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© Copyright 2012, John P. Fisher, All Rights Reserved
Liver: Metabolism & Energetics
Adapted From:
Textbook Of Medical Physiology, 11th Ed. Arthur C. Guyton, John E. Hall
Chapters 67, 68, 69, 70, 71, & 72
John P. Fisher
© Copyright 2012, John P. Fisher, All Rights Reserved
Overview of Liver: Metabolism and Energetics Introduction
• Next we consider bodily metabolism, or the chemical processes that make it possible for the cells to remain viable
• In particular • A review of the principal chemical processes of the cell • An analysis of their physiologic implications, especially the manner in which they
fit into the overall concept of homeostasis
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© Copyright 2012, John P. Fisher, All Rights Reserved
Metabolism Free Energy
• Cellular chemical reactions often involve making the energy in foods available for vital physiological functions
• Coupled Reactions • Carbohydrates, fats, and proteins can be oxidized in the cells to release large
amounts of energy • To provide this energy, chemical reactions are coupled with the systems
responsible for these physiologic functions
• Free Energy • The amount of energy liberated by complete oxidation of a food is called the free
energy (ΔG [=] calories per mole) • The amount of free energy liberated by complete oxidation of 1 mole (180
grams) of glucose is 686,000 calories
© Copyright 2012, John P. Fisher, All Rights Reserved
Metabolism Role of Adenosine Triphosphate in Metabolism
• Adenosine triphosphate (ATP) is an essential link between energy-utilizing and energy-producing functions of the body • Energy derived from the oxidation of
carbohydrates, proteins, and fats is used to convert adenosine diphosphate (ADP) to ATP
• ATP then consumed for cellular functions, including
• Active transport of molecules across cell membranes
• Contraction of muscles and performance of mechanical work
• Various synthetic reactions • Conduction of nerve impulses • Cell division and growth
• ATP is a combination of adenine, ribose, and three phosphate radicals
N
NN
N
H2N
O
OP
OP
OP
O-
O
O-
O
O-
O
O-
OHOH
adenine
ribose
phosphate
Adenosine Triphosphate (ATP)
ADP + Pi ATP
Energy production from oxidation of
food stuffs
Energy consumption for cell, tissue, and
organ function
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© Copyright 2012, John P. Fisher, All Rights Reserved
Metabolism Role of Adenosine Triphosphate in Metabolism
• The amount of free energy in each high energy bond of ATP varies with the surrounding conditions • 7,300 calories under standard conditions • 12,000 calories under physiological conditions
• ATP is present everywhere in the cytoplasm and nucleoplasm of all cells
• Essentially all physiologic mechanisms that require energy obtain it directly from ATP, or another similar high-energy compound, guanosine triphosphate (GTP)
• As food in cells is gradually oxidized, the released energy is used to form new ATP
• Normally, 90% or more of all the carbohydrates utilized by the body are used for ATP formation
N
NN
N
H2N
O
OP
OP
OP
O-
O
O-
O
O-
O
O-
OHOH
adenine
ribose
phosphate
Adenosine Triphosphate (ATP)
ADP + Pi ATP
Energy production from oxidation of
food stuffs
Energy consumption for cell, tissue, and
organ function
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Central Role of Glucose in Carbohydrate Metabolism
• The final products of carbohydrate digestion are almost entirely glucose, fructose, and galactose • Glucose comprises about 80% of total • After absorption from the intestinal tract,
much of the fructose and almost all the galactose are rapidly converted into glucose in the liver
• Glucose thus becomes the final common pathway for the transport of almost all carbohydrates to the tissue cells
• In liver cells, interconversions occur between glucose, fructose, and galactose • When the liver releases monosaccharides
back into the blood, the final product is almost entirely glucose
Guyton & Hall. Textbook of Medical Physiology, 11th Edition
4
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Transport of Glucose Through the Cell Membrane
• Before glucose can be used by the body's tissue cells, it must be transported through the tissue cell membrane into the cellular cytoplasm • Glucose cannot easily diffuse through the pores of the cell membrane as its
molecular weight (180 Da) is above the molecular weight cutoff (100 Da) • However, glucose is transported by a membrane bound protein through
facilitated diffusion • The transport of glucose in the gastrointestinal membrane or the epithelium of the
renal tubules occurs by an active sodium-glucose co-transport • Active transport of sodium provides energy for absorbing glucose against a
concentration difference
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Insulin Increases Facilitated Diffusion of Glucose • The rate of glucose transport as well as some other monosaccharides is greatly
increased by insulin
• When large amounts of insulin are secreted by the pancreas, the rate of glucose transport into most cells increases to 10+ times
• Conversely, the amount of glucose that can diffuse into most cells in the absence of insulin, with the exception of liver and brain cells, is far too little to supply the amount of glucose normally required for energy metabolism
• Thus, the rate of carbohydrate utilization by most cells is controlled by the rate of insulin secretion from the pancreas
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Carbohydrate Metabolism Phosphorylation of Glucose
• Immediately on entry into the cells, glucose combines with a phosphate radical to form glucose-6-phosphate
• Phosphorylation serves to capture the glucose in the cell, as phoshorylated glucose will not diffuse out of the cell
• Phosphorylation is promoted mainly by the enzyme glucokinase in the liver and by hexokinase in most other cells
• Phosphorylation of glucose is almost completely irreversible • In liver cells, renal tubular epithelial cells, and intestinal epithelial cells, glucose
phosphatase reverse phosphorylation
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Glucose Storage
• After absorption into a cell, glucose has two fates • Used immediately for energy to the cell • Stored in the form of a glucose polymer, glycogen
• Allows large quantities of carbohydrates to be stored without significantly altering the osmotic pressure of the intracellular fluids
• Average molecular weight is approximately 5x106 Da
• Most of the glycogen precipitates in the form of solid granules
• Liver cells can store up to 5 - 8% of their weight of glycogen
• Muscle cells can store up to 1 - 3% of their weight of glycogen
• Glycogenesis is the process of glycogen formation • Glucose-6-phosphate becomes glucose-1-
