Lecture 3 Flashcards
What are lipids? 5 Common classes of lipids?
Heterogeneous group of water insoluble (hydrophobic) organic molecules
Fatty acids, triacylglycerol, glycerophospholipid, steroid, sphingoglycolipid
Where do lipids begin digestion and are catalyzed by?
Digestion of lipids begin in the stomach and are catalyzed by lipase. Primary target is TAGs
Emulsification of lipids occurs in what part of the small intestine and carried out by what?
Occurs in the duodenum and is carried out by bile salts
Different types of pancreatic enzymes along with what/how they degrade
Pancreatic lipase - TAG (Removes FAs at C1 and C3)
Cholesterol esterase - Cholesterol esters (Hydrolyzed to cholesterol and free FAs)
Phospholipase A2 - Phospholipids (Removes 1 FA from C2 leaving a lysophospholipid)
Lysophospholipase - Phospholipids (Removes the FA at C1 leaving a glycerophosphoryl base)
2 Hormones that control lipid digestion in small intestine and how they do so.
Cholecystokinin - triggers your gallbladder and pancreas to contract so they can deliver bile and enzymes to your duodenum to help break down the food for absorption (Food is held longer in stomach)
Secretin - regulation of gastric acid and stimulates the secretion of bicarbonate
Where is the primary site of lipid absorption of the enterocytes?
The brush border membrane
What is inside a mixed micelle?
Lipids along with bile salts and fat soluble vitamins
What is the activating enzyme of fatty acids? What is the activated form of that fatty acid?
Fatty acyl-CoA synthetase (Thiokinases) activates long-chain fatty acids into fatty acyl-CoA (Activated form)
Chylomicron contain what? What is the relative position of them to one another
Contains TAG and cholesterol ester with TAGs being on the outermost position (of the inside)
What does lipid malabsorption result in?
Causes steatorrhea (Lipid in the feces)
What are chylomicrons surrounded by?
-Phospholipids
-Unesterified cholesterol
-Apolipoprotein
How are particles released from enterocytes and into where?
Released by exocytosis and into the lacteals (lymphatic vessels originating in the villi of the small intestine)
Why do chylomicron particles not pass through blood vessel instead of the lymphatic system?
Chylomicron particles are too large to pass through blood vessels
Where are the dietary lipids used by the tissue?
-TAGs are broken down in capillary beds of skeletal muscle and adipose tissues
-Fatty acids are taken up by muscle cells and adipocytes
-Glycerol is used almost exclusively by the liver to produce G3P to enter glycolysis or gluconeogenesis by oxidation to DHAP
-Remaining chylomicron components are taken up by the liver and hydrolyzed to their component parts
What are the digestive products produced from the small intestine?
Free fatty acids (Short, medium, long-chains)
Cholesterol
2-Monoacylglycerol
Structure of fatty acid
Hydrophobic hydrocarbon chain with terminal hydrophilic carboxyl group
(Amphipathic molecule)
Monocarboxylic acids that typically contain hydrocarbon chains of variable lengths( between 12 and 20 or more)
-Numbered from the carboxylate end
More than 90% of the FAs found in plasma are in the form of what?
Fatty acid esters (primarily TAGs, cholesteryl esters, and phospholipids contained in circulating lipoprotein particles)
What does albumin do?
Albumin (water soluble protein) transport unesterified (free) fatty acids in the circulation
What are saturated and unsaturated fatty acids?
Saturated FA - contain only carbon-carbon single bonds
Unsaturated FA - contain one or more double bonds and can be cis (more common) or trans isomeric forms
Cis Unsaturated FA cause a inflexible kink so they don’t pack as tightly together and have lower melting point (liquid at room temp)
Longer the hydrocarbon chain, higher the melting point
If a fatty acid has more than one double bond, how is it oriented?
They are always spaced at 3 carbon intervals
How to identify Arachidonic acid, 20:4 (5,8,11,14)
Linoleic acid 18:2 ω-6
Arachidonic Acid:
20 Carbons long
4 Double bonds between C5-6, C8-9, C11-12, and C14-15
Linoleic acid:
18 Carbons long
2 Double bonds starting 6 carbons away from the end
Know palmitic acid, linoleic acid, a-linolenic acid, and arachidonic acid
Palmitic acid 16:0 (Structural lipids and TAGs contain primarily fatty acids of at least 16 carbons)
Linoleic acid 18:2 (9,12) (Omega 6) and a-Linolenic acid 18:3 (9,12,15) (Omega 3) - Essential fatty acids (not produced by body)
Arachidonic acid 20:4 (5,8,11,14) - Precursor of prostaglandins
Where does fatty acid synthesis occur in adults?
