Metabolism - Exam #3, Lipids Flashcards
1
Q
What are the Simple Lipids?
A
- Fatty acids (simplest form)
- Waxes (sterol esters and non-sterol esters)
2
Q
What are Triacylglycerols (TAG)?
A
-Glycerol esterified to THREE fatty acids (full) → Most common!;
•Fats – solid at room temp → Saturated fatty acids or LONGER chains (give higher melting point making them solid!)
•Oils – liquids at room temp → Lots of SHORT-chain fatty acids or UNsaturated fatty acids
3
Q
What are Diacylglycerols (DAGs)?
A
Glycerol esterified to TWO fatty acids
4
Q
What are Monoacylglycerols (MAGs)?
A
Glycerol esterified to a SINGLE fatty acids
5
Q
How else are MAGs and DAG’s different form TAG’s?
A
- MAG and DAG can have them attached to ANY of the 3 carbons of the glycerol ;
- MAG and DAG are found in SMALL amounts in the body, but are very important intermediates in metabolic rxns and components of other lipids;
- MAG and DAG can occur in PROCESSED foods to serve as emulsifiers
6
Q
What must happen to fatty acids to be used for ENERGY?
A
To be used for energy, fatty acids must be RELEASED as FREE fatty acids from the glycerol backbone in adipose tissue by lipases (fat-breaking enzymes);
-And then transported by ALBUMIN to tissues as needed
7
Q
What are the Compounds lipids?
A
- Phospholipids (5-10% consumed) = Phosphatidic acids, Plasmologens, Sphingomyelins;
- Glycolipids = attached to a carb
- Lipoproteins = structures that transfer fats in the body
8
Q
Where are Phosphatidic acids found?
A
Major part of cells membranes
9
Q
Where are Plasmologens found?
A
- Found mostly in the nervous, immune and cardiovascular tissues;
- Myelin sheath component;
- Brain tissue
10
Q
Where is Sphinogomyelin found?
A
Found in the myelin sheaths of the nerves
11
Q
What are the Derived Lipids?
A
Cholesterol from sterols
12
Q
What is Ethyl Alcohol?
A
Not lipids perse but metabolized similarly & supply dietary energy
13
Q
What would occur if someone consumed NO fat in the diet?
A
Without ANY fat in the diet, humans develop a condition of retarded growth, dermatitis, kidney lesions, and early death
14
Q
What is the size of Lipids found within the body?
A
-WITHIN the body vary from 2-24 carbon atoms
15
Q
What are the different configurations of Lipids found within the body?
A
- Saturated – NO double bonds, only single C-C bonds and filled with H’s;
- MUFA – contain ONE double bond;
- PUFA – contain TWO or MORE double bonds → May have as many as 6 double bonds making them very important nutritionally
16
Q
What variation is caused by double bonds?
A
“cis” or “trans” geometric isomerism which greatly affects the molecules configuration :
- Cis – hydrogens are on the SAME side of the double bond creating a “U” shaped molecule = Natural!
- Trans – hydrogens are on OPPOSITE sides of the double bond creating a more linear molecule → Similar to a saturated FA = Rarely found in nature! Mostly derived from partially hydrogenated fats and oils
17
Q
What are Essential Fatty Acids?
A
- MUST be consumed within the diet and serve as precursors to other components within the body;
- CANNOT be synthesized in in animal cells and must be consumed from plant foods!
1. Linoleic Acid (18:2 n-6)
2. Alpha-Linolenic Acid (18:3 n-3)
18
Q
Why can’t humans synthesize the Essential Fatty Acids?
A
- These CANNOT be made in the body because humans LACK the enzymes Delta 12 and Delta 15 desaturases → add double bonds to these positions;
- Humans can’t ADD double bonds after the 9th carbon in the chain!!;
- So they must come PREFORMED within the diet
19
Q
What transformation CAN humans do to to the consumed essential fatty acids?
A
- CAN desaturate (add double bonds) after the 9th carbon;
- Creates of Arachidonic Acid (Linoleic) and Docosahexanoic Acid (Alpha-Linolenic) once the ESSENTIALS have been consumed
20
Q
What are Triacylglycerols composed of?
A
~95% of dietary lipids ;
- Glycerol backbone plus 3 fatty acids connected by an ESTER bond;
- Condensation rxn that forms ester bond and loses water;
- Fatty acids may be all the same or different → All saturated, MUFA, or PUFA, or a combination
21
Q
How do enzymes act on TAGs?
A
- Enzymes of the body CAN DISTINGUISH between the 3 carbons of the glycerol and are specific to which one they will act on the for both digestion and synthesis of triacylglycerols;
- HYDROLYZE (break) or CONDENSE (make) ester bonds
22
Q
What are Fatty Acids?
A
- *Straight hydrocarbon chain terminating with a carboxylic acid group;
- Most of the acids that are found within our diet;
- Simplest of the lipids;
- Contain a polar, hydrophilic end and a nonpolar, hydrophobic end = INSOLUBLE in water
23
Q
What is the Delta (D) system for naming fatty acids?
A
- Length;
- Number/ position of double bonds;
- Chemists
24
Q
What is the Omega system for naming fatty acids?
A
- Double bonds counted from omega (methyl) end;
* Nutritionists
25
What is Linoleic Acid?
- N-6 essential fatty acid;
- first double bond counting from the methyl group is at carbon 6;
- Precursor = CANNOT be used within the body until it is elongated and turned into Arachidonic Acid
26
What is the delta name for Linoleic Acid?