phosphate, which is converted to uridine diphosphate glucose, which is finally converted into glycogen
Guyton & Hall. Textbook of Medical Physiology, 11th Edition
6
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Glycogenolysis • Glycogenolysis involves the breakdown of glycogen to re-form glucose
• Here, each succeeding glucose molecule on each branch of the glycogen polymer is split away by phosphorylation, catalyzed by phosphorylase, which itself must be activated
• Epinephrine and glucagon can activate phosphorylase and thereby cause rapid glycogenolysis • Epinephrine is released by the adrenal medullae when the sympathetic nervous
system is stimulated • Glucagon is secreted by the alpha cells of the pancreas when the blood glucose
concentration falls too low
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Glycolysis • The most important means of releasing energy from the glucose is glycolysis
• End products of glycolysis are mainly oxidized to supply energy
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Carbohydrate Metabolism Glycolysis
ATP ATP
ADP ADP
ATP
ADP
ATP
ADP
2 NADH & 2 H+
x2 per mole glucose
6 1 1,6
follow the carbons
Glucose Glucose-6-phosphate Fructose-6-phosphate Fructose-1,6-diphosphate
Dihydroxyacetone phosphate
Glyceraldehyde-3-phosphate
1,3-Diphosphoglyceric acid 3-Phosphoglyceric acid 2-Phosphoglyceric acid Phosphoenolpyruvic acid Pyruvic acid
H O
OH
H
OHH
OHH
OH
CH2OH
HHCOHHHOOHHOHH
H2C
OH
O PO32-
CH2OHC OHHOOHHOHH
H2C O PO32-
H2CC OHHOOHHOHH
H2C O PO32-
O PO32-
H2CC OCH2OH
O PO32-
HC OOHH
H2C O PO32-
HC OC OHH
H2C O PO32-
CC OHH
H2C O PO32-
O OPO32-
CC OHH
H2C O PO32-
O O-CC OPO3
2-HH2C OH
O O-CC OPO3
2-HCH2
O O-CC OCH3
O O-
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Glycolysis and the Formation of Pyruvic Acid • Glycolysis occurs by 10 successive chemical reactions
• Each step is catalyzed by at least one specific protein enzyme • Only a small portion of the free energy in the glucose molecule is released at
most steps
• 4 moles of ATP were formed for each mole of fructose-1,6-diphosphate that is split into pyruvic acid
• 2 moles of ATP were required to phosphorylate the original glucose to form fructose-1,6-diphosphate
• A net gain of 2 moles of ATP were achieved with for each mole of glucose • Thus 24 kcal of energy were generated from the 56 kcal in the original glucose,
for an overall efficiency of 43% • Remaining 57% is lost as heat
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Carbohydrate Metabolism Glycolysis and the Formation of Pyruvic Acid • The next stage in the degradation of glucose
is a two-step conversion of the two pyruvic acid molecules
• Here, two carbon dioxide molecules and four hydrogen atoms are released, while the remaining portions of the two pyruvic acid molecules combine with coenzyme A, a derivative of the vitamin pantothenic acid, to form two molecules of acetyl-CoA
• In this conversion, no ATP is formed, but up to six molecules of ATP are formed when the four released hydrogen atoms are later oxidized
2 Pyruvate + 2 CoA + 2 NAD+
O
OHO
PO3--
N
N
N
N
NH2
O
PO
PO
N
N
HS
O
OOHCH3
O-O
O-O
H3C2 acetylCoA + 2 CO2 + 2 NADH + 2 H+
Acetyl-CoA
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Citric Acid Cycle
• The next stage in the degradation of the glucose molecule is called the citric acid cycle • Tricarboxylic acid cycle • Krebs cycle
• This is a sequence of chemical reactions in which the acetyl portion of acetyl-CoA is degraded to carbon dioxide and hydrogen atoms • Occurs in the matrix of the mitochondrion • Released hydrogen atoms will subsequently be oxidized releasing tremendous
amounts of energy to form ATP
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© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Citric Acid Cycle
NAD+
NADH & H+
NAD+
NADH + H+ +CO2
NAD+
CoASH
NAD+
NADH & H+
CoASH
NADH + H+ +CO2
6 1 1,6
follow the carbons
CC OCH3
O O-
SC OCH3
CoA
H2CC
H2C
COO-
COO-HO COO-
H2CCHC
COO-
COO-H COO-
OH
H2CCH2C
COO-
COO-
O
H2CCH2C
COO-
SO
CoAH2CH2C
COO-
COO-
HCHC
COO-
COO-
HCH2C
COO-
COO-
OH
CH2C
COO-
COO-
O
Fumarate
Succinate Succinyl-CoA
α-Ketoglutarate
Isocitrate
Citrate
Acetyl-CoA
Pyruvate
Malate
Oxaloacetate CoASH
CO2
H2O
H2O
FADH2
FAD
P
ADP
GDP GTP
ATP
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Citric Acid Cycle
• Considering the citric acid cycle as a whole • 2 acetyl-CoA molecules and 6 molecules of water enter into the citric acid cycle • 4 carbon dioxide molecules, 16 hydrogen atoms, 2 molecules of coenzyme A,
and 2 molecules of ATP are formed
• 24 H atoms are released from each molecule of glucose • 4 during formation of acetyl-CoA (x2) and 16 in the citric acid cycle • 20 of the 24 hydrogen atoms immediately combine with nicotinamide adenine
dinucleotide (NAD+), a derivative of the vitamin niacin, to form NADH • Reaction requires a specific dehydrogenase and NAD+ • Free H and NADH go on to form ATP
• Remaining 4 H go into oxidative processes
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Carbohydrate Metabolism Oxidative Phosphorylation
• Despite all the complexities of glycolysis, citric acid cycle, dehydrogenation, and decarboxylation, only small amounts of ATP are formed
• Almost 90% of total ATP created is formed during subsequent oxidation of H atoms • Thus, the principal function of earlier stages
is to make H atoms
• Oxidation of hydrogen is accomplished by a series of enzymatically catalyzed reactions in the mitochondria • H is splint into a hydrogen ion and an
electron • Electrons combine with dissolved oxygen to
form hydroxyl ions, which then combine with H to ultimately form water
Food
NADH + H+
FMN
FeS
O
b
FeS
C1
C
A
A3
6H+
2H+
2H+
2H+
ATPase
2e- + ½O2
H2O
6H+
ATP
ADP 3ADP
3ATP
Inner Membrane
Inner Matrix
Outer Chamber
2e- + NAD+ + H+
Cytoplasm Mitochondria
Outer Membrane
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Oxidative Phosphorylation
• First, mitochondria ionize H from food, to form of H+ as well as NADH
• Electrons, that are removed from H to cause the hydrogen ionization, immediately enter an electron transport chain in the inner membrane of the mitochondrion • Electron acceptors can be reduced or oxidized
by accepting or giving electrons • Electron transport chain members include
flavoprotein, several iron sulfide proteins, ubiquinone, and cytochromes B, C1, C, A, and A3
• Each electron is shuttled from one of these acceptors to the next until it finally reaches cytochrome A3, which is called cytochrome oxidase because it is capable of giving up two electrons and thus reducing elemental oxygen to form ionic oxygen, which then combines with hydrogen ions to form water
Food
NADH + H+
FMN
FeS
O
b
FeS
C1
C
A
A3
6H+
2H+
2H+
2H+
ATPase
2e- + ½O2
H2O
6H+
ATP
ADP 3ADP
