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LIPID METABOLISM

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OXIDATION OF LONG-CHAIN FATTY ACIDS

Two Forms of Carrying Fatty Acids:

ACTIVATION OF FATTY ACIDS: Fats are delivered to cells as free fats. They must be activated before they can be burned.

TRANSLOCATION OF FATTY ACYL-CoA THIOESTER: The Acyl-CoA must get into the mitochondrial matrix.

beta-OXIDATION: A four-step process. Called beta-Oxidation because most of the chemistry occurs on the beta-Carbon (beta to the carbonyl) per turn of the cycle.

ENERGETICS OF beta-OXIDATION:

REGULATION OF beta-OXIDATION:

REFSUM'S DISEASE:

CASE STUDY: FAILURE TO TAKE UP LONG CHAIN FATS INTO THE MITOCHONDRIA


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SYNTHESIS OF LONG-CHAIN FATTY ACIDS

ACETYL-CoA CARBOXYLASE. This is the enzyme we use to get Malonyl-CoA for fat-synthesis.

STEPS OF FATTY-ACID SYNTHESIS: Fatty-Acid Synthesis occurs in the cytosol.

FATTY ACID SYNTHASE: A single multi-functional enzyme is used to synthesize fatty acids. It has multiple catalytic domains, similar to the ribosomal complex (A-Site and P-Site) in translation of proteins.

REGULATION OF FATTY ACID SYNTHESIS: Fat synthesis is an anabolic process, so it is promoted by dephosphorylation.

HUMAN BREAST MILK:

DESATURATION OF LONG-CHAINS FATTY ACIDS:


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METABOLISM OF GLYCEROPHOSPHOLIPIDS

PHOSPHATIDATE <====> DIACYLGLYCEROL:

GLYCEROPHOSPHOLIPID STRUCTURE:

SYNTHESIS OF PHOSPHATIDATE:

SYNTHESIS OF CDP-ACTIVATED HEAD-GROUPS: This is used for PHOSPHATIDYLCHOLINE AND PHOSPHATIDYLETHANOLAMINE

PHOSPHATIDYLETHANOLAMINE ------> PHOSPHATIDYLCHOLINE: An alternative way to get phosphatidylcholine, directly from phosphatidylethanolamine.

REGULATION OF CHOLINE SYNTHESIS: We have two pathways for making phosphatidylcholine. Which one to use depends essentially on mass action.

BASE-EXCHANGE: SYNTHESIS OF PHOSPHATIDYLSERINE.

SYNTHESIS OF PHOSPHATIDYLINOSITOL AND PHOSPHATIDYLGLYCEROL: Use CDP-Activated Diacylglycerol to synthesize these two phospholipids. Here, instead of activating the polar head-group, we activate the diacylglycerol moiety.

CARDIOLIPIN: Also is produced from CDP-Diacylglycerol. Found in mitochondrial membranes only.

Cellular location of phospholipid synthesis:

SUMMARY OF PHOSPHOLIPID SYNTHESIS
Glycerophospholipid Pathway of Synthesis
Phosphatidylcholine 1) From CDP-Choline + Diacylglycerol

2) Via Methylation, from Phosphatidylethanolamine

Phosphatidylethanolamine From CDP-Ethanolamine + Diacylglycerol
Phosphatidylinositol From CDP-Diacylglycerol + Inositol
Phosphatidylglycerol From CDP-Diacylglycerol + Glycerol
Phosphatidylserine Via Base-Exchange, from Phosphatidylethanolamine
Cardiolipin From CDP-Diacylglycerol + Cardiolipin derivative
Phosphatidylinositol-4,5,-biphosphate via a Kinase, from Phosphatidylinositol

PHOSPHOLIPASES: There are three different phospholipases, each with specific activity

SYNTHESIS OF DIPALMITOYLPHOSPHATIDYLCHOLINE (DPPC)


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METABOLISM OF SPHINGOLIPIDS

CERAMIDE: Ceramide is the base of structure of all Sphingolipids.

