Prezentace aplikace PowerPoint

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Patofyziology of lipids, proteins, aminoacids
and purins
Pathophysiology of obesity
Prof. Jan Hanacek
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LIPIDS important part of structural and
functional systems of the human
body important part of
nutrition the most important
sorce of energy are dynamicaly
changed structures a lot of
them are essential for metabolic
processes, others are dangerous They are
divided into three main groups
triglycerides ? energy production
phospholipids ? creaqtion of structural and
cholesterol ? functional molecules,
transport
of signals in the cells

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Functions of some lipids Sphingolipids play an
essential role in maintaining
of normal skin function ceramides
are required for the normal permeability
of skin
they create permeability barrier which
prevents transcutaneous
water loss and
penetration of harmful drugs from the
environment(antigens) Example
of disorder patients suffering from atopic
dermatitis have
significantly decreased
amount of ceramides in the skin?
?permeability of skin for antigens
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Lipid's caveole and rafts structural units of
biologic membranes membrane microdomains
enriched in sphingolipids and cholesterol
part of plasma membrane signaling machinery
they swimm in more fluid phase of membranes
created by glycerophospholipids Functions of
lipid rafts They play key role in
transcytosis and endocytosis
signal transmission
internalisation
of toxins, viruses
and bacterias
cell calcium homeostasis
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Nutritional lipids with saturated fatty acids
(bed) with polyunsaturated fatty
acids(good) Transport of lipids in the body in
form of lipoproteins (LPs)(95) in form of
free fatty acids (FFA) Composition of LPs TAGs,
Cholesterol,
Phospholipids, Proteins Classification of LPs
according their density very low density
(VLDL) intermediate density (IDL)
low density (LDL) high density (HDL)

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I. Disturbancies of lipid metabolism
Essential types of disturbancies 1.
Hyperlipoproteinemias 2. Hypolipoproteinemias 3.
Dyslipidemias
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Essential terms a)Lipoproteins spheric
particles transporting non-polar
lipids (TAGs, cholesterol esters)by
blood Composition and properties inside
of sphere - non-polar lipids surfice of
sphere -polar molecules (phospholipids, non-
esterified
cholesterol- are important
for transport of particles in plasma
-apo-LPs -
are important for LPs
metabolism Different types of LPs
differs by their density, by volume of
transporting lipids, by size, by amount and kind
of apo, by location of their creation, by
their metabolism
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Characteristics of main types of LPs
Chylomicrons(CM) the lowest density, the
largest size VLDL smaller and more dense than
CM they transport endogenous
TAGs synthetised in liver,
mainly IDL particles with properties between
VLDL and LDL LDL containe cholesterol
esters, mainly HDL the smallest size and the
highest density they are able to
transport cholesterol from peripheral
tissues to liver (reversal transport of
cholesterol) Lipoprotein (a) important risk
factor for development
of atherosclerosis
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b) Enzyms important in lipids metabolism
Lipoprotein lipase (LPL) releses FFAs from
TAGs and from VLDL it is present in
endothelial cells it is activated by Apo C
II (it is present in CM and VLDL)
Liver lipase (LL ) it hydrolyses TAGs in
the liver it is activated by interaction
with Apo E Lecithin-cholesterol-acyl
transferase (LCAT) Cholesterol
ester-transfer-protein (CETP)

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LDL receptor it takes up LDL (IDL), it is
localised at cells
in different types of tissues,
predominantly at hepatocytes In
predispose patients ? intake of cholesterol
? down regulation of LDLr in liver ? ? uptake
of LDL from blood HDL receptor it takes off
HDL from blood, it is
localised predominantly in cells created
steroids
tropic hormons from anterior
hypophysis stimulates
creation of HDL
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Scavenger receptors (SR) uptake the LDL which
were not bind by LDLr uptake of oxidized LDL
particles they are present in macrophages, in
smooth muscle cells in vessel wall ?
atherogenesis
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• Hyperlipoproteinemias
• Definitions Pathologic process manifested by
• ? concentration of one or
  more types of LPs
• in the blood
• Hyperlipidemias ?concentration of lipids
• in the blood
  (usually TAGsCh)
• Dyslipoproteinemias disorder in lipid spectrum
• in blood,
  usually with
• increased
  concentration of
• 
  cholesterol

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• Hypercholesterolemias - ? concentration of Ch in
  blood
• It is dengerous situation for the organism
• 75 of blood Ch is LDL cholesterol
• LDL cholesterol is atherogenic
• atherogenity of LDL cholesterol increases
  with the
• degree of its oxidation and glycation
• oxidized and glycated LDL are taking off
  by SR on
• the surfice of macrophages and smooth
  muscle cells?
• ? development of foam cells
• b) Hypertriacylglycerolemias
• c) Combination of a) and b)