3ATP
Inner Membrane
Inner Matrix
Outer Chamber
2e- + NAD+ + H+
Cytoplasm Mitochondria
Outer Membrane
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© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Oxidative Phosphorylation
• As the electrons pass through the electron transport chain, large amounts of energy are produced and used to pump hydrogen ions into the outer chamber between the inner and outer mitochondrial membranes producing • A high concentration of positively charged
hydrogen ions in this chamber • A strong negative electrical potential in the
inner matrix
• ATPase converts ADP into ATP, utilizing the energy derived from this hydrogen ion flow as well as a free ionic phosphate radical (Pi)
• ATP is transferred from the inside of the mitochondrion back to the cell cytoplasm by facilitated diffusion • ADP is continually transferred in the other
direction for continual conversion into ATP
Food
NADH + H+
FMN
FeS
O
b
FeS
C1
C
A
A3
6H+
2H+
2H+
2H+
ATPase
2e- + ½O2
H2O
6H+
ATP
ADP 3ADP
3ATP
Inner Membrane
Inner Matrix
Outer Chamber
2e- + NAD+ + H+
Cytoplasm Mitochondria
Outer Membrane
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism ATP Formation From Glucose • During glycolysis, 4 molecules of ATP are formed, and 2 are expended to cause the
initial phosphorylation of glucose - giving a net gain of 2 molecules of ATP • During each citric acid cycle, 2 molecules of ATP are formed, 1 from each pyruvic
acid molecules formed from glucose • During glucose breakdown, a total of 24 hydrogen atoms are released during
glycolysis and the citric acid cycle • 20 H atoms are oxidized in oxidative phosphorylation, with the release of 3 ATP
molecules per 2 atoms of hydrogen metabolized, giving 30 ATP molecules • 4 H atoms hydrogen atoms are released by their dehydrogenase in oxidative
phosphorylation; 2 ATP molecules are usually released for every 2 H atoms oxidized, thus giving 4 ATP molecules
• Thus a maximum of 38 ATP molecules formed for each molecule of glucose degraded to carbon dioxide and water • Thus, 456,000 calories of energy can be stored as ATP, whereas 686,000
calories are released from glucose, giving an overall maximum efficiency of 66%
• The remaining 34% becomes heat
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Carbohydrate Metabolism Control of Energy Release from Stored Glycogen • Release of energy from glucose is controlled in accordance with the cells' need for
ATP
• The enzyme phosphofructokinase, which promotes the formation of fructose-1,6-diphosphate, is a key regulator • Inhibition of this enzyme, in response to excess cellular ATP, decreases or even
stops glycolysis • Increases in ADP and AMP greatly increases phosphofructokinase activity,
thereby increasing metabolism • The citrate ion, formed in the citric acid cycle, inhibits phosphofructokinase, thus
linking the citric acid cycle to glycolysis
• Finally, AMP-ADP-ATP provides its own regulation • If all ADP has been converted into ATP, additional ATP simply cannot be formed • Then, when ATP is used, the newly formed ADP and AMP turn on the energy
processes again, and ADP and AMP are almost instantly returned to the ATP state
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Anaerobic Glycolysis • In low oxygen conditions, glycolysis can still occur because it does not require
oxygen, but oxidative phosphorylation cannot take place • This process is extremely wasteful of glucose, because only 24,000 calories of
energy are used to form ATP for each molecule of glucose
• The two end products of the glycolytic reactions are pyruvic acid and hydrogen atoms in the form NADH and H+
• The buildup of either or both of these would stop the glycolysis • However, these two end products react with each other to form lactic acid
• Thus, under anaerobic conditions, the major portion of the pyruvic acid is converted into lactic acid, which diffuses readily out of the cells into the extracellular fluids and even into the intracellular fluids of other less active cells • Thus glycolysis can proceed for several minutes, supplying the body with
considerable extra quantities of ATP, in the absence of oxygen
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Carbohydrate Metabolism Anaerobic Glycolysis • Once oxygen is available again after anaerobic glycolysis, lactic acid is rapidly
reconverted to pyruvic acid and NADH plus H+
• These are immediately oxidized to form large quantities of ATP
• Thus, formed lactic acid is not lost from the body because, when oxygen is once again available, it can be either reconverted to glucose or used directly for energy • Reconversion occurs mainly in the liver
• Heart muscle is especially capable of converting lactic acid to pyruvic acid and then using the pyruvic acid for energy, allowing the heart extra energy during heavy exercise
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Pentose Phosphate Pathway • A second mechanism for the breakdown and oxidation
of glucose is called the pentose phosphate pathway, accounting for up to 30% of glucose breakdown • As an alternate pathway, it provides a source of
energy when enzymatic abnormalities occur • Glucose releases one molecule of carbon dioxide and
four atoms of hydrogen, forming a five-carbon sugar, D-ribulose-5-phosphate
• D-ribulose-5-phosphate can become one of several other five-, four-, seven-, and three-carbon sugars, and finally reforming glucose • Only 5 molecules of glucose are resynthesized for
every 6 reacted • By repeating the cycle, glucose can eventually be
converted into carbon dioxide and hydrogen • The released hydrogen combines with
nicotinamide adenine dinucleotide phosphate (NADP+), forming NADPH which can be used for the synthesis of fats from carbohydrates
Guyton & Hall. Textbook of Medical Physiology, 11th Edition
14
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Glucose Conversion to Glycogen or Fat
• When glucose is not immediately required for energy, the extra glucose that continually enters the cells is either stored as glycogen or converted into fat
• Glucose is preferentially stored as glycogen until the cells have stored an amount sufficient to supply the energy needs of the body for only 12 to 24 hours
• When the glycogen-storing cells, primarily liver and muscle cells, approach saturation with glycogen, the additional glucose is converted into fat in liver and is stored as fat in adipocytes
© Copyright 2012, John P. Fisher, All Rights Reserved
Carbohydrate Metabolism Gluconeogenesis • When the body's stores of carbohydrates decrease below normal, moderate
quantities of glucose can be formed from amino acids and the glycerol portion of fat - gluconeogenesis • Gluconeogenesis is especially important in preventing an excessive reduction in
