Module 4 Flashcards
1
Q
is a characteristic of starvation and of diabetes mellitus, and leads to increased ketone body production by the liver (ketosis).
A
Increased fatty acid oxidation
2
Q
Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ___, which is ultimately fatal
A
ketoacidosis
3
Q
Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to __
A
hypoglycemia
4
Q
hypoglycemia occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, for example, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, for example, __
A
hypoglycin
5
Q
also called unesterified (UFA) or nonesterified (NEFA) fatty acids —are fatty acids that are in the unesterified state.
A
Free fatty acids (FFAs)
6
Q
In plasma, __ are combined with albumin, and in the cell they are attached to a fatty acid binding protein, so that in fact they are never really “free.”
A
longer chain FFA
7
Q
__ are more water-soluble and exist as the unionized acid or as a fatty acid anion.
A
Shorter chain fatty acids
8
Q
Fatty acids must first be converted to an active intermediate before they can be catabolized. This is the only step in the complete degradation of a fatty acid that requires energy from __
A
ATP
9
Q
In the presence of ATP and coenzyme A, the enzyme __ catalyzes the conversion of a fatty acid (or FFA) to an “active fatty acid” or acyl-CoA, using one high-energy phosphate and forming AMP and PP
A
acyl-CoA synthetase (thiokinase)
10
Q
PPi is hydrolyzed by __ with the loss of a further high energy phosphate, ensuring that the overall reaction goes to completion
A
inorganic pyrophosphatase
11
Q
__ are found in the endoplasmic reticulum, peroxisomes, and inside and on the outer membrane of mitochondria.
A
Acyl-CoA synthetases
12
Q
is widely distributed and is particularly abundant in muscle
A
Carnitine
13
Q
Long-chain acyl-CoA (or FFA) cannot penetrate the inner membrane of mitochondria. In the presence of carnitine, however,__ , located in the outer mitochondrial membrane, transfers long-chain acyl group from CoA to carnitine, forming acylcarnitine and releasing CoA.
A
carnitine palmitoyltransferase-I
14
Q
Acylcarnitine is able to penetrate the inner membrane and gain access to the β-oxidation system of enzymes via the inner membrane exchange transporter __
A
carnitine-acylcarnitine translocase
15
Q
The transporter binds acylcarnitine and transports it across
the membrane in exchange for carnitine
The acyl group is then transferred to CoA so that acyl-CoA is reformed and carnitine is liberated. This reaction is catalyzed by ___ which is located on the inside of the inner membrane
A
carnitine palmitoyltransferase- II
16
Q
- two carbons at a time are cleaved from acyl-CoA molecules, starting at the carboxyl end
- chain is broken between the α(2)- and β(3)-carbon atoms
- The two-carbon units formed are acetyl-CoA; thus, palmitoyl-CoA forms eight acetyl-CoA molecules.
A
beta oxidation pathway
17
Q
Several enzymes that are found in the mitochondrial matrix or inner membrane adjacent to the respiratory chain. These catalyze the oxidation of acyl-CoA to acetyl-CoA via the β oxidation pathway.
A
fatty acid oxidase
18
Q
- process where large quantities of the reducing equivalents FADH2 and NADH are generated and are used to form ATP by oxidative phosphorylation
A
beta oxidation pathway
19
Q
The first step in Beta-Oxidation Cycle is the removal of two hydrogen atoms from the 2(α)- and 3(β)-carbon atoms, catalyzed by __ and requiring FAD. This results in the formation of Δ2-trans-enoyl-CoA and FADH2
A
acyl-CoA dehydrogenase
20
Q
The reoxidation of FADH2 by the respiratory chain requires the mediation of another flavoprotein, termed __
A
electron transferring flavoprotein
21
Q
(B-oxidation cycle)
Water is added to saturate the double bond and form 3-hydroxyacyl- CoA, catalyzed by __
A
Δ2-enoyl-CoA hydratase
22
Q
(B-oxidation cycle)
The 3-hydroxy derivative undergoes further dehydrogenation on the 3-carbon catalyzed by __ to form the corresponding 3-ketoacyl-CoA compound. In this case, NAD+ is the coenzyme involved.
A
l(+)-3hydroxyacyl-CoA dehydrogenase
23
Q
(B-oxidation cycle)
3-ketoacyl-CoA is split at the 2,3-position by __, forming acetyl-CoA and a new acyl-CoA two carbons shorter than the original acyl-CoA molecule
A
thiolase (3-ketoacyl-CoA-thiolase)
24
Q
the propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is __
A
glucogenic
25
Transport of electrons from FADH2 and NADH via the respiratory chain leads to the synthesis of __ for each of the seven cycles needed for the breakdown of the C16 fatty acid, palmitate, to acetyl-CoA (7 × 4 = 28).
four high-energy phosphates
26
A modified form of β-oxidation is found in peroxisomes and
leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step), which is broken down by __
catalase
27
- facilitates the oxidation of very long chain fatty acids (eg, C20, C22)
- also take part in the synthesis of ether glycerolipids, cholesterol, and dolichol
Peroxisomes
28
__ are degraded by the enzymes normally responsible for β-oxidation until either a Δ3-cis-acyl-CoA compound or a Δ4-cis-acyl-CoA compound is formed, depending upon the position of the double bonds
CoA esters of unsaturated fatty acids
29
Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of __
acetoacetate and d(-)-3-hydroxybutyrate
| β-hydroxybutyrate
30
Acetoacetate continually undergoes spontaneous decarboxylation to yield __
acetone
31
__ are interconverted by the mitochondrial enzyme d(–)-3-hydroxybutyrate dehydrogenase; the equilibrium is controlled by the mitochondrial [NAD+]/[NADH] ratio, that is, the redox state
Acetoacetate and 3-hydroxybutyrate
32
The concentration of total ketone bodies in the blood of well-fed mammals does not normally exceed __ except in ruminants, where 3-hydroxybutyrate is formed continuously from butyric acid (a product of luminal fermentation) in the rumen wall.
