chain Step 3: Acetyl group is transferred to the malonyl group with the release of carbon dioxide which is catalyzed by -ketoacyl-synthase and Aceto acetyl-ACP is formed.

Steps in fatty acid Biosynthesis

Step 4: Keto group is reduced to a hydroxyl group by the beta-ketoacyl reductase activity to form

Beta-hydroxybutyryl-ACP

Steps in fatty acid Biosynthesis

Step 5: Beta-hydroxybutyryl-ACP is dehydrated to form a trans- monounsaturated fatty acyl group catalyzed by -hydroxyacyl dehydratase in the form of crotonyl-ACP and oxidized NADP and water.

Step 6: Double bond is reduced by NADPH, yielding a saturated fatty acyl group (Butyryl ACP) two carbons longer than the initial one. It is catalyzed by enoyl-reductase.

Regulation of Fatty Acid Metabolism.

Fatty acid metabolism is regulated by the action of hormone, feedback inhibition and feed-forward activation. The free fatty acids from the adipose tissue are used as energy when insulin level is low. Insulin controls the storage and release of fatty acids in and out of the adipose tissue. When there is low insulin level and high glucagon level, the fatty acids will be released from the adipose tissue. Then it will be converted into ketone bodies in the liver. Therefore, fatty acid oxidation and ketone body synthesis is activated by glucagon.

Metabolic Fate of Fatty Acid

Fatty acids are stored in the form of triglyceride primarily in adipose tissue. Triglycerides must be hydrolyzed to release the fatty acids which are oxidized to acetyl CoA for energy. Fatty acids can also be converted to ketone bodies which can be used as source of energy for extrahepatic tissues. They also attach to a phosphate group to form the phospholipidsthat composed the cell membranes.Fatty acids are used for the biosynthesis of bioactive molecules such as arachidonic acid and eicosanoids.Cholesterol, steroids and steroid hormones are all derived from fatty acids.

ANABOLISM OF CHOLESTEROL

Cholesterol is widely distributed in the body because of its various roles. It is a biosynthetic precursor of bile acids, vitamin D and steroid hormones. Cholesterol is abundant in the tissue of the brain and nervous system where it contributes to the functioning of synapses' which allow nerves to communicate with each other. Exogenous cholesterol is derived in the diet while endogenous are those synthesized by the body. Cholesterol is produced in the liver and stored in the gallbladder. Cholesterol biosynthesis involved five major steps:

Cholesterol biosynthesis involved five major steps:

1. Acetoacetyl-CoA is converted to 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) which is catalyzed by HMG-CoA synthase.

Steps in biosynthesis of Cholesterol

2. HMG-CoA is converted to mevalonate which is catalyzed by HMG-CoA reductase

3. Mevalonate is converted to isopentenyl pyrophosphate (IPP) with the release of CO2.

4. IPP is converted to squalene.

5. Squalene is converted to cholesterol.

Fate of Cholesterol

Cholesterol can be stored in the gall bladder or transported to the cell membranes where it can be used to synthesize or repair the membranes. Stored cholesterol in the gallbladder can be concentrated and lead to the formation of gall stones. Since the body synthesizes enough cholesterol, excess endogenous cholesterol may builds up in the walls of arteries and form hard structures called plaques. The hardening of the arteries is known as atherosclerosis

Cholesterol can be recycled back to the liver, therefore only a small amount is excreted. The cholesterol that is excreted is first converted to the water soluble bile acids or bile salts. Cholesterol that is not excreted can be used in the synthesis of various classes of steroid hormones.