STRUCTURE OF SPHINGOLIPIDS: Except for sphingomyelin, all sphingolipids have a ceramide backbone, with at least one sugar group attached to it.

FUNCTION OF SPHINGOLIPIDS: Because sphingolipids are glycosylated, there are almost always found on the exoplasmic side of the membrane. That means that they are synthesized on the luminal side of the ER membrane, and they are exported to the exoplasmic side of the plasma membrane.

SYNTHESIS OF SPHINGOMYELIN: Sphingomyelin is simply a ceramide with Choline as its polar head-group.

GLUCOSYLCERAMIDE: Ceramide with one glucose group attached.

GANGLIOSIDES: A class of sphingolipids that contains Sialic Acid (an acidic sugar) as one of its sugar residues. The sugar residues are connected to the polar alcohol of ceramide, and they are usually highly branched.

DEGRADATION OF GLUCOSYLCERAMIDE (i.e. GANGLIOSIDES):

GAUCHER'S DISEASE: Partial or complete loss of Glucocerebrosidase (beta-Glucosidase) activity, resulting in the accumulation of Glucosylceramide in the lysosomes, and then in the cell and ECM.


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METABOLISM OF CHOLESTEROL

BIOSYNTHESIS OF CHOLESTEROL:

SYNTHESIS OF KETONE BODIES: Ketone bodies originate from an intermediate of Cholesterol synthesis, 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA)

WHERE IS CHOLESTEROL SYNTHESIZED:

REGULATION OF CHOLESTEROL BIOSYNTHESIS: HMG-CoA-Reductase is the target enzyme!

FORMATION OF CHOLESTEROL ESTERS: This is how we STORE cholesterol.

CYTOCHROME-P450: The common enzyme that is involved in HYDROXYLATION OF CHOLESTEROL. It is called a "mixed-function oxidase"

SYNTHESIS OF STEROID HORMONES:

OTHER IMPORTANT ISOPRENE DERIVATIVES:


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PULMONARY SURFACTANT

COMPOSITION OF SURFACTANT:

L/S RATIO: Around the 32nd - 36th weeks, synthesis of phosphatidylcholine in the infant increases markedly. This is in indication that pulmonary surfactant is being synthesized.

Respiratory Distress Syndrome (RDS): Any breathing problem in the newborn or adult.

Type-II Alveolar Cells: They produce surfactant.

Surfactant turns over very rapidly. Both Type-II lung cells and macrophages participate in the uptake of surfactant.

There are pharmacological agents available to emulate surfactant in the neonate until his/her lungs are mature enough to breathe on their own.

SURFACE TENSION: Surfactant decreases the surface tension in lungs, and therefore surface pressure. This prevents the coalescence of alveolar walls with each other.


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DIGESTION, ABSORPTION, AND TRANSPORT OF LIPIDS

SYNTHESIS OF BILE ACIDS: Bile acids are synthesized from cholesterol in the liver, stored in the gall bladder, and secreted through the common bile duct.

CHOLATE: The major bile acid. It has three OH-groups in the rings, and a carboxylic acid at the end of the side chain.

DEOXYCHOLATE: The minor bile acid. It is missing one of the OH-groups (at the 12 carbon)

SYNTHESIS OF BILE SALTS: Bile salts are just bile acids with the carboxylate function modified by adding an amine to it via an amide linkage. Bile Salts are even more polar than their corresponding acids.

SECONDARY BILE ACIDS AND SALTS: Bacteria in the intestine can modify bile salts by removing the 7alpha-carbon, to create a series of "secondary" bile salts.

BILE-ACID FUNCTIONS:

COMPOSITION OF HUMAN BILE: It contains pure cholesterol, phospholipid, and bile acids.

GALLSTONES: If the amount of cholesterol in bile acids get above 15%, then gallstones may result. If cholesterol gets too high, then they may crystallize out of solution in the gall bladder, where bile is concentrated tenfold before secretion.

ENTEROHEPATIC CIRCULATION: The circulation of bile between the intestine and liver.