-Mainly in liver
-Lactating mammary glands
-Adipose tissue (to a lesser extent)
Where does fatty acid synthesis occur and where do the carbons come from?
Occurs in the cytosol and incorporates carbons from acetyl CoA using ATP and NADPH
Synthesized by the repetitive addition of two-carbon units to the growing end of the hydrocarbon chain
How does acetyl-CoA in the mitochondria move to the cytosol for the synthesis of fatty acids to occur?
Acetyl-CoA + Oxaloacetate make citrate and citrate crosses the membrane to the cytosol where it is reconverted to oxaloacetate and acetyl-CoA
2 Fates of Acetyl-CoA in fatty acid synthesis
Conversion into acetyl-ACP (which makes acetyl-synthase) and malonyl-CoA (which makes malonyl-ACP)
Acetyl-Synthase and Malonyl-ACP combine to make Acetoacetyl-ACP and end product is 16 Carbon Palmitate through the enzyme fatty acid synthase
What is the rate-limiting step of fatty acid synthesis?
Conversion of Acetyl-CoA into malonyl-CoA by acetyl-CoA carboxylase
Where can further elongation of palmitate occur and how?
Further elongated by the addition of 2 carbon units in the smooth ER. The 2 carbons come from malonyl-CoA and NADPH supplies the electrons but requires separate enzymes other than FAS (Fatty Acid Synthase)
What do desaturases present in the SER do and how?
They desaturate long-chain fatty acids (adding cis double bonds) by typically inserting the first double bond between carbons 9 and 10 to produce primarily 18:1 (9) and small amounts of 16:1 (9)
From carbon 10 to the omega end of the chain, mammals cannot introduce a double bond*
Structure of TAGs
FA esterified to a molecule of glycerol
Carbon #1 FA is typically saturated
Carbon #2 FA is typically unsaturated
Carbon #3 FA can be either
What is the initial acceptor of FAs during TAG synthesis?
Glycerol phosphate accepts the activated form of FA 3 times to make TAGs
In adipose tissue, TAG is stored as?
Stored in a nearly anhydrous form as fat droplets in the cytosol of cells.
Little TAG is stored in the liver (most are exported, packaged with other lipids and apolipoproteins called VLDL)
Energy produced from the 3 macromolecules
Fats : 9 kcal/gram
Carbohydrates : 4 kcal/gram
Proteins : 4 kcal/gram
What does hormone-sensitive lipase do?
Removes a fatty acid from carbon 1 and or carbon 3 of TAGs
(Additional lipases specific for diacylglycerol or monoacylglycerol remove the remaining fatty acids)
What is B-oxidation?
A major pathway for catabolism of FA through 2 carbon fragments being removed from the Beta carbon of the carboxyl end producing acetyl-CoA, NADH and FADH2 and occurs in the mitochondria
How do long-chain fatty acids go through the inner mitochondrial membrane?
CoA can’t pass through the inner membrane so carnitine is attached and goes through carnitine palmitoyl-transferase II (Carnitine shuttle) where carnitine is then removed and CoA is reattached to make the activated long chain FA (LC Fatty acyl-CoA)
FA shorter than 12 carbons can cross the inner mitochondrial membrane without carnitine
What occurs in B-oxidation of odd chain FA?
Same as even FA until the final 3 carbons are reached (Propionyl CoA) and this is then metabolized to succinyl CoA which can then enter the Kreb cycle directly.
Propionyl CoA can be used to make odd chain FA
Do unsaturated FA provide more or less energy than saturated FA?
They provide less energy then saturated FA since they are less highly reduced
Where do very long chain FA (22 Carbons or longer) undergo preliminary B-oxidation?
In peroxisomes and then the shortened FA link to carnitine to diffuse into the mitochondria for further oxidation
What are the 3 Ketone body names and what mitochondria has the capacity to convert acetyl-CoA derived from FA oxidation into ketone bodies?
Acetoacetate, 3-Hydroxybutyrate, and acetone
Liver mitochondria
Why are ketone bodies made?