0.2 mmol/L
33
__ Is an Intermediate in the Pathway of Ketogenesis
3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA)
34
__ is the starting material for ketogenesis, also arises directly from the terminal four carbons of a fatty acid during β-oxidation
Acetoacetyl-CoA
35
Condensation of acetoacetyl-CoA with another molecule of acetyl-CoA by 3-hydroxy-3-methylglutaryl-CoA synthase forms __
3-hydroxy-3-methylglutaryl-CoA (HMGCoA)
36
__ causes acetyl-CoA to split off from the HMG-CoA, leaving free acetoacetate. The carbon atoms split off in the acetyl-CoA molecule are derived from the original acetoacetyl-CoA molecule
3-Hydroxy-3-methylglutaryl-CoA lyase
37
While an active enzymatic mechanism produces acetoacetate from acetoacetyl-CoA in the liver, acetoacetate once formed cannot be reactivated directly except in the __, where it is used in a much less active pathway as a precursor in cholesterol synthesis
cytosol
38
In extrahepatic tissues, __ is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA
acetoacetate
39
is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues
ketonemia
40
KETOGENESIS IS REGULATED AT THREE CRUCIAL STEPS
1. Ketosis does not occur in vivo unless there is an increase
in the level of circulating FFAs that arise from lipolysis of triacylglycerol in adipose tissue.
2. After uptake by the liver, FFAs are either a-oxidized to CO2 or ketone bodies or esterified to triacylglycerol and phospholipid.
3. In turn, the acetyl-CoA formed in β-oxidation is oxidized in the citric acid cycle, or it enters the pathway of ketogenesis to form ketone bodies
41
- are the precursors of ketone bodies in the liver.
Free Fatty Acids (FFA)
42
There is regulation of entry of fatty acids into the oxidative pathway by __, and the remainder of the fatty acid taken up is esterified.
carnitine palmitoyltransferase-I (CPT-I)
43
- the initial intermediate in fatty acid biosynthesis formed by acetyl-CoA carboxylase in the fed state, is a potent inhibitor of CPT-I
Malonyl-CoA
44
FFA enter the liver cell in low concentrations and are nearly all esterified to acylglycerols and transported out of the liver in __
very low density lipoproteins (VLDL)
45
The partition of __ between the ketogenic pathway
and the pathway of oxidation to CO2 is regulated so that the total free energy captured in ATP which results from the oxidation of FFA remains constant as their concentration in the serum changes.
acetyl-CoA
46
A fall in the concentration of oxaloacetate, particularly within the mitochondria, can impair the ability of the citric acid cycle to metabolize acetyl-CoA and divert fatty acid oxidation toward _
ketogenesis
47
fall in the concentration of oxaloacetate may occur because of an increase in the ___ caused by increased β-oxidation of fatty acids affecting the equilibrium between oxaloacetate and malate, leading to a decrease in the concentration of oxaloacetate, and when gluconeogenesis is elevated.
(NADH)/(NAD+) ratio
48
- can occur particularly in the newborn—and especially in preterm infants—owing to inadequate biosynthesis or renal leakage.
- Symptoms of deficiency include hypoglycemia, which is a consequence of impaired fatty acid oxidation and lipid accumulation with muscular weakness
Carnitine deficiency
49
_ affects only the liver, resulting in reduced fatty acid oxidation and ketogenesis, with hypoglycemia.
Inherited CPT-I deficiency
50
__ affects primarily skeletal muscle and, when severe, the liver.
CPT-II deficiency
51
The __ , used in the treatment of type 2 diabetes mellitus, reduce fatty acid oxidation and, therefore, hyperglycemia by inhibiting CPT-I.
sulfonylurea drugs (glyburide [glibenclamide] and tolbutamide)
52
- is caused by eating the unripe fruit of the akee tree, which contains the toxin hypoglycin.
- inactivates medium- and short-chain acyl-CoA dehydrogenase, inhibiting β-oxidation and causing hypoglycemia.
Jamaican vomiting sickness
53
- is characterized by the excretion of C6-C10 ω-dicarboxylic acids and by nonketotic hypoglycemia, and is caused by a lack of mitochondrial medium-chain acyl-CoA dehydrogenase.
Dicarboxylic aciduria
54
- is a rare neurologic disorder due to a metabolic defect that results in the accumulation of phytanic acid, which is found in dairy products and ruminant fat and meat
Refsum disease
55
- occurs in individuals with a rare inherited absence of peroxisomes in all tissues
- they accumulate C26-C38 polyenoic acids in brain tissue and also exhibit a generalized loss of peroxisomal functions
- causes severe neurological symptoms, and most patients die in the first year of life
Zellweger (cerebrohepatorenal) syndrome
56
Higher than normal quantities of ketone bodies present in
| the blood or urine constitute ketonemia (hyperketonemia) or ketonuria, respectively. The overall condition is called __
ketosis
57
__ are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol.
Fatty acids
58
__ in phospholipids of the cell membrane are important in maintaining membrane fluidity
Unsaturated fatty acids
59
- are used to form eicosanoic (C20) fatty acids, which give rise to the eicosanoids prostaglandins, thromboxanes, leukotrienes, and lipoxins.
essential fatty acids
60
- mediate inflammation, pain, and induce sleep and also regulate blood coagulation and reproduction.
Prostaglandins
61
- present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue
- cofactor requirements include NADPH, ATP, Mn2+, biotin, and HCO3− (as a source of CO2)
- Acetyl-CoA is the immediate substrate
- free palmitate is the end product
Lipogenesis
62
Bicarbonate as a source of CO2 is required in the initial reaction for the carboxylation of acetyl-CoA to malonyl-CoA in the presence of ATP and __.
acetyl-CoA carboxylase
63
are used to form eicosanoic (C20) fatty acids, which give rise to the eicosanoids prostaglandins, thromboxanes, leukotrienes, and lipoxins. Prostaglandins mediate inflammation, pain, and induce sleep and also regulate blood coagulation and reproduction.
essential fatty acids
64
is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue.
Lipogenesis
65
Lipogenesis
cofactor: requirements include NADPH, ATP, Mn2+, biotin,
and HCO3 − (as a source of CO2)
Immediate substrate: Acetyl-CoA
End product: free palmitate
66
- is required in the initial reaction for the carboxylation of acetyl-CoA to malonyl-CoA in the presence of ATP and acetyl-CoA carboxylase.