Delta 18:2 ^ 9,12 =
| 18 carbons, 2 double bonds at carbons 9 and 12
27
What is Alpha-Linolenic Acid?
- 18:3 n-3
- N-3 essential fatty acid;
- first double bond counting from the methyl group is at carbon 3;
- Precursor = cannot be used within the body it is elongated and turned into EPA
28
What are the effects of Trans fats on the body?
1. Raises blood cholesterol levels
- More than any other type of fat;
- Increases LDL (bad fat) and lowers HDL (good fat)
2. Increase risk for
- Heart disease
- Stroke
29
What are the current recommendations surrounding Trans fats?
- NO more than 1% of total calories (~2g on a 2000 cal diet);
- (Current availability in the average US diet is estimated at 8.1g/person/day);
- As LOW as possible;
- Added to food labels in 2006;
- Shortening or Partially hydrogenated oil on ingredient list
30
Where do Trans fat come from?
Partial hydrogenation =
- Process commonly used to make margarine and frying oil;
- Designed to solidify veggie oils at room temp;
- “Cis” double bonds not reduced in the process are rearranged to the “trans” state yielding much more stability
31
When are foods considered "Trans fat-free"?
Trans fat-free foods must contain less than 0.5 grams of BOTH trans and saturated fats;
*Per serving
32
What are the benefits associated with n-3 fatty acids?
* Alpha-Linoleic Acid and derivatives
- Hypolipidemic & antithrombotic effects = LOWER blood pressure and clotting caused by n-6;
- Fish oils are rich sources
33
What are the derivatives of Alpha-Linoleic acid (n-6)?
Starts as: 18:3 n-3...
1. Ecosapentanoic acid (EPA) = 20:5 n-3 (major tissue component);
2. Docosahexanoic acid (DHA) = 22:6 n-3 (major membrane phosholipid in photoreceptors, cerebral gray matter, testes and sperm) - MAJOR DERIVATIVE
* *Both are found preformed, elongated in fish/shellfish
34
What are the derivatives of Linoleic Acid (n-3)?
Starts as 18:2 n-6...
1. Dihomo-Gammala = 20:3 n-6;
2. Arachidonic Acid = 20:4 n-6 - MAJOR DERIVATIVE;
3. Continues to elongate and then shortens
35
What is similar between n-3 elongation and n-6 elongation?
Use the SAME enzymes to elongate and saturate the 18 carbon chains;
We CANNOT use 18 C's in any physiological manner!;
-Need the 20 and 22 loner carbon lengths;
-Can only convert WITHIN families, no crossing over!!
36
What are Sterols?
- Monohydroxy alcohols (one alcohol group) with 4-ring core structure called cyclopentanoperhydrophenanthrene (steroid) nucleus;
- Major component of HORMONES
37
What is Cholesterol?
- ANIMAL sterol; Most common;
- Component of cell membranes;
- PRECURSOR for steroids: bile acids, sex hormones, adrenocortical hormones, vitamin D;
- Obtained from animal sources;
- Want to LIMIT the amount consumed in the diet but highly important to physiological functions!;
- Very necessary due to several important roles → Hormonally, structurally, etc.
38
What is Cholesterol composed of?
- 4 ring steroid nucleus;
- Hydrocarbon tail on one end;
- Hydroxyl group (alcohol) on the other
- **When the hydroxyl forms an ester bond with a carbonyl carbon of a fatty acid, phospholipid or sphinogmyelin as CHOLESTEROL ESTER is made
39
What are Phospholipids?
- Contain a PHOSPHATE along with one or more other fatty acid residues;
- Divided into two groups depending on the nature of the CORE structure
1. Glycerophosphatides or
2. Sphilgolipids
40
What are Glycerophosphatides?
-GLYCEROL core with Phosphatidic Acid as the main component
41
What is Phosphatidic Acid?
- Formed by esterification of two fatty acids at C-1 and C-2 and esterification of the C-3 hydroxyl with the phosphate;
- Numbered from top to bottom like a TAG with sn-1, sn-2, and sn-3;
* *SFA in position 1;
* *Unsat’d FA in position 2;
* *Phosphate in position 3
42
What are the derivatives of Phosphatidic Acids?
- (Compounds are named Phosphatidyl derivatives of the alcohol)
1. Choline → Phosphatidyl choline AKA the more common phospholipid LECITHIN:
* Others are made by replacing the choline in the polar head group
2. Ethanolamine → Phosphatidyl ethanolamine
3. Serine → Phosphatidyl serine
4. Inositol → Phosphatidyl inositol
* *Each compound has an alcohol group where the other esterification to the phosphate takes place
43
What is Diphosphatidylglycerol?
- TWO phosphatidylglycerols connect with a GLYCEROL backbone in the center to form a dimeric structure;
- In several body tissues;
- AKA Cardiolipin = located in the inner mitochondrial membrane and attaches cytochrome c to the membrane (for the ETC)
44
What are Sphingolipids?
- Core composed of the amino alcohol SPHINGOSINE;
- 18-carbon amino alcohol sphingosine forms backbone of sphingolipids;
- Sphingosine combines with a long-chain fatty acid through an amide link to form CERAMIDE
45
What are the 3 subclasses of Sphigolipids?
1. Sphingomyelins
2. Cerebrosides
3. Gangliosides
* *Cerebrosidee and Gangliosides do NOT contain phosphate but instead a carbohydrate → Glycolipid
46
What are Sphigomyelins?