the blood glucose concentration during fasting
• The liver plays a key role in maintaining blood glucose levels during fasting by converting its stored glycogen to glucose (glycogenolysis) and by synthesizing glucose, mainly from lactate and amino acids (gluconeogenesis)
• Diminished carbohydrates in the cells and decreased blood sugar are the basic stimuli that increase the rate of gluconeogenesis
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Carbohydrate Metabolism Blood Glucose • The normal blood glucose concentration is about 90 mg/dl
• After a meal containing large amounts of carbohydrates, this level seldom rises above 140 mg/dl
• The regulation of blood glucose concentration is intimately related to the pancreatic hormones insulin and glucagon
© Copyright 2012, John P. Fisher, All Rights Reserved
Lipid Metabolism Introduction • Lipids include triglycerides, phospholipids, and
cholesterol • Triglycerides and phospholipids contain fatty acids,
or long hydrocarbon chains that may be saturated or unsaturated and contain a carboxylic acid group (-COOH)
• Cholesterol contains a sterol nucleus that is synthesized from fatty acids
• Typical triglycerides in the human body include • Stearic acid, CH3(CH2)16COOH • Oleic acid, CH3(CH2)7CH=CH(CH2)7COOH • Palmitic acid, CH3(CH2)14COOH
H2CO
O
CO
O
CH2O
O
H
Tristearin
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Lipid Metabolism Transport of Lipids in the Body Fluids • Almost all fats, broken down into monoglycerides and fatty acids, are absorbed from
the intestines and into the intestinal lymph
• In intestinal epithelial cells, triglycerides are reformed and dispersed as chylomicron droplets, with the protein apoprotein B decorating their surface • Chylomicrons contain 87% triglycerides, 9% phospholipids, 3% cholesterol, 1%
apoprotein B • After eating, chylomicrons constitute 1 - 2% of plasma volume
• The capillary endothelium of the liver and adipose tissue contain lipoprotein lipase, which hydrolyzes triglycerides within the chylomicrons and thus releasing fatty acids and glycerol • Constituents are absorbed by surrounding cells and resynthesized into
triglycerides
© Copyright 2012, John P. Fisher, All Rights Reserved
Lipid Metabolism Transport of Lipids in the Body Fluids • After chylomicrons have been removed from the blood, 95% of all the lipids in the
blood are lipoproteins containing triglycerides, cholesterol, phospholipids, and protein • Total lipoprotein concentration: 700 mg/dl
• Cholesterol concentration: 180 mg/dl • Phospholipid concentration: 160 mg/dl • Triglyceride concentration: 160 mg/dl • Protein concentration: 200mg/dl
• Most lipoproteins are formed in the liver, with some formed in the intestinal epithelium, and act to transport lipids in the blood
• Four major classes of lipoproteins include • Very low density lipoproteins, which are high in triglyceride concentration • Intermediate density lipoproteins, which are low in triglyceride concentration • Low density lipoproteins, which contain almost no triglyceride concentration • High density lipoproteins, which are high in protein concentration
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Lipid Metabolism Fat Deposits • Fat, contained primarily in adipose tissue and the liver, acts to store triglycerides
• Adipocytes, or fat cells, are essentially fibroblasts with 80 - 95 vol% triglycerides, stored as liquids within large vesicles • Lipases, which catalyze the deposition of triglycerides from chylomicrons,
lipoproteins, and adipocytes, continually function, turning over the triglyceride content of adipocytes every 2 to 3 weeks
• The liver acts to degrade fatty acids, synthesize triglycerides, and synthesize other lipids (phospholipids and cholesterol) • High triglyceride concentrations in the liver occur in early starvation and diabetes
• Here, triglycerides are being obtained from adipose tissue in order to boost energy
• Liver triglyceride concentration, alternatively, describes the rate of lipid consumption for energy
© Copyright 2012, John P. Fisher, All Rights Reserved
Lipid Metabolism Triglyceride Utilization • About 40% of calories consumed by Americans are fats, almost equal to the amount
of calories consumed as carbohydrates
• Upon ingestion, triglycerides are hydrolyzed into fatty acids and glycerol • Fatty acids are used by almost all cells as an energy source • Glycerol is converted into glycerol-3-phosphate and enters glycolysis
• Fatty acids are transported into the mitochondria and then undergo beta-oxidation to yield acetyl-CoA, which then enters the citric acid cycle • Four H atoms are also released per carbon in the fatty acid chain
ATP CoA
AMP Pyrophosphate
Thiokinase Acyl
Dehydrogenase Enoyl hydrase β-Hydroxyacyl Dehydrogenase Thiolase
FAD H2O NAD+ CoA
FADH2
NADH H+
OHO
R
SO
R
CoAS
O
R
CoAS
O
R
CoA
HO
SO
R
CoA
O
SO
R
CoA
OCoA
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© Copyright 2012, John P. Fisher, All Rights Reserved
Lipid Metabolism Triglyceride Utilization • The resulting acetyl-CoA is then converted in the liver into ketone bodies, particularly
acetoacetic acid, acetone, or β-hydroxybutyric acid • These compounds then diffuse freely out of the liver and into the blood, where
they are distributed throughout the body • When received in distal tissues, these compounds are re-converted back into
acetyl-CoA and enter the citric acid cycle
• During starvation, diabetes, and an extremely high fat diet, a condition termed ketosis occurs, where the concentration of ketone bodies becomes very high • Carbohydrate metabolism stops, either due to the lack of carbohydrates
(starvation or high fat diet) or due to inhibited glucose transport into the cells (diabetes)
• Energy must then come from fat metabolism, increasing ketone body blood concentration
• However, the scarcity of oxaloacetate limits this mechanism, further increasing ketone body concentration
© Copyright 2012, John P. Fisher, All Rights Reserved
Lipid Metabolism Synthesis of Triglycerides • Storage of carbohydrates first occurs in the form of glycogen, but once “filled”
carbohydrates are then stored as triglycerides • (1) carbohydrates are converted to acetyl-CoA by glycolysis, (2) acetyl-CoA is
converted to malonyl-CoA, (3) malonyl-CoA combines with acetyl-CoA and eventually forms a fatty acid in a manner similar to the reverse of beta-oxidation, and (4) fatty acids combine with glycerol to form a triglyceride
• Storage of carbohydrates as fat is highly efficient as fat storage capacity is much larger than glycogen storage, and energy storage in fat is much higher (x2.5) than in glycogen
ACP-SH
ADP P H+
NADP+
NADPH H+
CoASH
KSase
ACP-SH
ATP HCO3
- ACP-SH
CoASH
CO2 H2O NADP+
NADPH H+
β-Ketoacyl-ACP reductase
β-Hydroxyacyl- ACP dehydratase