Bicarbonate as a source of CO2
67
- has a major role in the regulation of fatty acid synthesis
- has a requirement for the B vitamin biotin and is a multienzyme protein containing biotin, biotin carboxylase, biotin carboxyl carrier protein, and a carboxyl transferase, as well as a regulatory allosteric site
Acetyl-CoA carboxylase
68
Biosynthesis of malonyl-CoA by acetyl carboxylase: two steps:
(1) carboxylation of biotin involving ATP and
| (2) transfer of the carboxyl group to acetyl-CoA to form malonyl-CoA
69
After the formation of malonyl-CoA, fatty acids are formed
by the fatty acid synthase enzyme complex. The individual
enzymes required for fatty acid synthesis are linked in this
multienzyme polypeptide complex that incorporates the __, which has a similar function to CoA in the β-oxidation pathway
acyl carrier protein (ACP)
70
(fatty acid synthase complex)
Initially, a priming molecule of acetyl-CoA combines
with a cysteine ´SH group, while malonyl-CoA combines with the adjacent ´SH on the 4′-phosphopantetheine of ACP of the other monomer (reaction 1b). These reactions are catalyzed by malonyl acetyl transacylase, to form __
acetyl (acyl)-malonyl enzyme
71
(fatty acid synthase complex)
The acetyl group attacks the methylene group of the malonyl residue, catalyzed by 3-ketoacyl synthase, and liberates CO2, forming __, freeing the cysteine —SH group
3-ketoacyl enzyme (acetoacetyl enzyme)
72
(fatty acid synthase complex)
The sequence of reactions is repeated six more times until a saturated 16-carbon acyl radical (palmitoyl) has been assembled. It is liberated from the enzyme complex by the activity of the sixth enzyme in the complex, __
thioesterase (deacylase)
73
(fatty acid synthase complex)
The free palmitate must be activated to acyl-CoA before it can proceed via any other metabolic pathway. Its possible fates are ___
1. esterification into acylglycerols
2. chain elongation or desaturation
3. esterification into cholesteryl ester
74
The __ used as a primer forms carbon atoms
| 15 and 16 of palmitate. The addition of all the subsequent C2 units is via malonyl-CoA.
acetyl-CoA
75
__ acts as primer for the synthesis of long-chain fatty acids having an odd number of carbon atoms, found particularly in ruminant fat and milk.
Propionyl CoA
76
is involved as a donor of reducing equivalents in both the reduction of the 3-ketoacyl and of the 2,3-unsaturated acyl derivatives.
NADPH
77
The oxidative reactions of the __ are the chief source of the hydrogen required for the reductive synthesis of fatty acids.
pentose phosphate pathway
78
Lipogenesis and Pentose Phosphate pathway are found in __
cytosol
79
Other sources of NADPH in Lipogenesis include the __
1. reaction that converts malate to pyruvate catalyzed by the “malic enzyme” (NADP malate dehydrogenase)
2. extramitochondrial isocitrate dehydrogenase reaction (probably not a substantial source, except in ruminants).
80
(Lipogenesis)
Acetyl-CoA is formed from glucose via the oxidation of pyruvate in the matrix of the mitochondria. However, as it does not diffuse readily across the mitochondrial membranes, its transport into the cytosol, the principal site of fatty acid synthesis, requires a special mechanism involving __
citrate
81
(Lipogenesis)
After condensation of acetyl-CoA with oxaloacetate in the citric acid cycle within mitochondria, the citrate produced can be translocated into the extramitochondrial compartment via the tricarboxylate transporter, where in the presence of CoA and ATP, it undergoes cleavage to acetyl-CoA and oxaloacetate catalyzed by ATP-citrate lyase, which increases in activity in the __
well-fed state
82
The NADPH becomes available for lipogenesis, and the pyruvate can be used to regenerate acetyl-CoA after transport into the __
mitochondrion
83
- elongates saturated and unsaturated fatty acyl-CoAs (from C10 upward) by two carbons, using malonyl-CoA as the acetyl donor and NADPH as the reductant, and is catalyzed by the microsomal fatty acid elongase system of enzymes
the “microsomal system”
84
Elongation of stearyl-CoA in brain increases rapidly during myelination in order to provide C22 and C24 fatty acids for
__
sphingolipids
85
__ converts surplus glucose and intermediates such as pyruvate, lactate, and acetyl-CoA to fat, assisting the anabolic phase of this feeding cycle.
Lipogenesis
86
- is the main factor regulating the rate of lipogenesis.
nutritional state of the organism
87
- is controlled in the short term by allosteric and covalent modification of enzymes and in the long term by changes in gene expression governing rates of synthesis of enzymes.
Long-chain fatty acid synthesis
88
- is an allosteric enzyme and is activated by citrate, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl-CoA
- is also regulated by hormones such as glucagon, epinephrine, and insulin via changes in its phosphorylation state.
Acetyl-CoA carboxylase
89
- promotes the conversion of the enzyme from an inactive dimer (two subunits of the enzyme complex) to an active polymeric form, with a molecular mass of several million.
Citrate
90
Acyl-CoA also inhibits the mitochondrial __, thus preventing activation of the enzyme by egress of citrate from the mitochondria into the cytosol.
tricarboxylate transporter
91
- stimulates lipogenesis by several other mechanisms
as well as by increasing acetyl-CoA carboxylase activity
- increases the transport of glucose into the cell
- inhibits lipolysis in adipose tissue and reducing the concentration of plasma-free fatty acids
Insulin
92
- enzymes adapt to the body's physiologic needs via changes in gene expression which lead to increases in total amount present in the fed state and decreases during intake of a high-fat diet and in conditions such as starvation, and diabetes mellitus.
Fatty Acid Synthase Complex and
| Acetyl-CoA Carboxylase
93
- are the only fatty acids known to be essential for the complete nutrition of many species of animals, including humans, and are termed the nutritionally essential fatty acids.
Linoleic and α-linolenic acids
94
- can be formed from linoleic acid. Double bonds can be introduced at the Δ4, Δ5, Δ6, and Δ9 positions in most animals, but never beyond the Δ9 position
arachidonic acid
95
The first double bond introduced into a saturated fatty acid is nearly always in the __
Δ9 position
96
- an enzyme system in the endoplasmic reticulum catalyzes the conversion of palmitoyl-CoA or stearoyl-CoA to palmitoleoyl-CoA or oleoyl-CoA,respectively
- enzymes appear to be similar to a monooxygenase system involving cytochrome b5
Δ9 desaturase
97
Additional double bonds introduced into existing monounsaturated fatty acids are always separated from each other by a __ except in bacteria.
methylene group
98
- are required for the synthesis of the other members of the ω6 or ω3 families and must be supplied in the diet
linoleic (ω6) or α-linolenic (ω3) acids
99
- are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation, and they also have various
other functions that are less well defined
- are found in the structural lipids of the cell, often in the position 2 of phospholipids, and are concerned with the structural integrity of the mitochondrial membrane.