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Classification of hyperlipoproteinemias
(according Necas et al., 2000)
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• Main types of hyperlipoproteinemias (HLP)
• Primary
• 1. Familial combined HLP
• it is the most frequent genetic HLP
• it manifests most likely in phenotypes 2a,
  2b, 5
• it acompanies metabolic X syndrome
• it is the strong risk factor for
  development of
• atherosclerosis and ischemic heart
  disease
• Mechanisms involved in development HLP
• genetic predisposition
• acquired (due to environmental factors)

?secretion of VLDL by liver
?
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2. Familial hypercholesterolemia (FHC) it
manifests predominantly by phenotype 2a it
leads to significant acceleration of
atherosclerosis development myocardial
infarction in 4th decade of life
xantomatosis of tendons and arcus lipoides
corneae Mechanisms involved in FHC development
mutation of LDL receptor ? decreased uptake
of LDL ? ?concentration of LDL in blood
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3. Polygenic hypercholesterolemia- the most
frequent hypercholesterolemia (type 2a)
there are not xantoms in 1st line
relatives in family is lower frequency
of hypercholesterolémia than in 2nd types of
HC Mechanisms of development genetic
predisposition changes of resorbtion and
endogenous synthesis of cholesterol, changes in
metabolism of LDL, other changes
environmental factors alcohol, DM, ?intake of
carbohydrates and lipids
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4. Familial dyslipoproteinemia there is
significant xantomatosis and acceleration of
atherosclerosis it manifests in form type 3
HLP Mechanism of development polygenic
disturbance 5. Familial hyper TAG quite
frequent disorder concentration of Ch in blood
must not be increased it manifests in form type
4 HLP Mechanism of development inherited
disorder
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6. Familial defect of lipoprotein lipase and Apo
C II rather rare genetic disorder in
homozygotes accumulation of TAGs in tissues,
xantoms,
hepatosplenomegaly,
high risk of acute pancreatitis it
manifests by phenotype 1 (when defect of LPL)
or by phenotype 5 (when defect of Apo C II )
7. Familial hyperalfalipoprteinemia
?concentration of HDL in blood ? ?risk of
atherosclerosis development Mechanisms of
development genetic disorder low
doses of alcohol estrogens
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B. Secondary are induced by other kind of
disease The most frequent
diseases accompanied by HLP diabetes mellitus
nephrotic syndroma chronic renal failure
hypothyreosis primary biliary cirhosis
chronic alcoholism some drugs, e.g.
contraceptives
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The role of lipid rafts in pathogenesis Disorders
of structure and function of lipid rafts is
involved in pathogenesis of virus infections
e.g. HIV Alzheimer disease, Parkinson
disease prionoses, e.g. Creutzfeldt- Jakob's
disease immunity disorders, e.g. allergy
tumors atherosclerosis systemic hypertension
- others
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II. Disorders of protein and aminoacids
metabolism

• Disorders of nitrogen balance
• a) positive nitrogen balance
• growth, convalescens, gravidity,
  sportsmen...
• b) negative nitrogen balance
• catabolic processes, e.g. chronic
  diseases as are
• CHOLD, cancer, fever, nutritional
  disorders
• 2. Disorders in blood protein spectrum
• a) ?production of monoclonal immunoglobulins,
• e.g. Waldenstrom's macroglobulinemia ?
  ?blood
• viscosity
• Mechanism ?production of IgM

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e.g. multiple myeloma ?? blood viscosity
Mechanism ? production of IgA b) ?production of
cryoglobulins ? disorders of
microcirculation Mechanism cryoglobulins
precipitation when
temperature of blood will decrease
(peripheral blood) c)
hyperfibrinogenemia, cryofibrinogenemia
disorders in hemocoagulation d) hypoalbuminemia
due to liver and renal diseases
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3. Disorders of aminoacids metabolism a)
Phenylketonuria Phenylalanin essential
AA ? tyrosine creation Mechanism - mutation
of gene for phenylalanin
hydroxylase Consequences phenylalanin
accumulation ? onset
of abnormal metabolits creation, e.g.
phenyl
pyruvate, phenylacetate
damage of nerve system
hypopigmentation ( due to
ihibitory
influence of phenylalanin on melanin
creation
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b) Albinism decreased amount or absence of
melatonin in skin, hairs and
eye Mechanism defect of tyrosinase
enzyme Consequences
oculocutaneous albinism increased
sensitivity of skin to UV radiation
photophobia and vision disorders
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c) Alkaptouria (ochronosis) disorders in
metabolism
of phenylalanin
homogentisic acid is created by metabolisation of
phenylalanin there is defect of
oxidation of homogentisic acid
Consequences accumulation of brown-red
pigment in connective tissues
(ochronosis) damage of joints cartilage
? arthrosis damage of heart valves
valvular heart disease excretion of
pigment by urine brown-red or blue-black
color of auricula and sclera
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d) Homocysteinuria accumulation of homocystein
in blood
due to disturbancies of
metabolism of sulphur
containing AA
Consequences ?? concentration of
homocystein in blood damage of
endothelial cells ? accelerated