2,3-trans-Enoyl- ACP reductase
SO
CH3
CoAS
OCH3
ACPS
OCH3
KSase
SO
CH3
CoAS
O
CoA
O-O
SO
ACP
O-O
SO
ACP
CH3O
SO
ACP
CH3HO
SO
ACP
CH3
SO
ACP
CH3
ACP = acyl carrier protein KSase = β-ketoacyl-ACP synthase
19
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Lipid Metabolism Phospholipids • The major phospholipids include
lecithins, cephalins, and sphingomyelin
• Phospholipids are formed throughout the body, however 90% are formed in the liver
• Phospholipid formation follows fat metabolism, although some compounds such as choline and inositol are required
• Phospholipids acts as • Lipoproteins in blood • Thromboplastin, for blood clotting • Sphingomyelin, in melin insulation • Phosphate donors in phosphate
chemistries • Formation of cell membranes
A Lecithin
H2COO
PO
N+CH3H3C
H3C
HO OO
O
H3C H3C
HC CH2
O
H2COO
PO
+H3N
HO OO
O
H3C H3C
HC CH2
O
H2COPO
N+CH3H3C
H3C
HO OHN
O
H3C
H3C
HC CH
OH
A Cephalin Sphingomyelin
© Copyright 2012, John P. Fisher, All Rights Reserved
Lipid Metabolism Cholesterol • Cholesterol may be ingested (exogenous) or synthesized (endogenous)
• Synthesized cholesterol is formed in the liver from multiple molecules of acetyl-CoA
• Cholesterol plasma concentration is upregulated by • Cholesterol ingestion, although this downregulates cholesterol
synthesis • High saturated fat ingestion, which increases liver synthesis of
acetyl-CoA • Low unsaturated fat ingestion • Lack of insulin of thyroid hormone
• Cholesterol is utilized to • Form cholic acid in the liver which, in the form of bile salts,
promotes digestion and absorption of fats • Form adenocortical hormones, progesterone, estrogen, and
testosterone • Provide the skin with the ability to resist the absorption of water
soluble substances • Form cellular membranes and regulates the stiffness of membranes
HO
Cholesterol
20
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Lipid Metabolism Atherosclerosis • Atherosclerosis involves the formation of fatty
lesions, atheromatous plaques, in the interior of arterial walls
• After damage to the vascular endothelium lining arterial wall, monocytes and lipids (LDLs) accumulate
• Monocytes adhere, migrate through, differentiate into macrophages
• Macrophages aggregate, cause inflammation, eventually causing a reduction in lumenal cross section, decreasing blood flow at very low lumen diameters
• Concurrently, sclerosis (fibrosis) of the artery becomes great, creating a stiff and rigid vessel
• Results include stiff arteries, clot formation, and potential block arterial blood flow
Guyton & Hall. Textbook of Medical Physiology, 11th Edition
© Copyright 2012, John P. Fisher, All Rights Reserved
Lipid Metabolism Atherosclerosis • Causes of atherosclerosis include
• High LDL concentrations due to a high saturated fat diet
• High LDL receptor expression due to genetic disposition
• Low HDL concentrations
• Risk factors for atherosclerosis include • Physical inactivity and obesity • Diabetes mellitus • Hypertension • Hyperlipidemia • Cigarette smoking
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Protein Metabolism • Proteins are polymeric amino acids, where the amino acid
sequence determines the protein function • An amino acid is formed from
• A central alpha-carbon, with one lone hydrogen • An amino (NH2) group • A carboxyl (COOH) group • An R side chain group determines the type of amino acid
• The central carbon atom is asymmetric, allowing the formation of L and D isomers • Proteins consist exclusively of L-amino acids
• A physiological pH (7.4) both the amino group and carboxyl group are ionized (amino group is NH3
+ / carboxyl group is COO-)
• Proteins are formed from a condensation reaction between an amino group and a carboxyl group, releasing water
CCOOH
H R
H2N
C
H
HOOC NH2
R
L isoform
D isoform
N terminus Always written
on the left C terminus
plane formed by rigid C-N bond
HN CH C
H
O
HN CH C
H
OH
O
NH
CH C
H
O
H2N CH C
H
O
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Protein Metabolism Transport and Storage • Upon food digestion, almost all proteins are digested and absorbed in the form of
amino acids - rarely are polypeptides or proteins absorbed into the blood
• The normal blood concentration of amino acids is between 35 and 65 mg/dl • Concentration rises only slightly after eating, due to
• Digestion and absorption occur over the course of hours • Amino acid uptake by tissues, especially the liver, is quick
• Amino acids are too large for diffusion through cell membranes, thus are taken up by facilitated transport or active diffusion
• In the kidneys, amino acids are actively reabsorbed by the proximal tubular epithelium
• Absorbed amino acids are quickly reused in protein synthesis, thus storage of amino acids is low • Cells do contain small quantities of amino acids, releasable during deficiency • The liver contains proteins that are easily broken down for use as a amino acids • Excess amino acids can be converted into energy, fat, or glycogen
22
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Protein Metabolism Plasma Proteins • The major plasma proteins include albumin, globulin,
and fibrinogen • Albumin contributes of colloid osmotic pressure • Globulins act in the immune response • Fibrinogen polymerizes to form blood clots
• Most plasma proteins are formed in the liver at extremely high rates (30 g/day), with the remainder - usually globulins - formed in the lymph tissues
• Plasma proteins act as a source of amino acids for the cellular needs of most tissues
• Total body protein synthesis is huge (400 g/day), establishing an equilibrium between bodily proteins and circulating plasma proteins
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Protein Metabolism Plasma Proteins • Ten amino acids are easily synthesized by cells in the human body
• Nonessential amino acids are formed from α-keto acids • Some amino acids, including glutamine, asparagine, glutamic acid, and aspartic
acid, act as a storehouse for amino radicals utilized in the formation of other amino acids
• Another ten amino acids are not synthesized, or synthesized at such low quantities, that they must be ingested - essential amino acids
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Protein Metabolism
H2N CH C
CH3
OH
O
alanine
H2N CH C
CH2
OH
O
CH2
CH2
NH
C
NH2
NH arginine
H2N CH C
CH2
OH
O
C
NH2
O
asparagine
H2N CH C
CH2
OH
O
C
OH
O
aspartic acid
H2N CH C
CH2
OH
O
SH
cysteine
H2N CH C
CH2
OH
O
CH2
C
OH
O
glutamic acid
H2N CH C
H
OH
O
glycine
H2N CH C
CH2
OH
O
N
NH
histidine
H2N CH C
CH
OH
O
CH3
CH2
CH3
isoleucine glutamine
H2N CH C
CH2
OH
O
CH CH3
CH3
leucine
H2N CH C
CH2
OH
O
CH2
CH2
CH2
NH2lysine
H2N CH C
CH2
OH
O
CH2
S
CH3
methionine
H2N CH C
CH2
OH
O
phenylalanine
HN
C OH
O
proline
H2N CH C
CH2
OH
O
OH
serine
H2N CH C
CH2
OH
O
HN
tryptophan