- Sphingophosphatides → Only sphingophosphatides which DOES contain a phosphate ;
- Can be found in the sheaths of the nervous system;
- Contain CERAMIDE (fatty acid residue attached with an amide link to the amino group of sphingosine) which is then esterified to phosphorycholine
47
What are Glycolipids?
- Cerebrosides - monosaccharide CHO attached;
- Gangliosides - oliogosaccharide CHO attached;
- •Main physiological role, like phospholipid is STRUCTURAL → Occur in medullary sheaths of nerves & in brain tissue;
* *Found on the surface of blood cells and yield different blood types
48
What are Cerebrosides?
-Glycolipids found in animal muscle and neural cell tissues;
-Ceramide structure with a single SUGAR (monosaccharide) residue = NO PHOSPHATE;
-Residue can be either glucose or galactose
•Glucocerebrosides – other bodily tissues , such as the muscle
•Galactocerebrosides – neural tissues
49
What are Gangliosides?
- Glycolipids;
- CERAMIDE structure (like sphingomyelin and cerebrosides);
- Then connected to an OLIOGOSACCHARIDE with various monosaccharide derivatives = NO PHOSPHATE;
- Involved in certain RECOGNITION events at the cell surface
50
What is the most important property of Phospholipids in their biological functions?
- Hydrophilic! (water-loving)
- Have a CHARGE to them!;
- Much MORE POLAR than TAG and sterols so attract water much more;
- Being hydrophilic allows then to stabilize other blood-borne lipid particles such as chylomicrons in the aqueous environment
51
Where are Phospholipids most commonly found?
- Cell membranes = serve as the passageway for the water-soluble and fat-soluble materials ACROSS the membrane;
- Source of Physiologically active compounds;
- Cell functions such as anchoring protein WITHIN the cell membranes
52
How are Phospholipids a source of Physiologically active compounds on the cell membrane?
EX: Arachidonate (derivative produced from the EFA Linoleic Acid - can be released on demand from the membrane-bound phosphatidylcholine and phosphatidylinositol when needed for synthesis of EICOSANOIDS (20-C fatty acid chains)
53
How do Phospholipids anchor proteins within the cell membranes?
- Holds the membrane proteins to the cell when they are covalently attached to lipids;
- Phosphatidylinositols anchor many surface antigens and other surface enzymes in eukaryotic cells;
- Also, certain hydrolytic products of phosphatidylinositols are active in cell signaling and second messengers for hormone function
54
What makes bile acids so important?
- WITHOUT bile acids you CANNOT digest lipids!;
- Play a role in pairing dietary fat to digestive enzymes and allow absorption in the GI tract, through the intestine and finally into the body and tissues for utilization
55
What are the conjugated bile acids?
- glycocholate;
- taurocholate;
- glychochenodeoxycholate;
- taurochenodeoxycholate
56
What are the major lipid components of our diet?
- TAG (major dietary lipid);
- Phospholipids (mostly phosphatidylcholine);
- Sterols (mostly cholesterol)
57
Lipids are...
- Hydrophobic;
- Body is a “Water” Environment that must have a special mechanisms to allow hydrophobic fats to be used → CAN’T interact on their own with the hydrophilic digestive enzymes (proteins)
* *Need to be solubilized for aqueous intestine
58
What is the purpose of Emulsification by Bile acids?
- Increases surface area for digestive enzymes;
| - Allow the interaction with the proteins in the aqueous environment
59
What are the digestive enzymes that act on lipids?
* *Esterases – cleave the ester bonds within the various lipids
1. Lipases → for TAGs
2. Phospholipase → for phospholipids
3. Cholesterol esterase → for cholesterol esters
60
Where does most TAG digestion take place?
- Lumen of the small intestine;
| - Mostly in the the JEJUNUM
61
What are the roles of Lingual and Gastric Lipase?
LIMITED digestion (10-30%)
- Lingual – found in the mouth, secreted by the serous gland under the tongue;
- Gastric – found in the stomach
- - Lingual and gastric lipase work best on TAGs with SHORT/MEDIUM-chain fatty acids;
- Hydrolyze at the sn-3 position producing a free fatty acid and 1,2-DAG
62
How does emulsification of lipids take place in the STOMACH?
- Occurs through muscle contractions and squirting of fats through sphincter to provide enough force for emulsification;
- Fats are suspended within the aqueous (watery) environment of the stomach;
- Very LIMITED digestion;
- Presence of lipids in stomach DELAYS gastric emptying providing high satiety
63
How does emulsification of lipids take place in the SMALL INTESTINE?
1. Mechanical shearing continues, BILE is released form the gallbladder by the stimulation of CCK;
2. Forms BILE SALTS that are AMPHIPATHIC =
- Hydrophobic end IN to fat;
- Hydrophilic end OUT to water phase;
* *“binding” allows for the lipase (enzyme) to act on the fat particle
64
Why is Bicarbonate released with Pancreatic Lipase in to the small intestine?
- Bicarbonate elevates the pH (still acidic from the stomach) so Lipase can function ;
- Pancreatic lipase is directed FIRST at the sn-1 position and then the sn-3 fatty acid
* *Very few TAG are hydrolyzed all the way to free glycerol
65
What is required for the activation of Pancreatic Lipase?
Requires Colipase, calcium ions and bile salts
66
What is Colipase?