Essential fatty acids
100
- is present in membranes and accounts for 5% to 15% of the fatty acids in phospholipids.
Arachidonic acid
101
- which is synthesized to a limited extent from α-linolenic acid or obtained directly from fish oils, is present in high concentrations in retina, cerebral cortex, testis, and
sperm
- is particularly needed for development of the brain
and retina and is supplied via the placenta and milk
- retinitis pigmentosa are reported to have low blood levels of this fatty acid
Docosahexaenoic acid (DHA; ω3, 22:6)
102
nonessential polyenoic acids of the ω9 family, particularly __ replace the essential fatty acids in phospholipids, other complex lipids, and membranes.
Δ5,8,11-eicosatrienoic acid (ω9 20:3)
103
The __ in plasma lipids can be used to diagnose the extent of essential fatty acid deficiency.
triene:tetraene ratio
104
Arachidonate and some other C20 polyunsaturated fatty acids give rise to __, physiologically and pharmacologically active compounds known as prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and lipoxins (LX)
eicosanoids
105
- which may be obtained from the diet, but is usually derived from the position 2 of phospholipids in the plasma membrane by the action of phospholipase A2
Arachidonate
106
- is the substrate for the synthesis of the PG2, TX2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate
phospholipase A2
107
- involves the consumption of two molecules of O2 catalyzed by cyclooxyrgenase (COX) (also called prostaglandin H synthase)
Prostanoid synthesis
108
- an enzyme that has two activities, a cyclooxygenase and peroxidase
- is present as two isoenzymes, COX-1 and COX-2.
cyclooxyrgenase
109
- is converted to prostaglandins D and E as well as to a thromboxane (TXA2) and prostacyclin (PGI2)
endoperoxide (PGH)
110
“Switching off ” of prostaglandin activity is partly achieved by a remarkable property of __—that of self-catalyzed destruction; that is, it is a “suicide enzyme.”
cyclooxygenase
111
- are a family of conjugated trienes formed
from eicosanoic acids in leukocytes, mastocytoma cells, platelets, and macrophages by the lipoxygenase pathway in response to both immunologic and nonimmunologic stimuli.
leukotrienes
112
Three different lipoxygenases (dioxygenases) insert oxygen into the 5, 12, and 15 positions of arachidonic acid, giving rise to __
hydroperoxides (HPETE)
113
Only __ forms leukotrienes
5-lipoxygenase
114
__ are a family of conjugated tetraenes also arising in leukocytes. They are formed by the combined action of more than one lipoxygenase
Lipoxins
115
- compete with essential fatty acids and may exacerbate essential fatty acid deficiency
- they are structurally similar to saturated fatty acids
Trans fatty acids
116
- are synthesized in platelets and upon release cause vasoconstriction and platelet aggregation. Their synthesis is specifically inhibited by low-dose aspirin
Thromboxanes
117
- are produced by blood vessel walls and are potent inhibitors of platelet aggregation
Prostacyclin (PGI2)
118
- formed from eicosapentaenoic acid (EPA), inhibit the release of arachidonate from phospholipids and the formation of PG2 and TX2.
PG3 and TX3
119
PGI3 is as potent an antiaggregator of platelets as PGI2, but
TXA3 is a weaker aggregator than TXA2, changing the balance of activity and favoring __
longer clotting times
120
- is a mixture of leukotrienes C4, D4, and E4.
- This mixture of leukotrienes is a potent constrictor of the bronchial airway musculature.
- These leukotrienes together with leukotriene B4 also cause vascular permeability and attraction and activation of leukocytes and are important regulators in many diseases involving inflammatory or immediate hypersensitivity reactions, such as asthma.
Slow-reacting substance of anaphylaxis (SRS-A)
121
- are the major lipids in fat deposits and in food, and their roles in lipid transport and storage and in various diseases such as obesity, diabetes, and hyperlipoproteinemia
Triacylglycerols
122
- is a major component of lung surfactant, which is lacking in respiratory distress syndrome of the newborn.
dipalmitoyl lecithin
123
__ in the cell membrane act as precursors of hormone second messengers, and platelet activating factor is an alkylphospholipid
Inositol phospholipids
124
- containing sphingosine and sugar residues as well as fatty acid that are found in the outer leaflet of the plasma membrane with their oligosaccharide chains facing outward, form part of the glycocalyx of the cell surface
Glycosphingolipids
125
Triacylglycerols must be hydrolyzed by a __ to their constituent fatty acids and glycerol before further catabolism can proceed.
lipase
126
The utilization of glycerol depends upon whether such tissues have the enzyme __, which is found in significant amounts in liver, kidney, intestine, brown adipose tissue, and the lactating mammary gland.
glycerol kinase
127
Important substances such as triacylglycerols, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and cardiolipin, a constituent of mitochondrial membranes, are formed from __
glycerol-3-phosphate
128
Significant branch points in the pathway occur at the __
phosphatidate and diacylglycerol steps
129
Phosphoglycerols containing an ether link (—C—O—C—),
| the best known of which are plasmalogens and platelet activating factor (PAF), are derived from __
dihydroxyacetone phosphate
130
__ are intermediates in glycolysis, making a very important
| connection between carbohydrate and lipid metabolism
Glycerol 3-phosphate and dihydroxyacetone phosphate
131
__ Is the common precursor in the Biosynthesis of Triacylglycerols, Many Phosphoglycerols, and Cardiolipin
Phosphatidate
132
- catalyzes the activation of glycerol to sn-glycerol 3-phosphate
Glycerol kinase
133
If the activity of this enzyme is absent or low, as in muscle
or adipose tissue, most of the glycerol-3-phosphate is formed from dihydroxyacetone phosphate by __
glycerol-3-phosphate dehydrogenase
134
Two molecules of acyl-CoA, formed by the activation of fatty acids by acyl-CoA synthetase, combine with
glycerol-3-phosphate to form __
phosphatidate
135
Phosphatidate is converted by phosphatidate phosphohydrolase (also called phosphatidate phosphatase (PAP)) and diacylglycerol acyltransferase (DGAT) to __
1,2-diacylglycerol and then triacylglycerol
136
- a family of three proteins, have PAP activity and they also act as transcription factors which regulate the expression of genes involved in lipid metabolism
Lipins
137
__ catalyzes the only step specific for triacylglycerol synthesis and is thought to be RATE LIMITING in most circumstances
diacylglycerol acyltransferase (DGAT)
138
In intestinal mucosa, __converts monoacylglycerol to 1,2-diacylglycerol in the monoacylglycerol pathway.
monoacylglycerol acyltransferase
139
(Biosynthesis of Phospholipids)
In the biosynthesis of phosphatidylcholine and phosphatidylethanolamine, __ must first be activated by phosphorylation by ATP followed by linkage to CDP.
choline or ethanolamine
140
(Biosynthesis of Phospholipids)
The resulting __ reacts with 1,2-diacylglycerol to form either
phosphatidylcholine or phosphatidylethanolamine, respectively.