H2N CH C
CH2
OH
O
OH
tyrosine
H2N CH C
CH
OH
O
CH3
CH3
valine
H2N CH C
CH
OH
O
OH
CH3
threonine
H2N CH C
CH2
OH
O
CH2
C
NH2
O
essential amino acids
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Protein Metabolism Protein Utilization • Additional amino acids are utilized as a source of energy or as fat
• First, amino acids are deaminated, with the resulting amine group (-NH3) converted into urea and excreted
• Next, resulting keto acids are oxidized and enter the citric acid cycle • Alternatively, keto acids may be utilized to synthesize glucose (gluconeogenesis)
or fatty acids (ketogenesis)
• The body, lacking protein intake, will degrade approximately 20 to 30 gm of protein each day • Thus, the minimum protein intake is 20 to 30 gm per day • In times of starvation, once stored carbohydrates and fats are utilized, protein
degradation increases to 125 gm per day as the body seeks out alternative sources of energy
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Protein Metabolism Hormonal Regulation • Some well known hormones have a profound affect upon protein synthesis
• Human growth hormone increases protein synthesis, although the mechanism is not fully understood
• Insulin is required for protein synthesis, likely due to its role in transport amino acids into cells
• Glucocorticoids decrease tissue protein content and increase plasma amino acid concentration
• Testosterone increases protein synthesis, although this is limited in contrast to human growth hormone
• Estrogen causes minor protein synthesis
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Liver Physiology • The liver is the largest internal organ of the body,
weighing about 1.5 kg • The functional unit of the liver is the liver lobule, a
cylindrical structure 2 - 3 mm in length and 1 - 2 mm in diameter • A human liver contains 50,000 - 100,000
lobules
• Briefly, blood enters the lobule from the portal vein (1050 ml/min) and hepatic artery (300 ml/min)
• Blood then empties into the central vein, the hepatic vein, and then into the vena cava
• Kupffer cells remove substances and bacteria from the blood, with the filtrate entering into Space of Disse and then into the lymphatic system
• Liver cells, hepatocytes, also remove unwanted substances, with the filtrate entering the bile canaliculi and the bile duct
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Liver Physiology • Large quantities of blood can be stored in the liver
• Normally, 10% (0.45 liters) of blood is retained in the liver
• High right atrial pressure can increase liver volume to 1.00 to 1.50 liters
• Liver lymph flow is also very high • Due to high permeability, liver lymph has a
protein concentration of up to 6 g/dl, only slightly less than plasma
• Half of all lymph is formed in the liver • Liver has great capacity to regenerate
• Partial hepatectomy, up to 70% of the liver, causes the remaining lobules to enlarge and restore the liver to its original size in 5 to 7 days
• HGF promotes liver cell division • TGF-β inhibits liver cell proliferation
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Liver Metabolic Functions • The liver performs vital metabolic functions for maintaining bodily homeostasis • Carbohydrate Metabolism
• Storage of glycogen • Conversion of galactose and fructose into glucose • Gluconeogenesis • Consumption of carbohydrate metabolism products
• Fat Metabolism • Oxidation of fatty acids for energy • Synthesis of cholesterol, phospholipids, and most lipoproteins • Synthesis of fat from proteins and carbohydrates
• Protein Metabolism • Deamination of amino acids • Formation of urea • Formation of plasma proteins • Interconversion of amino acids and proteins
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Liver Metabolic Functions • Vitamin Storage
• Storage of vitamin A, vitamin D, and vitamin B12
• Iron Storage • The liver stores iron in the form of ferritin, which is sequestered by hepatocytes
by the protein apoferritin • Formation of Coagulation Substances
• Fibrinogen, prothrombin, accelerator globulin, and Factor VII are all key players in blood coagulation and are formed in the liver
• Removal of Substances in the Bile • Drugs including sulfonamides, penicillin, ampicillin, and erythromyocin are all
sequestered by the liver for excretion in the bile • Hormones, including thyroxine, estrogen, cortisaol, and aldersterone are also
removed into the bile • Calcium is also removed into the bile
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Liver Bilirubin • The formation of bile is a major functional outcome of
the liver
• Many substances are excreted into the liver, including bilirubin • Bilirubin is a major end product of hemoglobin
degradation • Bilirubin is a valuable tool for measuring
hemolytic blood diseases as well as liver disease
• Red blood cells have a life span of approximately 120 days, when macrophages then take up the released hemoglobin • Hemoglobin is then split into globin and heme • Heme is degraded to give free iron as well as a
pyrrole nuclei from which bilirubin is formed and released into the blood by macrophages
• Bilirubin binds albumin, and the complex is transported throughout the circulation
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Liver Bilirubin • Bilirubin is absorbed through the hepatic cell
membrane, released from albumin and then conjugated • 80% forms bilirubin glucuronide • 10% forms bilirubin sulfate • 10% forms other substances
• Finally, most of these conjugated forms of bilirubin are excreted • In the intestine, bacteria convert some into
urobilinogen, which is taken back up into the blood
• Most returns to the liver, but about 5% leaves through the kidneys as urine
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Liver Bilirubin • When large quantities of bilirubin collects in the
extracellular fluids, the bodily tissues including the skin turns a yellowish color known as jaundice • Normal plasma contains bilirubin at 0.5 mg/dl • Jaundice is visible at about 1.5 mg/dl, and can
increase to as high as 40 mg/dl
• Jaundice is caused by • Increased red blood cell destruction (hemolytic
jaundice), where most of the bilirubin is free • Obstruction of the bile ducts (obstructive
jaundice), where most of the bilirubin is conjugated
• In neonatal cases, the liver functions poorly and cannot conjugate significant amount of bilirubin with glucuronic acid (physiologic hyperbilirubinemia)
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Dietary Balances Introduction • The intake of carbohydrates, fats, and proteins provides energy to perform bodily
functions
• Stability of bodily weight and composition requires that energy intake must closely follow energy output • Intake too much, high levels of fat are stored and body mass increases • Intake too little, energy stores are depleted and body mass decreases