– Acts as a “bridge” between the lipid and the enzyme (pancreatic lipase) allowing it to be acted upon and broken down;
- Contains ~ 100 amino acids residues and distinctly hydrophobic regions that act as lipid-binding sites (protein-like end, lipid-like end);
- Associated strongly with pancreatic lipase to attach the enzyme to the bile salt-stabilized micelles
67
What essentially happens to fats consumed in the diet?
1. Fats are consumed, emulsified and allowed to interact with enzymes;
2. Digested and broken down;
3. Absorbed by the enterocyte (single layer of cells to get INTO the body);
4. Then are put back together as triglycerides WITHIN the lymphatic system of the body (actually INSIDE the body)
68
What lipid digestion takes place in the MOUTH?
MINOR;
- Limited digestion by lingual lipase found under the tongue (Serous/Salivary gland);
- Enzymes Not very active in adults; Highly important to the digestion of infants;
- Cleaves fatty acids from the SN3 position → Stereospecific actions!
* *Products = TAGs + DAGs + free fatty acids
69
What lipid digestion takes place in the STOMACH?
Some additional;
- Have TAG, DAGs, and fatty acids;
-HCl from parietal cells helps some cleavage;
- Gastric lipase produced in the stomach acts on the lipids;
-Cleaves at the SN3 position again;
-ONLY TAGs are acted upon in the stomach (in tact fats);
**Products = TAGs + DAGs + free fatty acids
(ONLY
70
What lipids digestion takes place in Phase 1 in the SMALL INTESTINE?
Phase 1:
- Emulsifications occurs making the fats more water soluble → BILE emulsifies, no lipase action;
* *Products = EMULSIFIED TAGs, DAGs, and fatty acid micelles
71
What lipid digestion takes place in Phase 2 in the SMALL INTESTINE?
Phase 2:
- Enzymatic DIGESTION by Pancreatic Lipase (produced by the pancreas) first at the SN1 and then SN3;
* *Products = MAGs + free fatty acids
72
What happens to the Short-Chain free fatty acids products of digestion?
-SHORT-chain free fatty acids move DIRECTLY in to the PORTAL vein toward the LIVER!!;
73
What happens to the Medium/Long Chain products of digestion?
Enter the LYMPHATIC system:
1. Glycerol, glucose, cholesterol, and Long-chain fatty acids are absorbed into the enterocyte with transfer proteins
2. Repackaged:
- MAG and DAG are reformed to TAGs
- Lysophosphatides are re-esterified with fatty acids to make phospholipids
- Cholesterol is re-esterified to cholesterol esters
74
What happens to Medium/Long chain products that have been recombined?
Reformed lipids are combined with apoproteins (apo-B48) and made into large CHYLOICRONS and then enter the lymph
75
What are the Stereospecific actions of the digestive enzymes?
- Pancreatic lipase = SNI cleavage;
- Lingual lipase and Pancreatic Lipase = SN3 cleavage
* *PRODUCTS of Digestion by Pancreatic and Lingual Lipase = TAG → 1,2 diacylglycerols + monoacylglycerol + free fatty acids
76
What happens to cholesterol consumed within the diet that must be digested?
1. Esterified cholesterol undergoes HYDROLYSIS to free cholesterol & a FA catalyzed by the enzyme cholesterol esterase =
2. Then C-2 FA of lecithin hydrolytically removed by Phospholipase A2, to produce lysolecithin & a free FA
77
What are the products of Cholesterol digestion?
Lysolecithin + a Free Fatty acid
78
What are the products of PARTIAL digestion of dietary lipids?
- 2-Monoacylglycerols;
- Lysolecithin;
- Cholesterol;
- Fatty acids;
* *All of these products combine with BILE SALTS to form negatively charged polymolecular aggregates (many molecules put together) called MICELLES
79
What are Micelles?
-Fatty acids + monoglycerides + bile =
Allow for the transport of the hydrophobic lipids in the aqueous environment of the GI and their much SMALLER, condensed diameter allows them to get to the intramicrovillus spaces on the intestinal membrane and be absorbed by the enterocytes
80
How does Phospholipase act on Phospholipids?
- Phospholipase have enzymatic activity at the C2 carbon (unlike with pancreatic and lingual lipase acting on TAGs);
- Cleaves fatty acid at CARBON 2;
- C-2 FA removed;
* *Products = lysophospholipid + free fatty acid
81
How are fatty acids ABSORBED from Micelles through the intestine?
- Micelles interact at brush border & lipid contents diffuse out into enterocytes;
- BILE ACIDS allow aggregation → Then can move to the wall of the intestinal tract and then absorbed by the enterocyte;
- Free fatty acids (digested products) move or jump from micelle to micelle toward the unstirred water layer of the GI tract where they will be taken in to the enterocyte cell
82
What happens to fatty acids that are absorbed and are LARGER than 10-12 Carbons?
* Re-esteridied!;
- Long chain fatty acids are added to MAGs and DAGs and eventually become chylomicrons in the LYMPH;
- Put “back together” into phospholipids once absorbed through the enterocyte
83
How are the long chains "put back together"?
- Once absorbed, products of TAG digestion are taken to the endoplasmic reticulum;
- Acyl--TRANSFERASES transfer CoA-fatty acids;
- Acyl-SYNTHETASE then adds them onto the MAG and DAG products to RECREATE TAGs ;
- These triglycerides will then be aggregated to form Chylomicrons for dispersal around the body through the Lymphatic System
84
What is Orlistat?