ABSORPTION and DIGESTION of DIETARY FATS: Order of events that happens in digesting fats

GENERAL STRUCTURE OF LIPOPROTEINS:

CATEGORIES OF LIPOPROTEINS: Lipoproteins are often categorized according to density, which is dependent upon the relative amount of protein present. The more protein present, the higher the density of the lipoprotein.

KRINGLE DOMAINS: Lipoproteins have multiple kringle domains -- (a supersecondary protein-structure motif).

FUNCTION AND TRANSPORT OF LIPOPROTEINS:

SUMMARY: Two ways of getting cholesterol from the tissues back to the liver -- Chylomicron-Remnants and Reverse-Transport HDL-Particles.

LIPOPROTEIN ENZYMES: Following are the enzymes that breakdown lipoproteins.


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LIPIDS AS METABOLIC FUELS

FUEL RESERVES: Triacylglycerols are the major form of fuel reserve, found in adipose tissue. In muscle, fuel is stored primarily as protein. Liver stores some as protein, fat, and glycogen.

SYNTHESIS OF TRIACYLGLYCEROL: Triacylglycerol can be synthesized in multiple ways.

REGULATION OF TRIACYLGLYCEROL SYNTHESIS: INSULIN turns it on.

MOBILIZATION OF TRIACYLGLYCEROLS (LIPOLYSIS) -- GETTING RID OF THE FAT

REGULATION OF LIPOLYSIS: Lipolysis generally is stimulated by catabolic hormones and inhibited by insulin.

BROWN ADIPOSE TISSUE: Most adipose is white. This is an exception.

KETONE BODIES: Ketone Bodies are a fuel. They are made primarily in the liver.

SYNTHESIS OF KETONE BODIES: Synthesis occurs in the mitochondria only. HMG-CoA ------> Acetoacetate + Acetyl CoA.

UTILIZATION OF KETONE BODIES: How we use them as energy

KETONE BODY UTILIZATION: Tissue distribution. A low Insulin:Glucagon ratio promotes the production of ketone-bodies. That is, Glucagon promotes it.

KETOACIDOSIS IN DIABETES: This is the buildup of ketone bodies with Diabetes, due to low Insulin and hence excessive GLucagon.


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ATHEROSCLEROSIS

ANATOMY OF A VESSEL: The layers, from innermost to outermost

DEGREES OF DAMAGE: Whether or not damage to an artery is reversible depends on how deep the damage is. It is only when there is damage to the endothelial, intimal, and medial layers that extreme damage may occur

CAUSES OF VASCULAR INJURY: Oxidized LDL-Cholesterol accumulating in the blood is the most common cause, but not the only cause.

LESIONS OF ATHEROSCLEROSIS: Different levels of injury

TYPES OF APO-PROTEINS:

THREE CELLULAR RECEPTORS INVOLVED IN LIPOPROTEIN METABOLISM: All of the following receptors recognize various Apo-Proteins and take up lipoprotein-particles into the cell via receptor-mediated endocytosis.

EXPORT OF CHOLESTEROL BY LIVER:

VASCULAR INJURY -- HOW IT CAUSES A PLAQUE:

STEPS IN ENDOCYTOSIS OF LDL-RECEPTOR: Various diseases are associated with defects in these steps.

FAMILIAL HYPERCHOLESTEROLEMIA (FH): Caused by a defect in the LDL-Receptor, such that it can no longer take up LDL-particles so cholesterol build up in the blood.

NEWBORNS: Have maximal Apo-B receptors and low LDL-Cholesterol. Adults are in the middle, and people with familial hypercholesterolemia have way too much LDL-Cholesterol.

HIGH-DENSITY LIPOPROTEINS (HDL) -- WHY ARE THEY GOOD?

ESTROGEN: Estrogen increases the levels of HDL. Hence pre-menopausal women are at lower rish for CHD than men. Other things (exercise and loss of body fat) also increase HDL.


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Copyright 1999, Scott Goodman, all rights reserved