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 termsa)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)

TypTyp lipoproteinlipoprotein lipidlipid

11 CMCM TAGTAG

2a2a LDLLDL cholesterolcholesterol

2b2b LDL,VLDLLDL,VLDL cholesterol, TAGcholesterol, TAG

33 IDL,CM- remnantsIDL,CM- remnants TAG, cholesterolTAG, cholesterol

44 VLDLVLDL TAGTAG

55 VLDL,CMVLDL,CM TAG, cholesterolTAG, cholesterol

Classification of hyperlipoproteinemias (according Necas et al., 2000)

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 • genetic predisposition • acquired (due to environmental factors)

secretion of VLDLby 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 developmentMechanisms 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 disorders2. 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 increaseb) Body water amountc) Body fat mass increse

Expression of overweight degree by BMI:

Overweight: 25-30 - (grade 1Obesity: 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 involvedin 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

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

EnergyIntake(kJ)

0

1000

3000

5000

Control(saline)

CCK CCK1ng 3ng

Influence of i.v. infusion of CCK- 8 on energy intake in 12 healthy young men and women (from MacIntosh et al, 2001)

-- 25%25%

Energy intake(kJ)

0

4000

8000

Saline Loxiglumide

Effect of i.v. infusion of CCK receptor antagonistLoxiglumide on energy intake in 40 healthy male subject

(from Beglinger et al, 2001)

P<0.004

• 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 CNSresponsible 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 hyperfagiaExplanation:

• 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