Result of excess acetyl-CoA from B-oxidation
High lipid intake and low carbohydrate intake (not enough oxaloacetate)
Starvation (body consumes fats)
Diabetes (problems with carbohydrate catabolism since oxaloacetate comes from carbs)
What is diabetic ketoacidosis and symptom of it?
When the rate of formation of ketone bodies is greater than the rate of their use, their levels begin to rise in the blood (ketonemia) and eventually in the urine (ketonuria) which is frequently seen in uncontrolled type 1 diabetes.
The symptom is a fruity odor of the breath since high amounts of acetone
What are phospholipids?
Polar, ionic compounds composed of alcohol that is attached by a phosphodiester bridge to either diacylglycerol or sphingosine.
They are the predominate lipids of cell membranes
2 Classes of phospholipids?
Glycerophospholipids or phosphoglycerides - have a glycerol backbone with phosphate attached (Major class)
Sphingophospholipids - Contain a sphingosine backbone with phosphate attached
They all contain (or are derivates of) phosphatidic acid (diacylglycerol with a phosphate group on the third carbon)
Phosphate group on the PA can be esterified to another compound containing an alcohol group (serine, ethanolamine, or choline)
Why is sphingomyelin significant? What is its structure?
Is the only significant sphingophospholipid in humans where it is an important constituent of the myelin of nerve fibers.
It is also a major structural lipid in membranes.
Backbone of sphingomyelin is the amino alcohol sphingosine instead of glycerol.
Long chain FA can attach to the amino group of sphingosine through amide linkage to produce a ceramide
Alcohol group at carbon 1 of sphingosine is esterified to phosphorylcholine producing sphingomyelin
What 2 phospholipids are the most abundant in eukaryotic cells?
Phosphatidylethanolamine and phosphatidylcholine
What is the function of phospholipase and what specific site do each enzyme cleave?
They hydrolyze the phosphodiester bonds of phosphoglycerides where A1 cleaves carbon 1, A2 cleaves carbon 2, and C/D cleaves carbon 3 in C->D order.
How is sphingomyelin degraded?
By sphingomyelinase, a lysosomal enzyme that hydrolytically removes phosphorylcholine, leaving a ceramide
What are glycolipids?
Molecules that contain both carbohydrate (attached to ceramide by O-glycosidic bond) and lipid components and don’t have phosphate and found primarily in nerve tissue.
They are derivatives of ceramide in which long-chain FA is attached to the amino alcohol sphingosine to be called glycosphingolipids.
Carbohydrate portion is antigenic and has been identified as a source of blood group antigens and some tumor antigens.
What are examples of neutral and acidic glycosphingolipids?
Neutral: Cerebrosides (ceramide monosaccharides that contain either a molecule of glucose or galactose)
Acidic: Negatively charged provided by N-acetylneuraminic acid in gangliosides or by sulfate groups in sulfatides
Where does synthesis of glycosphingolipids occur and the enzyme involved?
Occurs primarily in the Golgi by sequential addition of glycosyl monomers transferred from UDP-sugar donors to the acceptor molecule.
Enzyme involved are glycosyl transferases which are each specific for a particular sugar nucleotide and acceptor
What are the 2 enzymes important for the degradation of sphingolipids and what do they cleave?
B-Galactosidase - Cleaves Galactose out
Neuraminidase - Cleaves NANA out
What are eicosanoids and their function?
Eicosanoids such as prostaglandins, thromboxanes, leukotrienes are polyunsaturated fatty acids with 20 carbons that elicits a wide range of responses: physiologic (inflammatory response) and pathologic (hypersensitivity)
Synthesis of prostaglandins and thromboxanes
Requires dietary precursor linoleic acid (w-6 FA) in which the first step is the oxidative cyclization of free arachidonic acid to yield PGH2 by enzymes COX-1 (constitutive) and COX-2 (nonconstitutive)
Prostaglandin synthesis can be inhibited by cortisol and aspirin through inhibition of COX-1 and COX-2 to give pain relief but does not inhibit 5-Lipoxygenase for Leukotriene synthesis
What are leukotrienes and what enzyme synthesizes it from amino acids?
They are mediators of allergic response and inflammation and can be synthesized from AA by lipoxygenases
What are cholesterol and its functions?
It is a steroid alcohol and its functions include:
1. Structural component of membranes to make it more rigid but excess amounts can make it more fluid
2. Precursor of bile acids, steroid hormones, and vitamin D
Liver plays central role in cholesterol regulation
How does cholesterol enter and leave the liver?