- Therapeutic inhibition of fat absorption;
- Semisynthetic derivative of lipstatin;
- OTC (over the counter) form is Alli;
- Prescription form is Xenical
85
How does Orlistat inhibit fat absorption?
- INHIBITS pancreatic lipase → enzyme that should cleave fatty acids off the glycerol backbone at the C2 position;
- Fatty acids CANNOT be broken off the glycerol backbone and therefore NOT digested;
- If the fats are not digested, then they never really ENTER the body;
* * No hydrolysis of TAGs, so therefore less dietary fat is absorbed and decreased caloric intake, ~ 200kcals
86
How is Cholesterol absorbed?
- About half in intestines is excreted, other half absorbed;
- Cholesterol is found in intestinal MICELLES to allow passage through the unstirred-water layer (barrier between the lumen and enterocytes)
87
What must happen to dietary cholesterol for absorption?
- Cholesterol from DIET must be HYDROLYZED to free cholesterol to be absorbed;
- Energy-Independent process and facilitated by specific transporter proteins
88
What happens to cholesterol once absorbed?
- Once absorbed in the enterocyte, cholesterol is transported to the ER, esterified by acyl-CoA and cholesterol acyltransferase 1 & 2;
- These SPECIFIC enzymes will ONLY esterify Cholesterol!! (and not plant sterols);
- Esterified cholesterol will then be able to react with with apolipoproteins and form chylomicrons
89
What are Apolipoproteins?
- Protein component of lipoprotein complexes;
- Stabilize the lipoprotein complexes in blood circulation;
- Makes complexes specific for certain receptors on cell membranes;
- Stimulate enzymatic reactions that regulate lipoprotein function;
90
What are the roles of the LIVER in lipid metabolism?
1. Hepatic synthesis of bile salts is INDESPENSIBLE for lipid digestion;
2. Synthesizes lipoproteins from endogenous lipids and apolipoproteins;
3. Can synthesize lipids from NONlipid precursors such a glucose and amino acids;
4. Catabolizes dietary lipids delivered to it in the form of chylomicron remnants and LDL → Repackages their lipids into HDL and VLDL forms
91
What nutrients enter the liver after a fatty meal?
- Glucose, Amino Acids, and Medium-Chain fatty acids rise in the portal blood → Goes DIRECTLY to the liver;
- Chylomicron remnants are also sent from the lymph once nutrients have been removed by Lipoprotein Lipase
92
What happens to Glucose in the liver?
- Glucose not taken up by other organs is taken by hepatocytes and phosphorylated for metabolism in glycolysis;
- Glycogenesis occurs after glycolysis until hepatic glycogen stores are replenish;
- Excess glucose is converted to fatty acids ;
- As dietary glucose is metabolized, Triose-P generates GLYCEROL = backbone for TAG
93
What happens to Amino Acids in the Liver?
- They can be converted to pyruvate or OAA and enter the TCA cycle and used for energy metabolism; OR;
- Can serve as precursors for lipid synthesis because they can be converted to acetyl-CoA and/or pyruvate that can be used to synthesize TAG
94
How are DIETARY lipids delivered to the liver?
- As chylomicron remnants and medium-chain fatty acids that were absorbed from the portal blood;
- ApoE is on the surface of the remnants and binds with receptors for ApoE on the membranes of vascular endothelial cells in the liver;
- Chylomicron remnants enter the hepatic system by ENDOCYTOSIS with the receptor (similar to LDLs)
95
What is contained in the lipid portion of the remnants?
- Free fatty acids;
- MAGs;
- DAGs;
- Glycerol;
- Cholesterol;
- Cholesterol esters
96
What can the cholesterol and cholesterol esters of the remnants be used for?
- Bile salts and secreted in bile;
- Secreted into bile as neutral sterol;
- Incorporated into VLDL and HDL and sent to blood
97
What happens to the TAGs repacked by the liver?
-Combined with phospholipids, cholesterol, and protein → VLDLs are created by the liver!
98
What other lipoprotein does the liver synthesize?
- HDLs are also synthesized;
- Contain majority TAGs with phospholipids and cholesterol;
- Much smaller and tightly packed due to LESS fat composition;
* *Used for Reverse Cholesterol Transport!!
99
What do BOTH Chylomicrons and VLDLs have that allows them to be used by tissues of the body?
Apolipoproteins C-2 on surface → Activator of Lipoprotein Lipase
100
What happens to the dietary nutrients that enter the Liver?
1. Dietary nutrients enter from portal vein
- -Glucose enter glycolysis or becomes glycogen;
- -AAs enter AA pool and some are metabolized to pyruvate and OAA as needed
- -Short-Chian FFA bound to albumin enter FA pool and make TAGS;
- -Remnants attach to apoA,E binding sites and taken by lysosomes releasing FFA, MAG, DAG and Cholesterol.
2. Lipids are reformed to TAG and Cholesterol esters
101
What then happens to the repacked lipids?
- TAGs, cholesterol, and phospholipids are combined with Apoproteins and enter circulation in the blood ad VLDLs or HDLs;
- -VLDLS = deliver meal's li[ids to NON-hepatic tissue
- - HDL = reverse cholesterol transport
102
Why are chylomicrons circulating in the lymph after a fatty meal?