atherosclerosis damage of vision

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III. Disorders of purin's metabolism
purins -compounds created nucleic acids (NA)
metabolism of purins ? uric
acid (UA) Hyperurikemia and gout
hyperurikemia ?concentration of uric acid in
blood
sorces of uric acid food, NA of the own
organism Primary hyperurikemia the cauce is
not clearly known Possible factors involved
genetic predisposition limited excretion
of UA by kidney high dose of NA in food
?activity of enzymes created AMP, GMP from UA
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Secondary hyperurikemia due to some diseases
renal failure cytostatic therapy of cancer
Uric acid is well excreted when urine is
alkalic Solubility of UA in synovial fluid
decreses with decreasing of its
temperature Gout disease developed due to
hyperurikemia and accumulation of
urates to the distal joints of
foot (microtophi) Pathogenesis creation of
microcrystals of UA in tissues
phagocytosis of microcrystals by LE
cascade of local inflammatory
processes
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Results damage of joints, kidney, vessels
asseptic inflammation of joints and
tissues around them ?
deformation of joints acute
urate nephropathy
IV. Disorders of porfirin's metabolism
see the Color Atlas of Pathophysiology
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Pathophysiology of obesity
Prof. J. Hanacek, M.D., Ph. D.
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Essential epidemiologic data on obesity More
than 7 world population suffer from obesity
Incidence of overweight and obesity has
increased during the last two decades ?
epidemic of obesity Frequency of obesity is
increasing significantly especially in
countries with high of pauperised
inhabitants for a prolonged period, when the
accesability of food suddenly improved There
is increased incidence of obesity in children
Negative influence of obesity on men health is
now convincingly proven
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Definition of obesity We considere as obese
the person whose weight is significantly over
the upper limit of physiologic range, due to
accumulation of fat in men more then 25,
in wumen more tha 30 of total body weight
Obesity is considered as chronic disease
which can result in multiorgan damage
manifeted as complications of obesity
Obesity is the result of influence of many
pathogenic mechanisms
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Physiologic remarks The preponderance of
stored energy consists of fat Intake of energy
and energy expanditure is during longer
period of life in balance Energetic substrates
of food are used in the body for
essential metabolic processes (75) for
thermogenesis (10-15) for exercise
(10-15)
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• Methods used for diagnosis of obesity
• Simple methods
• a) BMI body weight(kg)/ hight (m2)
• Normal BMI 18,5 25
• b) Waist-to-hip ratio
• Normal values 0.7-0.95 men 0.7-0.85 women
• c) Waist circumference lt95 for men lt81 for
  women
• d) Skinfold thickness (on the trunk and
  extremities)
• 2. Sophisticated techniques
• CT, denzitometria, dilutional methods,
  spectrometry...

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• Main causes of body weight increse
• Muscle mass increase
• Body water amount
• Body fat mass increse
• Expression of overweight degree by BMI
• Overweight 25-30 - (grade 1
• Obesity 30-35 (grade 2)
• Obesity 36-40 (grade 2)
• Gross obesitygt40 (grade 3)
• Classification of obesity
• Etiopathogenetic- 1. Primary
• 2. Secondary

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B. Pathologic anatomy 1. Hypertrophic form
2. Hypertrophic-hyperplastic form C.
According fat distribution 1. Android type
(apple shaped) fat localised in trunk
and in abdominal cavity ?risk of DM,
AMI, brain ischemia, other deseases
of CVS 2. Gynoid type (pear shaped)
fat localised at gluteal part, at thighs
? risk of joints damage, mainly
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The main causes and mechanisms involved in
obesity development The essential
pathomechanism Caloric intake exceeds for a
longer time the energy expanditure The
particular mechanisms I. Primary increase of
energy intake II. Primary decrease energy
expanditure III, Combination of both
previous mechanisms
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• Main groups of causes lading to obesity
• Genetic disorders
• about 33 existing forms of obesity is
  the result
• of genes dysfunction
• Environmental factors (with some influence of
  genes)
• socio-economic stress ? lover level of
  education,
• 
  lover incom, lover cultural
• 
  level...
• insufficient physical activity (life
  style)
• national and regional eating habits
• increased intake of alkoholic beverages
  (no chronic
• alcoholism)