• On average, the physiologically available energy of foodstuffs are Carbohydrates 4 kcal/gram Fat 9 kcal/gram Protein 4 kcal/gram
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Dietary Balances Introduction
% Protein % Fat % Carbohydrate Calories per 100 Grams
Apples 0.3 0.4 14.9 64
Asparagus 2.2 0.2 3.9 26
Bacon, fat 6.2 76.0 0.7 712
Beef 17.5 22.0 1.0 268
Beets, fresh 1.6 0.1 9.6 46
Bread, white 9.0 3.6 49.8 268
Butter 0.6 81.0 0.4 733
Cabbage 1.4 0.2 5.3 29
Carrots 1.2 0.3 9.3 45
Cashew nuts 19.6 47.2 26.4 609
Cheese, cheddar, American 23.9 32.3 1.7 393
Chicken 21.6 2.7 1.0 111
Chocolate 5.5 52.9 18.0 570
Corn 10.0 4.3 73.4 372
Haddock 17.2 0.3 0.5 72
Lamb, leg 18.0 17.5 1.0 230
Milk, fresh whole 3.5 3.9 4.9 69
Molasses 0.0 0.0 60.0 240
Oatmeal, dry, uncooked 14.2 7.4 68.2 396
Oranges 0.9 0.2 11.2 50
Peanuts 26.9 44.2 23.6 600
Peas, fresh 6.7 0.4 17.7 101
Pork, ham 15.2 31.0 1.0 340
Potatoes 2.0 0.1 19.1 85
Spinach 2.3 0.3 3.2 25
Strawberries 0.8 0.6 8.1 41
Tomatoes 1.0 0.3 4.0 23
Tuna, canned 24.2 10.8 0.5 194
Walnuts, English 15.0 64.4 15.6 702
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Dietary Balances Introduction • Overall, bodily protein consumption is approximately 20 - 30 gm per day and thus an
average person must intake approximately 30 - 50 gm of protein per day
• Animal derived proteins tend to be complete, in terms of their inclusion of all essential amino acids, when compared to those derived from vegetable or grain sources
• A diet high in carbohydrates and fats will depress energy consumption from proteins
• In starvation, after carbohydrate and fat stores have been consumed, proteins stores are utilized as an energy sources
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Dietary Balances Introduction • Nitrogen can be utilized to assess protein consumption
• Average protein contains 16% nitrogen by mass • Excretion of nitrogen occurs approximately 90% in urine (urea, uric acid,
creatinine) and 10% in feces • Thus, 8 gm nitrogen excreted in the urine indicates a consumption of
approximately 55 gm of protein
• Carbon dioxide can be utilized to assess carbohydrate and fat consumption • Respiratory quotient is defined as the ratio of carbon dioxide output to
oxygen usage during metabolism • Carbohydrates have a respiratory quotient of approximately 1.0 • Fats have a respiratory quotient of approximately 0.7
• Here, oxygen is consumed by excess hydrogen atoms • Thus, measuring carbon dioxide output and oxygen consumption
provides an estimate of consumption composition • As the respiratory quotient tends towards 1.0 a high carbohydrate
diet is found, as the respiratory quotient tends towards 0.7 a high fat diet is fond - note that proteins are ignored
30
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Dietary Balances Regulation of Food Intake and Energy Storage • Food intake is largely driven by the body demands for
energy
• Neuronal centers in the hypothalamus drive the control of food intake • The lateral nuclei act as a feeding center,
stimulating a desire for food • The ventromedial nuclei provide a nutritional
satisfaction stimulus, inhibiting the feeding center • The arcuate nuclei bind circulating hormones that
also regulate food consumption
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Dietary Balances Regulation of Food Intake and Energy Storage • The arcuate nuclei contains two sets of neurons
that respond to circulating hormones • Stimulated proopiomelanocortin (POMC)
neurons produce α-melanocyte-stimulating (α-MSH) hormone and cocaine-and-amphetamine related transcript (CART)
• Stimulation decreases food intake and increases energy expenditure
• Other stimulated neurons produce orexigenic substances including neuropeptide Y (NPY) and agouti-related protein (AGRP)
• Stimulation increases food intake and reduces energy expenditure
• Circulating hormones include leptin, insulin, cholecystokinin, and ghrelin
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Dietary Balances Regulation of Food Intake and Energy Storage • Short term regulation of food intake concerns control mechanisms that are exerted at
each meal
• Gastrointestinal filling provides inhibitory signals to the feeding center, reducing the desire for food
• Gastrointestinal hormones are also released • Cholecystokinin (CCK) is released in response to fat entering the duodendum,
reducing subsequent eating • Peptide YY (PYY) is also released, with level of release reflecting the level of
incoming fat content • Glucagon-like peptide is released, stimulating insulin production and secretion
and suppressing appetite • The stomach releases ghrelin during fasting, with blood levels of ghrelin peaking right
before eating • Oral receptors also respond to food intake by decreasing hunger, but this level of
control is significantly less than the inhibition caused by gastrointestinal filling
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Dietary Balances Regulation of Food Intake and Energy Storage • Intermediate and long term regulation of food intake controls the maintenance of
normal quantities of energy stores in the body
• Blood concentrations of glucose, amino acids, and lipids are key controlling mechanisms, increasing hunger as their concentrations fall, indicating glucostatic, aminostatic, and lipostatic theories of regulation
• High temperatures reduce food intake, while low temperature increase food intake due to an interaction between temperature regulating and food intake regulating systems • Increased food intake at low temperatures increases metabolic rate, thus heat
generation, and increases fat content, thus heat insulation • High fat storage increases leptin production from adipocytes, which stimulates POMC
neurons and results in a decrease fat storage due to • Decreased production NPY and AGRP • Release of α-MSH and corticotropin-releasing hormone • Increased metabolic rate and energy expenditure • Decreased insulin secretion
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Dietary Balances Obesity • Obesity, or an excess of body fat, can be defined by two clinical measures
• Body Mass Index (BMI), where BMI = weight (kg) / height (m)2
• BMI > 25 is defined as overweight, and BMI > 30 is defined as obese • Percentage of body fat
• Body fat > 25% (men) or > 35% (women) is defined as obese
• Obesity results when energy intake is much greater than energy output • Energy excess is stored as fat in adipocytes
• For each 9.3 kcal of excess energy intake, approximately 1 gm of fat is stored
• Adipocyte storage of fat can occur by both increasing the number of adipocytes (hyperplastic) and increasing the size of adipocytes (hypertrophic)