- Dietary lipids CANNOT circulate (hydrophobic) and CANNOT be directly used;
- Chylomicrons are the products of digestion that have been ABSORBED through the enterocyte and then REPACKAGED!!
103
How are Chylomicron circulated in the Lymph?
1. Newly formed chylomicrons contain ApoB-48 and Apo-A;
2. Apo-E and Apo-C are TRANSFERRED to the chylomicron from HDLs;
3. Chylomicrons deliver TAG to NONhepatic tissues, mostly adipose and muscle;
4. Adipose/muscle CANNOT phosphorylate glycerol backbone -- send it to the serum for the liver/kidney;
5. When most TAGs are removed, REMNANTS remain;
6. Remnants transfer Apo-A and Apo-C back to the HDL;
7. Remnants attach to liver at HEPATIC LIPOPROTEIN LIPASE;
8. Fatty acids, cholesterol and cholesterol esters enter the liver
104
Why are Apo-E and Apo-C transferred to the Chylomicron from the HDLs?
These apoproteins serve as "markers" so Lipoprotein Lipase in the tissues to act on the chylomicrons and remove the needed fatty acids
105
What happens to VLDLs?
1. New VLDLs are made in the golgi apparatus of the liver and sent into circulation;
2. Apo-E and Apo-C are transferred from HD;
3. Fatty acids from TAG are hydrolyzed by lipoprotein lipase in NONhepatic tissues;
4. TAGs are removed and VLDLs become smaller IDLs and further loss creates LDLs;
5. LDLs are taken up by B-100 receptors in the liver and NONhepatic tissues
106
What do Chylomicrons and VLDLs have in common and how are they different?
- BOTH chylomicrons and VLDLs have Apo-C and Apo-E that activate lipoprotein lipase so that the lipids can be taken off and used by the body;
- -Chylomicrons carry DIETARY lipids;
- -VLDLs carry repacked, endogenous LIPIDS
107
What are LDLs used for?
Created from breakdown of VLDL to IDL to LDL;
- Marjor transporter of cholesterol to tissues;
- Binds about 60% of serum cholesterol;
- Once in the tissues cholesterol is used for membrane construction, construction/conversion to other metabolites (EX: steroid hormones)
108
How do LDLs deliver cholesterol to cells?
- Bind with LDL receptors on cells → LDL B-100 receptors;
- Leads to the REMOVAL of lipoprotein from circulation;
- Receptors are located on the hepatocytes and cells of NONhepatic TISSUES;;
- Rate of transport depends on transcapillary transport and activity of LDL receptors on cell surfaces
109
What happens to the LDLs once bound to the receptors on tissues?
-Once bound to receptor , BOTH LDLs and receptor are internalized into cell where component parts are metabolized by lysosome enzymes WITHIN the cell
110
What cells do LDL bind to?
- LDL binds to NORMAL fibroblasts (immune response cells) with HIGH affinity and specificity (and other cells, such as hepatocytes and adrenal and ovarian corpus leteum cells);
- Mutant calls CAN’T bind efficiently
111
How do receptors bring the membrane-bound LDLs into the cells?
-Membrane-bound LDL is pulled into the cell by the LDL- apoB 100, E receptors (SAME as for chylomicrons);
-Receptor interacts with the LIPOPROTEINS that contain either apoB-100 or apoE → KEY TO CELL INTERNALIZATION = Endocytosis
112
What happens once the LDL and receptor are INSIDE the cell?
- Once inside, lipoprotein interacts with lysosomes;
- Receptor is RETURNED to the cell surface;
- Lysosomal enzymes HYDROLYZE the protein and cholesterol ester components to amino acids, free fatty acids, and free cholesterol
113
What is the FREE cholesterol in the cell used for?
* * Synthesize cholesterol to meet needs!;
- FREE cholesterol = REGULATORY functions;
2. Modulates 2 microsomal enzymes = HMG-CoA reductase and cholesterol acyl transferase (ACAT) -- HMG-CoA reductase is regulated by FEEDBBACK inhibition
2. Lowers the concentration of receptor mRNA which suppresses synthesis of LDL receptors, PREVENTING LDL entry into cells
* *Normally body should prevent overproduction of cholesterol
114
What lipoproteins are high in concentration in the blood during FASTING state?
- During FASTING, chylomicrons and remnants are NOT found in the blood → Only found right after a meal;
- VLDLs have quick interconversion into IDL and then LDLs;
- MOSTLY LDLs during a fasting state
115
What is the main function of HDLs?
- Removes UNESTERIFIED cholesterol from cells/other lipoproteins;
- RETURNS it to the liver for excretion in bile;
- REVERSE cholesterol transport = takes cholesterol AWAY from the cells of the body = LOWERS serum cholesterol
116
Why is cholesterol important for bile?
- Need cholesterol so the liver can synthesize bile!;
| - Bile salts are required for solubilization of fats in the GI tract!
117
What are the key properties of HDLs?
1. Binds to receptors on BOTH hepatic and non-hepatic cells;
| 2. HDL is mediated through its apoA-1 component that stimulates the activity of cholesterol acyltransferase (LCAT)
118
How can HDLs bind receptors in both hepatic and nonhepatic cells?
- Receptors may be HDL specific;
- But also include LDL-receptor, to which HDL can bind through its apoE component → HDLs might compete with LDLs at this receptor
119
What is Cholesterol acyltransferase (LCAT)?