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The roles of brain in obesity development brain
controls of caloric intake and energy
expanditure brain structure or/and function
disorders can lead to disorders in energy
intake and energy expanditure
B R A I N
Aferent signals nerv humoral-metabolic
(e.g. insulin, glucose, CCK, specific cytokines)
Eferent signals control of intake control of
expanditure control of fat mass
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Damage of ventro-medial hypothalamus (VMH)
Consequences hyperfagia
?setpoint for body weight ? obesity
Characteristic features of metabolism
?efficacy of metabolism ( glucose is oxidised,
fat is stored)
hyperinsulinemia increased vagal
activity decreased sympathetic
activity Abnormal function of SNS and PSNS
Consequences ?activity of SNS in pancreas,
heart, fat tissues
? abnormal thermogenesis
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Probably common end-part of pathway in
CNS responsible for onseting of obesity Aberant
control of neurons producing NPY (Physiology
-glucose, insulin, leptin... monoamins
in CNS ? inhibition of NPY
production by neurons
in n. arcuatus ? inhibition
energy intake) In obese persons
possible resistance of NPY neurons
to aferent metabolic
signals ? NPY
production is not inhibited ? energy
intake is not inhibited
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Effects of food composition on obesity
onset Hypothesis High concentration of fat in
food ? ? intake of
calories ? development of obesity Results of
research satiating efficiency of fat is
smaller than carbohydrates and proteins ?
passive overeating high energy concentration
in fat unit of food fat in meals taste very
well ? facilitation of eating, speed and
amont of food intake are increased later
development of satiating signal during eating
fatty meals
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Fat paradox signals of satiety induced by fat
intake versus hihg fat
hyperfagia Explanation If fat come to small
intestine ? strong pre-absorbtive signal is
mediated by mainly CCK, also by
glukagon, enterostatin, by products of fat
digestion Signals from energy sorces ? e.g.
satietin, adipsin, leptin... ? modulation of
regulatory circuits in CNS involved in calory
intake control
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Intake of fat per os ? fat will come to small
intestine
with time lap Result less intens and
later signals of satiation ? ?
slowness in decrease of hunger feeling Fat in
mouth ? intens stimulation of taste receptors ?
? facilitation of fat
intake ? nice taste
of fat is able overcome the
satiation signals coming to CNS
High density of energy in fat ? intake of large
amount of energy till satiation signals are
able to inhibit feeling of hunger
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Visceral obesity accumulation of fat
in abdominal cavity
Strong relation does exist between visceral
obesity and development of metabolic
complications Example 2 groups of obese
persons with equal BMI 1st
group fat localised subcutaneously
at trunk 2nd
group fat localised in abdominal cavity
Differences in metabolic parameters
persons in the 2nd group had ?values of PGTT and
?TAG in blood compared with 1st
group Increased fat mass in abdominal cavity
leads to ? sensitivity to insulin
indipentendly on BMI
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Causes and mechanisms involved in visceral
obesity development Ageing Hormons
estrogens ? gynoid type of obesity
progestagens ? slowing of fat
accumulation in viceral locality
androgens ? android type of
obesity
?cortisol level ? visceral
obesity ? sex steroids ?
visceral obesity
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Why visceral obesity is so dengerous? Answer
due to specific properties of visceral
fat Properties of visceral fat its amont is
controled by H-H-A axis it is prone to
lypolysis high intensity of lipolysis by
increased ?-adrenergic activity ? ?FFA in blood
? ? development of insuline resistance
development of dyslipidemia ?TAG, ?LDL

?HDL
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Consequences of obesity Disorders of lipid
metabolism a) ?TAG ? ?production of Ch ?
?secretion of Ch to bile ??risk of
cholelythiasis b) ?TAG ? ?HDL, ?LDL c)
hyperglycemia ? ?risk of DM type 2 development
d) hyperurikemia ? urolythiasis, gout development
e) vascular damage ? atherosclerosis,
hypertension
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Consequences of obesity increased risk of
sudden death development of cardiomyopathy and
cardiomegaly dysturbancies in breathing
Pickwick sy, Sleep related breathing
disorders gonadal dysfunction
osteoarthrosis incresed risk of accidents
dysturbancies of blood coaguability