CDP-choline or CDPethanolamine
141
(Biosynthesis of Phospholipids)
- is formed from phosphatidylethanolamine directly by reaction with serine
- may re-form phosphatidylethanolamine by decarboxylation.
Phosphatidylserine
142
(Biosynthesis of Phospholipids)
The regulation of triacylglycerol, phosphatidylcholine, and
phosphatidylethanolamine biosynthesis is driven by the availability of __.
free fatty acids
143
- is a phospholipid present in mitochondria. It is formed from phosphatidylglycerol, which in turn is synthesized from CDPdiacylglycerol and glycerol 3-phosphate
- found in the inner membrane of mitochondria, has a key role in mitochondrial structure and function, and is also thought to be involved in programmed cell death (apoptosis).
Cardiolipin (diphosphatidylglycerol)
144
(Biosynthesis of Glycerol Ether Phospholipids)
In glycerol ether phospholipids, one or more of the __ is attached to a hydrocarbon chain by an ether linkage rather than an ester bond.
glycerol carbons
145
(Biosynthesis of Glycerol Ether Phospholipids)
- is the precursor of the glycerol moiety.
- combines with acyl-CoA to give 1-acyldihydroxyacetone
phosphate, and the ether link is formed in the next reaction,
producing 1-alkyldihydroxyacetone phosphate, which is then converted to 1-alkylglycerol 3-phosphate
Dihydroxyacetone phosphate
146
(Biosynthesis of Glycerol Ether Phospholipids)
After further acylation in the 2 position, the resulting 1-alkyl-2-acylglycerol 3-phosphate (analogous to phosphatidate) is hydrolyzed to give the __
free glycerol derivative
147
(Biosynthesis of Glycerol Ether Phospholipids)
- which comprise much of the phospholipid in mitochondria,
are formed by desaturation of the analogous
3-phosphoethanolamine derivative
Plasmalogens
148
- is synthesized from the corresponding 3-phosphocholine derivative
- is formed by many blood cells and other tissues and aggregates platelets at concentrations as low as 10–11 mol/L
Platelet-activating factor (PAF) or (1-alkyl-2-acetyl-sn-glycerol-3-phosphocholine)
149
__ catalyzes the hydrolysis of glycerophospholipids to form a free fatty acid and lysophospholipid, which in turn may be reacylated by acyl-CoA in the presence of an acyltransferase
- found in pancreatic fluid and snake venom as well as in many types of cells
Phospholipase A2
150
- is attacked by lysophospholipase, forming the corresponding glyceryl phosphoryl base, which may then be split by a hydrolase liberating glycerol 3-phosphate plus base.
lysophospholipid
151
is one of the major toxins secreted by bacteria
phospholipase C
152
- is known to be involved in mammalian
| signal transduction
phospholipase D
153
__ may be formed by an alternative route that involves lecithin: cholesterol acyltransferase (LCAT).
Lysolecithin (lysophosphatidylcholine)
154
This enzyme, found in plasma, catalyzes the transfer of a fatty acid residue from the 2 position of lecithin to cholesterol to form cholesteryl ester and lysolecithin,
and is considered to be responsible for much of the cholesterol ester in plasma lipoproteins
cholesterol acyltransferase (LCAT)
155
__ are found predominantly in the 1 position of phospholipids, whereas the polyunsaturated fatty acids (eg, the precursors of prostaglandins) are incorporated more frequently into the 2 position
Long-chain saturated fatty acids
156
The incorporation of fatty acids into lecithin occurs in three
ways:
1. by complete synthesis of the phospholipid
2. by transacylation between cholesteryl ester and lysolecithin
3. by direct acylation of lysolecithin by acyl-CoA.
157
- is synthesized in the endoplasmic reticulum from the amino acid serine
- is an important signaling molecule (second messenger)
regulating pathways including programmed cell death
(apoptosis), the cell cycle, and cell differentiation and
senescence.
Ceramide
158
- are phospholipids and are formed when ceramide reacts with phosphatidylcholine to form sphingomyelin plus diacylglycerol
- occurs mainly in the Golgi apparatus and to a lesser extent in the plasma membrane.
Sphingomyelins
159
The simplest glycosphingolipids (cerebrosides) are __
galactosylceramide (GalCer) and glucosylceramide
| GlcCer
160
- is a major lipid of myelin, whereas GlcCer
is the major glycosphingolipid of extraneural tissues and a
precursor of most of the more complex glycosphingolipids.
GalCer (Figure 24–8B) is formed in a reaction between
ceramide and UDPGal (formed by epimerization from
UDPGlc—Figure 20–6
GalCer
161
- are synthesized from ceramide by the stepwise addition of activated sugars (eg, UDPGlc and UDPGal) and a sialic acid, usually N-acetylneuraminic acid.
Gangliosides
162
- are constituents of the outer leaflet of plasma membranes and are important in cell adhesion and cell recognition.
Glycosphingolipids
163
-is composed mainly of lipid with some proteins and carbohydrate and prevents the alveoli from collapsing
Lung surfactant
164
The phospholipid __ decreases surface tension at the air-liquid interface and thus greatly reduces the work of breathing, but other surfactant lipid and protein components are also important in surfactant function.
dipalmitoyl-phosphatidylcholine
165
Deficiency of lung surfactant in the lungs of many preterm newborns gives rise to infant __
respiratory distress syndrome (IRDS)
166
- is a demyelinating disease, there is loss of both phospholipids (particularly ethanol amine plasmalogen) and of sphingolipids from white matter
multiple sclerosis
167
__ are a group of inherited diseases that are caused by a genetic defect in the catabolism of lipids containing sphingosine.
sphingolipidoses (lipid storage diseases)
168
__ results in accumulation of sulfogalactosylceramide, steroid sulfates, and proteoglycans owing to a combined deficiency of arylsulfatases A, B, and C and steroid sulfatase.