-Enzyme that forms cholesterol esters from free cholesterol by catalyzing the transfer of fatty acids (mostly PUFA) from the C2 position of phosphatidylcholine to free cholesterol
120
How does HDL, through LCAT, promote the REMOVAL of cholesterol from nonhepatic tissues?
- By taking up free cholesterol and creating esters, LCAT promotes the net transfer of cholesterol OUT of nonhepatic tissues and other lipoproteins;
- Cholesterol esters made can then react readily with plasma lipoproteins!
121
How do the cholesterol esters react with the plasma lipoproteins?
- Mediated by cholesterol ester transfer protein (CETP);
| - Once CETP transfer the cholesterol esters they can readily go back to the liver with HDL or indirectly by LDLs
122
What happens to the cholesterol esters once they are BACK inside the LIVER from HDLs and LDLs (reverse transport)?
Once INSIDE the liver, cholesterol esters are HYDROLYZED by cholesterol esterase;
-Free cholesterol is EXCRETED in BILE as BILE SALT (major excretion route)
123
How does reverse cholesterol transport benefit the CVD system?
**Reverse cholesterol transport REDUCES the amount of deposited cholesterol in the vascular endothelium, reducing the risk of fatty plaque formation and athresclerosis
124
How do LDLs go through endocytosis to enter cells?
1. LDL particle with ApoB and ApoE attach to LDL receptor;
2. Endocytosis of LDL and receptor;
3. LDL fuses with lysosome (contains proteinases that release AA and cholesterol);
4. LDL receptor back to membrane;
5. FREE cholesterol is released form the LDL;
6. HMG-CoA reductase is involved in CHOLESTEROL SYNTHESIS;
7. Cholesterol transferred to Golgi, esterified with ACAT and stored in the cell = Cholesterol esters!!
125
What happens when EXCESS cholesterol is present?
-DOWN regulation of receptors and HMG-CoA reductase;
-HMG-CoA reductase and synthesis of LDL receptors are INHITIBED (feedback inhibition);
→ DECRAESE Chol synthesis;
126
What is the absorption of cholesterol into cell controlled by?
- Amount of cholesterol taken into the cell is controlled by cholesterol CONTENT within the cell;
- Plenty, cholesterol uptake is INHIBITED and receptors are blocked
127
Where are HDLs synthesized?
- HDL is synthesized primarily in the Liver with a lesser amount from the intestine;
- APO-E and APO-C are synthesized in the liver and ADDED to the HDL
128
What do newly made HDL contain?
- Phospholipids;
- Cholesterol;
- Lecithin:cholesterol acyltransferase (LCAT)
129
What are the HDL receptors of Non-hepatic tissues?
- Adenosine triphosphate (ATP)-binding cassette transporter family (ABCA1);
- Transport cholesterol and phospholipids to circulating HDL UNIDIRECTIONALLY
130
What are the HDL receptors in Arterial walls, Artheroma, Muscle and adipose tissues?
Scavenger receptor family (SR-B1) transfer lipids BIDIRECTIONALLY to and from circulating HDLs
131
What happens as the HDL picks up phospholipids and and cholesterol esters?
A polar bilar of phospholipids is formed with a non-polar core of cholesterol and cholesterol esters
132
How does the HDL transfer the cholesterol to the liver?
- HDL particle cycles in size and lipid content;
- Continually transfers cholesterol esters to the liver by SR-B1 site;
- Chain reaction passing cholesterol from the non-hepatic tissue through the HDLs and back to the liver
- Mediated by cholesterol ester transferase protein
133
What happens to the phospholipids and lysolechithin that were also in the HDL?
- Phospholipids go the liver;
| - Lysolecithin in transferred to albumin
134
What is the life span of HDL?
~ 2 days;
| -Actively works at reverse transport of cholesterol to the liver for excretion via bile
135
What lipids are of interest CVD risk?
- Cholesterol risk → Major component of atherogeneic fatty plaque ;
- Saturated and unsaturated fatty acids (omega-3 FA);
- Trans fatty acids;
- Lipoprotein A (HDL);
- Apolipoprotein E (Associated with increased CVD risk)
136
What is Atherosclerosis?
Inflammatory disease and disorder of lipid metabolism;
| -May cause an INCREASE in the synthesis of lipoprotein cells
137
What is Atherogenesis?
- Plaque in the lining of the arteries;
| - Caused by an increase of CVD inflammation (atherosclerosis) and increased lipoproteins -- LDL (BAD cholesterol)
138
How are the arteries damaged with Atherogenesis?
- DAMAGE of the smaller arteries is caused by OXIDIZED cholesterol, free radicals, high BP, etc.;
- Local macrophages are called in and release cytokines (chemicals that cause further injury to the artery) which summon leukocytes;
- Become macrophages and engulf LDL particles;
- Forms a fibrous “cap” and stabilizes the plaque
139
Why are the macrohphages ultimately damaging?
-Inflammatory response at the site of injury and macrophages attack and try and “fix” it but end up totally clogging the artery with plaque trying to seal the holes
140
What is a "healthy" cholesterol profile?
-High HDL + Low LDL = HEALTHY profile
141
How are Apo-A and Apo-B used to asses CVD risk?
High Apo-B vs. Apo-A = INCREASED risk for coronary heart disease
142
How do individuals respond differently to dietary cholesterol?
- Absorption of biosynthesis;
- Formation and receptor-mediated clearance of LDL;'
- Rates of LDL removal and excretion
143
What fats have a POSITIVE correlation with CVD?