There are five groups of steroid hormones synthesized from cholesterol which perform various metabolic functions:
Steroid hormones Glucocorticoid Metabolic Function Stimulation of gluconeogenesis Enhance the expression of enzymes involved in gluconeogenesis Mobilization of amino acids from extrahepatic tissues Inhibition of glucose uptake in muscle and adipose tissue Stimulation of fat breakdown in adipose tissue

Mineralocorticoids

Aldosterone acts on the kidneys to provide active reabsorption of sodium and an associated passive reabsorption of water, as well as the active secretion of potassium Inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function Increase hepatic production of binding proteins Precursors to other steroids

Androgens

Estrogen Progestogens

Steroidogenesis is the process of steroid hormone production in living organisms. This process requires several oxidative enzymes located in both mitochondria and endoplasmic reticulum.The biosynthetic pathway for different steroid hormones is depicted in Figure 13.7

Anabolism of Complex and derived lipid

Complex lipids include the glycerolipids, for which glycerol is the backbone, and sphingolipids, which are built on a sphingosine backbone.

The phospholipids, which include both glycerophospholipids and sphingomyelins, are crucial components of membrane structure.

The biosynthetic precursor of glycerolipids is phosphatidic acid. Phosphatidic acid is derived from the phosphorylation of glycerol to form glycerol-3-phosphate which is catalyzed by glycerokinase. It is also synthesized from dihydroxyacetone phosphate (DHAP) which can be reduced to glycerol-3-phosphate by glycerol-3-phosphate dehydrogenase. Another way is the addition of first acyl chain to the DHAP catalyzed by acyltransferase. It is followed by reduction of the backbone keto group by acyldihydroxyacetone phosphate reductase, using NADPH as the reductant. Then the phosphatidic acid is converted directly to glycerolipids which is catalyzed by phosphatidate cytidyltransferase.

Sphingolipid Biosynthesis

Sphingolipids are present in myelin sheath that insulates nerve axons. The initial reaction, which involves condensation of serine and palmitoylCoA with release of bicarbonate, is catalyzed by 3-ketosphinganine synthase. Reduction of the ketone product to form sphinganine is catalyzed by 3-ketosphinganine reductase, with NADPH as a reactant. Then sphinganine is acylated to form Nacyl sphinganine, which is then desaturated to form ceramide. Ceramide is the building block for all other sphingolipids. (Figure 13.16)

Eicosanoid Biosynthesis

Eicosanoids are cyclopentanoic acids derived from the fatty acid which is the arachidonic acid. They include prostaglandins, thromboxanes, prostacyclins,and leukotrienes. Eicosanoids are not stored within cells, but are synthesized whenever the body needs them. Usually theyare release in the body during inflammation.

Eicosanoid Biosynthesis

Arachidonic acid which is the precursor of eicosanoidsis derived from the catabolism of phospholipids. Step 1- The release of the precursor fatty acids from the membrane phospholipids which is catalyzed by phospholipase. Step 2- Then prostaglandin H (PGH) synthase catalyzed the conversion of arachidonic acid to prostaglandin. Prostaglandin is the precursor of prostacyclin and thromboxane. Step 3- Arachidonic acid can also be converted to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is catalyzed by lipoxygenase. 5hydroperoxy-eicosatetraenoic acid (5HPETE) is the precursor of leukotrienes.

Prostaglandinisoriginally shown to be synthesized in the prostate gland. One of the important function of prostaglandin is the contraction and relaxation of smooth muscle tissue. Prostaglandins are autocrine or paracrine hormones which exert effect on the immediate vicinity of the site of their secretion.

Prostacyclin is produced in endothelial cells from prostaglandinby the action of the enzyme prostacyclin synthase. (Figure 13.17) Prostacyclin inhibits platelet activation thus preventing the formation of the platelet plug which is involved in blood clot formation.

Thromboxaneisproduced by activated platelets from prostaglandin by the action of the enzyme thromboxane synthase. It act as vasoconstrictorand it facilitate platelet aggregation. (Figure 13.17)

Leukotriene was first found in leukocytes. It is produced in the body from arachidonic acid by the activity of the enzyme 5lipoxygenase.(Figure 13.17) It triggers contractions in the smooth muscles lining the trachea and their overproduction is a major cause of inflammation in asthma and allergic rhinitis.

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Lipid Catabolism