Transcript Prezentace aplikace PowerPoint

Patofyziology of lipids, proteins,
aminoacids and purins
Pathophysiology of obesity
Prof. Jan Hanacek
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
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
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
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)
I. Disturbancies of lipid metabolism
Essential types of disturbancies
1. Hyperlipoproteinemias
2. Hypolipoproteinemias
3. Dyslipidemias
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, nonesterified 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
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
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)
• 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
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
1. 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 TAGs+Ch)
Dyslipoproteinemias – disorder in lipid spectrum
in blood, usually with
increased concentration of
cholesterol
a) 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)
Classification of hyperlipoproteinemias
(according Necas et al., 2000)
Typ
 lipoprotein
 lipid
1
CM
TAG
2a
LDL
cholesterol
2b
LDL,VLDL
cholesterol, TAG
3
IDL,CM- remnants
TAG, cholesterol
4
VLDL
TAG
5
VLDL,CM
TAG, cholesterol
Main types of hyperlipoproteinemias (HLP)
A. 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
secretion
• genetic predisposition

• acquired (due to environmental factors) of VLDL
by liver
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
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
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
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
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
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
II. Disorders of protein and aminoacids
metabolism
1. 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
– 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
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
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
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
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
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
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
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
Pathophysiology of obesity
Prof. J. Hanacek, M.D., Ph. D.
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
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
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%)
Methods used for diagnosis of obesity
1. 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: <95 for men; <81 for women
d) Skinfold thickness (on the trunk and extremities)
2. Sophisticated techniques:
CT, denzitometria, dilutional methods, spectrometry...
Main causes of body weight increse
a) Muscle mass increase
b) Body water amount
c) 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 obesity:>40 – (grade 3)
Classification of obesity
A. Etiopathogenetic- 1. Primary
2. Secondary
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
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
Main groups of causes lading to obesity
1. Genetic disorders
– about 33% existing forms of obesity is the result
of genes dysfunction
2. 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)
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
BRAIN
Aferent signals
– nerv
– humoral-metabolic
(e.g. insulin, glucose,
CCK, specific cytokines)
Eferent signals
– control of intake
– control of expanditure
– control of fat mass
Influence of i.v. infusion of CCK- 8 on energy intake in
12 healthy young men and women (from MacIntosh et al, 2001)
5000
Energy
Intake
(kJ)

3000
- 25%
1000
0
Control
(saline)
CCK
1ng
CCK
3ng
Effect of i.v. infusion of CCK receptor antagonist
Loxiglumide on energy intake in 40 healthy male subject
(from Beglinger et al, 2001)
Energy
intake
(kJ)
8000
P< 0.004
4000
0
Saline
Loxiglumide
• 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
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
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
Satiety cascade
Satiation
Satiety
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
• 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
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
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
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
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
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