- Total fat;
- Saturated FAs;
- Cholesterol;
- Trans fat
* *Potential genetic variations → Family histories are very important
144
What happens to the products of Lipase activity on TAGs?
- Glycerol = Used for energy via glycerokinase or used to make glucose (liver & other tissues)
- 3 Fatty Acids = Beta-oxidation
145
What must first happen to FREE fatty acid before they can be used for energy?
- Fatty acids MUST be ACTIVATED first to be used for energy;
- Acyl-CoA Synthetase catalyzes the activation of fatty acids;
- Binds fatty acid with CoA to create and ACTIVATED fatty acyl-coA;
- Can now enter beta-oxidation
146
Where does Beta-Oxidation of fatty acids take place?
Oxidation of fatty acids occurs primarily in the MITOCHONDRION producing energy through oxidative phosphorylation
147
How do the fatty acids get into the Mitochondrial Matricx for oxidation?
- SHORT-chain fatty acids can pass directly into the mitochondrial matrix and form acyl-CoA derivatives in the matrix;
- LONG-Chain fatty acids and their CoA derivatives CANNOT cross the inner mitochondrial membrane , ONLY can cross the permeable outer membrane → require membrane transport system
148
What is the carrier for Long-Chain free fatty acids to get in to the matrix?
Carnitine;
149
How does Carnitine carry the fatty acids?
1. ACTIVATED fatty-acids (acyl-CoA) join covalently to Carnitine at the cytoplasm side of the outer membrane by enzyme Carnitine Acyltransferase I (CAT I );
2. CAT I moves the acylcarnitine (carnitine + activated long-chain fatty acid) across the inner membrane ;
3. A SECOND transferase, CAT II (on the inner membrane surface) releases the acylcarnitine to form acyl-CoA and carnitine
150
What is Beta-Oxidation of Fatty Acids?
-Degradation pathway where 2-C units (acetyl-CoA) are cleaved one acetyl-CoA at a time from the carboxyl end of the activated fatty acid
151
How do fatty acids enter Beta-Oxidation?
-Activated fatty acids are first acted on by the ezyme acyl-CoA dehygrogenase to produce a double bond between the alpha and beta carbons;
-There are 4 dehydrogenases → Each specific to a certain chain length
•Those for longer chains are bound to the INNER membrane;
•Those for shorter chains are FREE in the matrix → Passed freely in and did NOT require a carrier, so the fatty acids are already free in the matrix
152
What are the products of the of Beta-Oxidation?
- Products of this reaction are acetyl-CoA and a saturated CoA-activated fatty acid that has TWO fewer carbons that the original fatty acid;
1. Acetyl CoA product enters the TCA cyle for further oxidation ;
2. Activated fatty acids continues the Beta-oxidation cycle; losing 2 carbons with each round
153
What energy is derived from Beta-Oxidation of Fatty Acids?
- -5 ATPs (FADH2 and NADH) for each carbon – carbon cleavage;
- -12 ATPs for each acetyl CoA
- -MINUS 2 ATPs for initial activation of FA
154
How do the energy compare from Saturated and Unsaturated Fatty Acids?
- About equal;
- Saturated gives MORE than Unsaturated ;
- FADH2 “lost” for each double bond
155
How are odd chain fatty acids metabolism differently?
* *Still give the same number of fatty acids;
| - Require conversion to methylmalonyl CoA and then Succinyl CoA to enter the TCA cycle
156
What are Ketone Bodies?
- Formation occurs in the Mitochondria;
- Result of ACCELERATED fatty acid β-oxidation;
- Formed in Insulin Resistance;
- Result of fatty acid β-oxidation in absence of CHO
157
When do Ketone bodies accumulate?
- Acetyl CoA cannot be processed through TCA cycle;
| - Fat oxidation is excessive (starvation)
158
Why wouldn't Acetyl-CoA be processed in the TCA cycle?
Due to lack of oxaloacetate from CHO metabolism to form citrate of TCA cycle (diabetes);
-Don’t have OAA to go through condensation with of acetyl-CoA to create citrate and enter the TCA cycle
159
When is Fat Oxidation excessive?
- Without enough OAA, carb use diminishes or diet lacking glucose, oxidation of fats accelerates to prodivide energy through the TCA cycle of substrates (acetyl-CoA);
- **Fat catabolism couple with reduced OAA =accumulation of acetyl-CoA;
- A sharp increase in ketone body formation follows → Ketosis! – can be dangerous by disrupting the body’s acid-base balance
160
What does the liver do with Ketone Bodies?
-Liver’s ability to deliver ketone bodies to peripheral tissues (brain, muscle) is very important to provide fuel in times of starvation!!
161
What happens to the excess Acetyl-CoA as it accumulates?
{NON-Hepatic Tissues}
1. Acetyl CoA condenses with ANOTHER Acetyl-CoA → Forms Acetoacetyl CoA
2. Acetoacetyl CoA then loses the CoA and becomes Acetoacetate
3. Acetoacetate becomes either Acetone or Beta-Hydroxybutyrate = Ketone Bodies
162
What happens the ketone bodies produced?
- Beta-hydroxybutyrate and Acetone are NOT further oxidized in the liver;
- Transported to the blood to peripheral tissues;
- Converted back to acetyl-CoA and oxidized through the TCA cycle by tissues;
- Reversible conversion of Beta-hydroxybutyrate to acetoacetate to acetyl-CoA is how ketone bodies can serve as a source of fuel