Multiple sulfatase deficiency
169
Enzyme Deficiency: Hexosaminidase A
Lipid Accumulating: Cer—Glc—Gal(NeuAc) GalNAc GM2
Ganglioside
Clinical Symptoms: Mental retardation, blindness, muscular weakness
Tay-Sachs disease
170
Enzyme Deficiency: α-Galactosidase
Lipid Accumulating: Cer—Glc—Gal— Gal Globotriaosylceramide
Clinical Symptoms: Skin rash, kidney failure (full symptoms only in males; X-linked recessive)
Fabry disease
171
Enzyme Deficiency: Arylsulfatase A
Lipid Accumulating: Cer—Gal— OSO3
3-Sulfogalactosylceramide
Clinical Symptoms: Mental retardation and psychologic disturbances in adults; demyelination
Metachromatic leukodystrophy
172
Enzyme Deficiency: β-Galactosidase
Lipid Accumulating: Cer— Gal
Galactosylceramide
Clinical Symptoms: Mental retardation; myelin almost absent
Krabbe disease
173
Enzyme Deficiency: β-Glucosidase
Lipid Accumulating: Cer— Glc
Glucosylceramide
Clinical Symptoms: Enlarged liver and spleen, erosion of long bones, mental retardation in infants
Gaucher disease
174
Enzyme Deficiency: Sphingomyelinase
Lipid Accumulating: Cer— P—choline
Sphingomyelin
Clinical Symptoms: Enlarged liver and spleen, mental retardation; fatal in early life
Riemann-Pick disease
175
Enzyme Deficiency: Ceramidase
Lipid Accumulating: Acyl— Sphingosine
Ceramide
Clinical Symptoms: Hoarseness, dermatitis, skeletal deformation, mental retardation; fatal in early life
Farber disease
176
A __ is a biochemical assembly that contains both proteins and lipids
lipoprotein
177
Lipids are transported in the plasma as lipoproteins, because __
lipids are insoluble in an aqueous medium
178
__ consist of TAG, phospholipids, cholesterol, and cholesteryl esters (CE), and free fatty acids
Plasma lipids
179
Classification of lipoproteins: Listed in order from larger and less dense (more fat than protein) to smaller and more dense (more protein, less fat):
1. Chylomicrons
2. Very low density lipoproteins (VLDL)
3. Intermediate density lipoproteins(IDL)
4. Low density lipoproteins (LDL)
5. High density lipoproteins (HDL)
180
- carry triacylglycerol & other dietary lipids from the intestines to the liver and to adipose tissue
Chylomicrons
181
- pre- β -lipoproteins
| - carry newly synthesized triacylglycerol from the liver to adipose tissue.
Very low density lipoproteins (VLDL),
182
- are intermediate between VLDL and LDL. They are not usually detectable in the blood.
Intermediate density lipoproteins(IDL)
183
- β -lipoproteins
- carry cholesterol from the liver to cells of the body.
- Sometimes referred to as the "bad cholesterol" lipoprotein.
Low density lipoproteins (LDL)
184
- α- lipoproteins
- collects cholesterol from the body's tissues, and brings it back to the liver
- Sometimes referred to as the "good cholesterol" lipoprotein.
High density lipoproteins (HDL)
185
```
Source: Intestine
Diameter (nm): 90-1000
Protein (%): 1-2
Lipid (%): 98-99
Main Lipid Components: Triacylglycerol
Apolipoproteins: A-I, A-II, A-IV,a B-48,
C-I, C-II, C-III, E
```
Chylomicrons
186
Source: Chylomicrons
Main Lipid Components: Triacylglycerol, phospholipids, cholesterol
Apolipoproteins: B-48, E
Chylomicron remnants
187
Source: Liver (intestine)
Main Lipid Components: Triacylglycerol
Apolipoproteins: B-100, C-I, C-II, C-III
VLDL
188
Source: VLDL
Main Lipid Components: Triacylglycerol, cholesterol
Apolipoproteins: B-100, E
IDL
189
Source: VLDL
Main Lipid Components: Cholesterol
Apolipoproteins: B-100
LDL
190
Source: Liver, intestine, VLDL, chylomicrons
Main Lipid Components: Phospholipids, cholesterol
Apolipoproteins: A-I, A-II, A-IV, C-I, C-II, C-III, D,b E
HDL
191
Source: Adipose tissue
Protein (%): 99
Lipid (%): 1
Main Lipid Components: Free fatty acids
Albumin/free fatty acids
192
- are lipid-binding proteins which are the constituents of the plasma lipoproteins
- The amphipathic (detergent-like) properties: solubilize the hydrophobic lipid constituents of lipoproteins
- also serve as enzyme co-factors, receptor ligands, and lipid transfer carriers
Apolipoproteins (Apoproteins)
193
METABOLISM OF CHYLOMICRONS
- Chylomicrons are synthesized in intestinal cells
- The TAG is from dietary lipid
- Major apoprotein is apo B-48
- Travel through the lymph into the blood
- Apo C II
- In peripheral tissues (adipose and muscle), TAG is digested by lipoprotein lipase
- Chylomicron remnants interact with liver receptors and are taken up by endocytosis
- Contents of remnants are degraded by lysosomal enzymes and the products (amino acids, fatty acids, glycerol, cholesterol) are reutilized
194
- the activator of lipoprotein lipase (an enzyme which hydrolyzes lipids in lipoproteins), and apo E are transferred to nascent (newly synthesized) chylomicrons from HDL. Mature chylomicrons are then formed
Apo C II
195
METABOLISM OF VLDL
- synthesized in liver after a high-carbo meal
- formed from TAG that are packaged with Cholesterol, apoproteins (esp. apo B-100 w/c is recognized by hepatic receptors), and phospholipids, and are released to the bloodstream
- In peripheral tissues (adipose, muscle), VLDL TAG are digested by lipoprotein lipase, and VLDL is converted to IDL
- IDL returns to the liver and is degraded
- IDL may also be degraded by lipoprotein lipase to LDL
- LDL reacts with receptors on various cells, is taken up by endocytosis in the liver, and is digested by lysosomal enzymes
196
METABOLISM OF HDL
- HDL cholesterol is converted to cholesteryl ester by LCAT (lecithin-cholesterol acyltransferase) which is activated by Apo A I
- A fatty acid from position 2 of lecithin forms an ester with the 3-hydroxyl group of cholesterol, producing lysolecithin and cholesterol ester
- As choleterol ester accumulates, HDL becomes spheroidal
- HDL particles are taken up by the liver and hydrolyzed
197
ROLE OF THE LIVER
1. It facilitates the digestion and absorption of lipids by the production of bile, which contains cholesterol and bile salts synthesized within the liver de novo or from uptake of lipoprotein cholesterol
2. It actively synthesizes and oxidizes fatty acids
3. It synthesizes triacylglycerols and phospholipids
4. It converts fatty acids to ketone bodies (ketogenesis)
5. It plays an integral part in the synthesis and metabolism of plasma lipoproteins
198
- Main storage area of triacylglycerol
- Storage stimulated by insulin and nicotinic acid, PGE; and inhibited by glucagon, epinephrine, norepinephrine, thyroid hormone, growth hormone, and steroids
- Cannot utilize glycerol to synthesize TAG, since it has no glycerol kinase
ADIPOSE TISSUE
199
- which inhibits phosphodiesterase, stimulates lipolysis
Caffeine
200
- is the most common liver disorder worldwide. When accumulation of lipid in the liver becomes chronic, inflammatory and fibrotic changes may develop leading
to nonalcoholic steatohepatitis (NASH), which can progress
to liver diseases including cirrhosis, hepatocarcinoma,
and liver failure
Nonalcoholic fatty liver disease (NAFLD)
201
Fatty livers fall into two main categories.