• An extremely obese person can have 4 times the number of adipocytes, each containing twice the lipid content, of a lean person
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Dietary Balances Obesity • There have been a number of factors that have been implicated in obesity
• Sedentary lifestyle • Abnormal feeding, including both food content and eating habits • Childhood over nutrition • Neurogenic abnormalities and genetic factors
• See previous discussion of neurotransmitters involved in eating regulation
• Treatment of obesity involves the reduction of energy consumption and in the increase in energy output • Reduction in consumption of 500 kcal per day will achieve a weight loss of
approximately 1 pound per week • Reduction can be realized by a number of mechanisms
• Increase in consumption of non-nutritious substances • Drugs which attempt to decrease hunger • Drugs which alter fat metabolism, causing increased fat excretion • Increase in physical activity
33
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Dietary Balances Inanition • Inanition is the opposite of obesity, and is characterized by extreme weight loss
• Anorexia • A reduction of food intake caused primarily by diminished appetite
• Anorexia nervosa • The loss of all desire for food due to an abnormal psychic state
• Cachexia • A metabolic disorder of increased energy expenditure leading to weight loss
• Almost all types of cancer cause both anorexia and cachexia • Central neural and peripheral factors are believed to play a major role in the
development of these disorders
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Dietary Balances Vitamins and Minerals • A vitamin is defines as an organic compound needed in small quantities for normal
metabolism that cannot be manufactured by the body • Storage of vitamins occurs in all cells, but is concentrated in some areas
including the liver
• Minerals are elements, such as sodium, potassium, and calcium, utilized by the body for a host of bodily functions, primarily at the cellular level
34
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Dietary Balances Vitamins and Minerals Important Vitamins • Vitamin A (Retinol) • Thiamine (Vitamin B1) • Niacin • Riboflavin (Vitamin B2) • Vitamin B12 • Folic Acid • Pyridoxine (Vitamin B6) • Pantotheni Acid • Ascorbic Acid (Vitamin C) • Vitamin D • Vitamin E • Vitamin K
Important Minerals § Sodium § Potassium § Chloride § Calcium § Phosphorous § Iron § Iodine § Magnesium § Cobalt § Copper § Manganese § Zinc
© Copyright 2012, John P. Fisher, All Rights Reserved
Energetics Introduction • As described earlier, the consumption of carbohydrates, fats, and proteins is largely
the first step in the synthesis energy for cellular functions - and this occurs by the production of ATP • ATP contains 12,000 calories per mole under physiological conditions and can
“power” nearly all chemical reactions is the body
• ATP is the power source for many cellular functions • Protein synthesis from amino acids • Muscle contraction due to actin-myosin crossbridge formation • Molecular transport across cellular membranes by active mechanisms • Action potential transmission by the establishment of ion gradients across cell
membranes
35
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Energetics Introduction • The most abundant source of energy in the body, however, is not
ATP but phosphocreatine which is 3 to 8 times more abundant • Phosphocreatine contains a high energy phosphate bond,
capable of producing 13,000 calories per mole under physiological conditions
• Phosphocreatine does not couple directly with chemical reactions that drive cellular functions, but acts as a buffer to maintain ATP concentration • High ATP concentrations increase phosphocreatine production • Low ATP concentrations cause phosphocreatine consumption
• The higher phosphate bond energy in phosphocreatine favors the production of ATP, while high ATP concentrations favor the retention of phosphocreatine
Phosphocreatine + ADP Creatine + ATP
N NPOH
CH3
NHO
OH
OH
O
Phosphocreatine
© Copyright 2012, John P. Fisher, All Rights Reserved
Energetics Introduction
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Energetics Metabolic Rate • Metabolism refers to the chemical reactions that underlie all normal cellular processes
in the body
• Metabolic rate is normally expressed as the rate of heat liberation during these chemical reactions, as heat is the major byproduct
• Metabolic rate may be measured by a number of techniques • Calorimetry, where bodily heat generation is realized by a change of air or water
temperature • Indirect Calorimetry, where it is assumed that the average energy liberation is
4.825 kcal per liter of oxygen utilized
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Energetics Metabolic Rate • A 70 kg man in bed consumes 1650 kcal per day • Eating and digestion consumes an additional 200
kcal per day • Sitting without exercising consumes an additional
150 to 400 kcal per day • Thus, a sedentary man consumes about 2000
kcal per day
• The minimal amount of energy needed to exist is defined as the basal metabolic rate (BMR) and accounts for 50 - 70% of daily energy needs in a sedentary person • Normal BMR is 65 - 70 kcal per hour • Skeletal muscle accounts for 20 - 30% of
BMR • BMR falls dramatically with age, following the
loss in skeletal muscle
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Energetics Metabolic Rate • BMR is a function of many inputs
• Thyroid hormone increases BMR as much as 50 to 100% in response to thyroxine secretion
• Testosterone increases BMR 10 to 15% by increasing muscle mass
• Growth hormone increases BMR 15 to 20% due to increased cellular metabolism
• Increased temperature, as occurs in fever, increases BMR (12% per 1°C increase)
• Sleep decreases BMR due to decreased muscle and neural activity
• Malnutrition decreases BMR
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Energetics Metabolic Rate • Ingestion of food increases BMR due to the chemical reactions associated with
digestion, absorption, and storage of the food • Thermogenic effect of food, accounts for 8% of total daily energy expenditure • High carbohydrate meals increase BMR 4% • High protein meals increase BMR up to 30%
• Specific dynamic action of protein
• In response to cold, the body can engage in nonshivering thermogenesis • Here, the sympathetic nervous system releases norepinephrine and epinephrine,
causing brown fat, which is high in mitochondria content, to undergo uncoupled oxidative phosphorylation - producing heat, but little ATP
• Neonates have a high brown fat content • Adults have little brown fat content
• Note that shivering itself is a means of inducing skeletal muscle activity as a protection from cold temperatures