Enters from:
-diet, cholesterol synthesized by the liver, or extrahepatic tissues
Eliminated as:
-unmodified cholesterol in the bile, converted to bile salts that are secreted into the intestinal lumen, or secreted as VLDL
Structure of cholesterol, cholesteryl esters, and sterols
Cholesterol: 4 Fused hydrocarbon rings with a 8 carbon, branched hydrocarbon chain attached to carbon 17 of the D ring
Cholesteryl Esters: esterified form with a fatty acid attached at carbon 3 of the A ring
Sterols: Steroids with a 8-10 carbon, branched hydrocarbon chain attached to carbon 17 of the D ring and OH group at carbon 3 on the A ring
Where is cholesterol synthesized?
Mainly by the liver
Intestine
Adrenal cortex
Reproductive tissues, including ovaries, testes, and placenta
3 Phases of cholesterol synthesis along with enzymes of each
- Conversion of acetyl CoA to HMG-CoA (Enzyme - Thiolase)
- Conversion of HMG-CoA to Mevalonate -> squalene (HMG CoA Reductase is key enzyme with Mevalonate being rate limiting product)
Statin inhibit HMG CoA Reductase to lower cholesterol levels - Conversion of squalene to cholesterol
How is cholesterol degraded?
Ring structure of cholesterol cannot be metabolized to CO2 and H2O in humans so the intact sterol nucleus is eliminated from the body by conversion to bile acids and bile salts in the liver
What is the rate limiting step in bile acid synthesis?
Cholesterol 7-alpha-hydroxylase converts cholesterol to 7-alpha-hydroxycholesterol which make cholic acid (a triol) or chenodeoxycholic acid (a diol) and both are primary bile acids
What molecule do bile acids conjugate to before they leave the liver?
Conjugates to glycine or taurine (an end product of cysteine metabolism)
Cholesterol is converted to bile acids and then bile salts in the liver
What does bile contain and its function?
Bile salts, cholesterol, phospholipids, and bile pigments bilirubin (yellow) and biliverdin (green).
Produced by hepatocytes and stored in the gall bladder
Help to emulsify fats and fat-soluble vitamins thereby aiding absorption
4 Types of Lipoproteins and characteristics of each
Chylomicrons:
-Assembled in the intestine
-Transport lipids from intestine to peripheral tissues
VLDL:
-Produced in the liver
-Transport lipids from liver to peripheral tissues
-Become LDLs when depleted
LDL: (Bad cholesterol) (Composed mainly of cholesterol)
-Transport cholesterol to tissues
-Deposit cholesterol in the arteries
HDL: (Good cholesterol) (High in protein and low in lipid)
-Transports cholesterol from peripheral tissues to the liver for conversion to bile acids and for disposal
Classes of steroid hormones
Precursor of all steroid hormones is cholesterol
Glucocorticoids (Cortisol)
Mineralocorticoids (aldosterone)
Sex hormones (Androgens, estrogens, and progestins)
Synthesis and secretion of steroid hormones. Also Order sequence of steroid hormones
Adrenal cortex (Cortisol, aldosterone, and androgens)
Ovaries and placenta (estrogens and progestins)
Testes (testosterone)
Due to their hydrophobicity, they must form a complex with a plasma protein
Cholesterol -> Pregnenolone -> Progesterone
What two amino acids do not undergo transamination?
Lysine and Threonine
(Let Them Deanimate)
Vitamin names and their deficiencies
B1: Thiamine - Beriberi and Wernicke-Korsakoff syndrome
B2: Riboflavin - Cheilosis and Glossitis
B3: Niacin - Pellagra
B5: Panthothenic Acid
B6: Pyridoxine - Scaly dermatitis, anemia
B7: Biotin - Part of coenzyme used in carboxylation reactions (Acetyl-CoA carboxylase in FA synthesis)
B9: Folic acid - Anemia, Spina bifida, and anencephaly
B12: Cobalamin - Pernicious anemia
Vitamin A: Night blindness, xerophthalmia, and keratomalacia
Vitamin D (Calciferol) - Rickets, Osteomalacia, and Osteoporosis
Vitamin E (Tocopherols) - Red blood cell breakage and nerve damage
Vitamin K (Phylloquinone, Menaquinone) - Hemorrhaging