1. The first type is associated with raised levels of plasma free fatty acids resulting from mobilization of fat from adipose tissue or from the hydrolysis of lipoprotein triacylglycerol by lipoprotein lipase in extra hepatic tissues
2. The second type of fatty liver is usually due to a metabolic block in the production of plasma lipoproteins, thus allowing triacylglycerol to accumulate.
202
- is the first stage in alcoholic liver disease (ALD) which is caused by alcoholism and ultimately leads to cirrhosis.
Alcoholic fatty liver
203
A cyt P450 enzyme called __ becomes more active in chronic alcoholics.
- utilizes NADPH and O2
- Thus alcohol also competes with drug metabolism
MEOS (microsomal ethanol oxidizing system)
204
Other causes of Fatty Liver
1. Malnutrition (lack of protein)
2. Abetalipoproteinemia
3. Drugs and toxins
205
- is one of the two types of adipose tissue (the other being white adipose tissue) that is present in many newborn or hibernating mammals as well as migratory birds
- Its primary purpose is to generate body heat
- contains more capillaries since it has a greater need for oxygen than most tissues.
Brown Adipose Tissue
206
EFFECT OF HORMONES ON LIPID TRANSPORT
1. Insulin- reduces the release of free fatty acids into the bloodstream
- enhances glucose uptake into adipose tissues via the GLUT 4 transporter
- increases the activity of PDH and Acetyl CoA carboxylase, stimulating fat synthesis
2. Many hormones, including epinephrine, glucagon, ACTH, TSH, GH, and vasopressin accelerate the release of free fatty acids from adipose tissue stores
3. Leptin, a newly discovered body weight regulatory hormone, stimulates lipolysis
207
- Lipid droplet-associated protein
- Protein involved in the formation of lipid droplets in adipocytes
- Inhibits lipolysis by preventing access of lipases to the TAGs
- With activation by protein kinase A, perilipins translocate away from the lipid droplet and allow hormone-sensitive lipase to hydrolyze the adipocyte triglycerides to release nonesterified fatty acids (NEFA).
PERILIPIN
208
FAST FACTS
- Cholesterol is produced mainly in the liver and intestine
- Cholesterol and its esters are transported via lipoproteins
- All the carbons of cholesterol come from Acetyl CoA
- The TAG of the chylomicrons and VLDL are digested by lipoprotein lipase
- LDL provides cholesterol to tissues
- HDL picks up cholesterol from tissues
209
BIOLOGIC IMPORTANCE OF CHOLESTEROL
- Structural component of all cell membranes
- Modulates membrane fluidity
- At temperatures below melting temperature, it increases membrane fluidity
210
- is a precursor of bile acids, steroid hormones, and Vitamin D
- is a component of plasma lipoproteins sent to the peripheral tissues
- When produced in excess, it causes atherosclerotic plaque formation and leads to an increased risk for coronary artery disease
Cholesterol
211
CHOLESTEROL STRUCTURE
1. Highly hydrophobic
2. Has 4 fused hydrophobic rings (steroid nucleus) with 8-carbon branched hydrocarbon chain attached to C-17 of the D ring
3. Ring A has a hydroxyl group at C3
4. Ring B has a double bond between C5 and C6
5. Steroids with 8 to 10 carbon atoms in the side chain at C17 and a hydroxyl group at C3 are called sterols
6. Cholesterol is the major sterol in animal tissues
212
- Most plasma cholesterol is in an esterified form with a fatty acid attached at C3
- This makes the structure even more hydrophobic than free cholesterol
- Not normally found in membranes
- Must be transported in association with a protein (lipoprotein), or be solubilized by phospholipids and bile salts in bile
CHOLESTERYL ESTERS (CE)
213
SYNTHESIS OF CHOLESTEROL
1. Cholesterol is synthesized by virtually all tissues, but is largely contributed by the liver, intestine, adrenal cortex, and reproductive tissues
2. All C atoms are from acetate
3. NADPH provides reducing equivalents
4. Synthesis occurs in the cytoplasm, with enzymes in both cytosol and ER membrane
214
- Similar to the pathway that produces ketone bodies
- In the liver, the cytosolic HMG CoA synthase participates in cholesterol synthesis, while the mitochondrial enzyme synthesizes ketone bodies
SYNTHESIS OF 3-HYDROXY-3-METHYGLUTARYL CoA (HMG CoA)
215
- Rate-limiting step in cholesterol synthesis
- Irreversible
- Occurs in the cytosol
- HMG CoA reductase is an intrinsic membrane protein of the ER with the catalytic domain projecting into the cytosol
- This step is inhibited by statins (Simvastatin, Atorvasatin, etc.)
