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					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, 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
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                Eferent signals
– nerv                         – control of intake
– humoral-metabolic            – control of expanditure
  (e.g. insulin, glucose,      – control of fat mass
 CCK, specific cytokines)
    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       CCK         CCK
                   (saline)      1ng          3ng
   Effect of i.v. infusion of CCK receptor antagonist
Loxiglumide on energy intake in 40 healthy male subject
                (from Beglinger et al, 2001)
         8000                P< 0.004
Energy
intake
(kJ)


         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

				
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