SYNTHESIS OF MEVALONIC ACID (MEVALONATE)
216
CHOLESTEROL SYNTHESIS 1
1. Mevalonate (6C) is converted to Mevalonate 5 phosphate in 2 steps requiring ATP
2. IPP (5C) is synthesized by decarboxylation. It is the precursor of the isoprenoids
3. IPP is isomerized to DPP
4. IPP and DPP condense to form the 10-carbon GPP
5. A second molecule of IPP condenses with GPP to form a 15-C FPP
217
CHOLESTEROL SYNTHESIS 2
6. Two molecules of FPP combine, releasing pyrophosphate, and are reduced to form Squalene (30C)
7. Squalene is converted to lanosterol in a series of steps. Squalene hydroxylation triggers cyclization to lanosterol
8. A multistep process converts lanosterol to cholesterol.
218
A multistep process converts lanosterol to cholesterol. This involves:
a. Shortening of C chain from 30 to 27
b. Removal of 2 methyl groups at C4
c. Migration of double bond form C8 to C5
d. Reduction of the double bond between C24 and C25
219
Many of the reactions involved in converting lanosterol to cholesterol and other steroids are catalyzed by members of the __
cytochrome P450 enzyme superfamily
220
- an intermediate on the pathway for cholesterol synthesis, also serves also as precursor for synthesis of various non-steroidal isoprenoids.
Farnesyl pyrophosphate
221
REGULATION OF CHOLESTEROL SYNTHESIS
1. Major control point is the reaction catalyzed by HMG CoA reductase, which is inhibited by mevalonate, cholesterol, and statin drugs
2. It is only hepatic synthesis that is inhibited by dietary cholesterol
3. Insulin or thyroid hormone increases HMG CoA reductase activity, while glucagon or glucocorticoids decrease it
222
CELL CHOLESTEROL INCREASE IS DUE TO:
1. Uptake of cholesterol-containing lipoproteins by receptors
2. Uptake of free cholesterol from cholesterol-rich lipoproteins to the cell membrane
3. Cholesterol synthesis
4. Hydrolysis of cholesteryl esters by the enzyme cholesteryl ester hydrolase
223
CELL CHOLESTEROL DECREASE IS DUE TO:
1. Efflux of cholesterol from the cell membrane to HDL promoted by LCAT (lecithin:cholesterol acyltransferase). LCAT is also known as PCAT
2. Esterification of cholesterol by ACAT (Acyl-CoA:cholesterol acyltransferase)
3. Utilization of cholesterol for synthesis of other steroids, such as hormones, or bile acids in the liver
224
ROLE OF CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) IN PLASMA LIPID TRANSPORT
- CETP facilitates the transfer of CE from HDL to VLDL, IDL, and LDL in exchange for TAG.
- This allows LCAT conversion of free cholesterol to CE, facilitating REVERSE CHOLESTEROL TRANSPORT
225
METABOLISM OF LDL AND THE ROLE OF THE LDL RECEPTOR
- VLDL is produced from the liver and is composed mostly of TAG
- VLDL transfers TAG from liver to tissues. When TAG synthesis exceeds VLDL synthesis, it results in fatty liver
- VLDL is the precursor of LDL
226
METABOLISM OF LDL AND THE ROLE OF THE LDL RECEPTOR
- LDL contains less TAG than VLDL
- LDL has a high concentration of cholesterol and cholesterol esters
- The primary function of LDL is to provide cholesterol to the peripheral tissues, or return cholesterol to the liver
- LDL binds to cell surface receptors that recognize apolipoprotein B-100
227
- The ring structure of cholesterol cannot be metabolized to carbon dioxide and water in humans
- The intact sterol nucleus is eliminated by conversion to bile acids and bile salts
- Bile acids and bile salts are excreted in the feces
- Some cholesterol is also secreted into the bile
DEGRADATION OF CHOLESTEROL
228
- is one of the predominant mechanisms for the excretion of excess cholesterol
However, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol.
Synthesis of bile acids
229
- Some of the cholesterol in the intestine is modified by bacteria before excretion. The primary compound made is __, a reduced derivative of cholesterol
coprostanol
230
- Consists of a watery mixture of organic and inorganic compounds
- Lecithin and bile salts (conjugated bile acids) are quantitatively the most important organic components of bile
- Can pass directly from the liver where it is synthesized to the duodenum through the common bile duct, or be stored in the gallbladder
BILE
231
STRUCTURE OF BILE ACIDS
- Contains 24 carbons with 2 or 3 hydroxyl groups and a side chain that terminates in a carboxyl group
- Has a pKa of 6 and is not fully ionized at physiologic pH
- Amphipathic, with the hydroxyl groups above the plane of the steroid ring and the methyl groups below the plane
- Act as emulsifying agents to prepare fats for degradation
232
The reaction catalyzed by the __ is the rate limiting step in bile acid synthesis . This step is DOWN-REGULATED BY CHOLIC ACID AND UP-REGULATED BY CHOLESTEROL.
7α-hydroxylase
233
SYNTHESIS OF BILE SALTS
- Before the bile acids leave the liver, they are conjugated to a molecule of either glycine or taurine by an amide bond between the carboxyl group of the bile acid and the amino group of the added compound
- Conjugation takes place in PEROXISOMES
- The ratio of glycine to taurine forms in the bile is 3:1
- The salt forms are fully ionized (negatively charged) at physiologic pH
- Because of their enhanced amphipathic nature, bile salts are more effective solubilizers
234
ACTION OF INTESTINAL FLORA ON BILE SALTS
- Bacteria in the intestine can remove glycine and taurine and regenerate bile acids
- They can also form secondary bile acids through deconjugation and dehydroxylation
235
ENTEROHEPATIC CIRCULATION OF BILE ACIDS AND BILE SALTS
- Of the 15 to 30 grams of bile salts secreted from the liver, more than 95% are reabsorbed through the ileum, pass through the portal vein, and are reused
- Only 0.5 g are lost in the feces
- Because bile acids are hydrophobic, they are carried by albumin noncovalently through the circulation
236
Bile acid sequestrates like __ bind bile acids in the gut and prevent their reabsorption, promoting cholesterol excretion
cholestyramine
237
- also binds bile acids and promotes their excretion
Dietary fiber
238
- is due to the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins to the artery walls
- A high HDL and low LDL protects a person from this complication. This is one of the benefits provided by exercise
Atherosclerosis
239
- Due to various defects in lipoprotein formation, transport, or destruction
- Not all are harmful
- Diseases such as Diabetes Mellitus, Hypothyroidism, Kidney disease, and atherosclerosis exhibit abnormal lipoprotein patterns that resemble dyslipoproteinemias
DYSLIPOPROTEINEMIAS
240
- Occurs when more cholesterol enters the bile than can be solubilized by the bile salts and lecithin present
- Surgery is the treatment of choice, but administration of chenodeoxycholic acid may help to supplement the body’s supply of bile acids
CHOLELITHIASIS (GALLSTONES)
