Physiologic importance of lipids
• Lipids:
- Triacylglycerols (TAG)
- Phospholipids (PL)
- Free cholesterol (CH) and cholesteryl (CHE)
- Free fatty acids (FFA)
• Importace of lipids are
- (1) an important source of energy (TAG)--adipose tissue (TAG) form in lean
humans about 1/5 of body weight represents the supply of ca. 570000 kJ, enough
for about 3 months a complete starvation
- (2) The starting material for the formation of a variety of substances
(CH)
-- signaling molecules (steroids, prostaglandins, enzymes, cofactors)
-- components of cell membranes (esp. Phospholipids and CH)
-- formation of bile acids
Disorders: hyperlipoproteinemia (HLP) / dyslipidemia
- group of metabolic diseases characterized by increasing lipid and lipoproteins
in the plasma due to
--their increased synthesis
-- reduced catabolism of particles
--respectively. reduction of particulate matter (esp. HDL)
many HLP is atherogenic
- but beware! increased levels of atherogenic lipoproteins in the plasma may not
be at all in relation to the amount of subcutaneous fat, thus HLP ≠ obesity!
• Lipoproteins (concetration of lipoproteins in plasma is a result of the interaction
of genetic factors with the external factors environment)
Digestion and absorption of lipids
Water insoluble lipids contained in the diet (TAG, CH,
phospholipids) are mechanically emulsified by
movements of the gastrointestinal tract and bile so
that they reach the enzymes necessary for their
absorption
- TAG: intestine are digested by pancreatic lipase to
free fatty acids and monoacylglycerol
- PL: digested by pancreatic phospholipases
- CH: cholesterol esters Pancreatic cholesteryl ester
hydrolase to free CH
incomplete absorption (~ 30-60%)
together with bile acids, vitamins soluble in fats and
other substances make up the. mixed micelles, which
are either diffusion or incorporation and release from
the membrane absorbed into enterocytes are
undergoing re-re-esterification into TAG to resorbed
lipids are added apolipoproteins and thus
chylomicrons are formed they are released from
enterocytes into lymph and then into the blood
In plasma circulating lipids as part of lipoprotein (LP)
Lipoproteins
lipoproteins = macromolecular complexes (particles)
consisting of - a protein (= apolipoproteins and
enzymes), structural integrity, binding to receptors,
lipid exchange lipidů- (CH, CHE, TAG, PL), the outer
layer - PL, CH, core - CHE TAG,
circulating lipoproteins:
- (1) resulting from intestine- chylomicrons, HDL;
- (2) formed in the liver: VLDL (very low density
lipoproteins), IDL (intermediate density
lipoproteins), LDL (low density lipoproteins), HDL
(high density lipoproteins)
- (3) incurred in circulation: Lp (a) - the Circus. LDL
and apo-a (liver)
composition (lipids and apolipoproteins) differs
between lipoproteins - VLDL and chylomicrons are
rich in TAG (TAG >>>> CH)
- LDL and HDL conversely CH >>>> TAG
Different lipoproteins have a different metabolic
fate
plasma normally contains: - <1% chylomicrons, - <10%
VLDL - residue of LDL and HDL
Apolipoproteins
are part of the particles varies with its proportion and
accordingly also the working of lipoproteins
- Participates in the structure of the particles and allow the
transport of lipids in an aqueous medium
- Are enzyme cofactors of lipid metabolism
- Particle mediate binding to specific cellular receptors
- Participate in the exchange between lipid particles
all particles that contain apoB (apoB-100, or apo B-48)
are atherogenic - apoB-100 - binding to the LDL receptor apoB-48
- receptor binding chylomicrons "leftovers"
apoC are cofactors LPL (lipoprotein lipase) - apoC-II enables
and apoC-III inhibits - and thus affect the rate of
hydrolysis of TAG
apoE influences the uptake of lipoprotein or 'tails' livers
apoA contributes to the structure of HDL, LCAT cofactor
and binding to HDL receptor-reduced levels of apoA are
atherogenic
apo (a) with their considerable homology with plasminogen
acts as a competitive inhibitor of plasminogen (an enzyme
dissolving fibrin, i.e. blood clot), however, without its
catalytic activity, and an increased risk of thrombosis
Lipid transport
• postprandial phase – digestion of lipids from
the diet
• fasting state – delivery of lipids to the
tissues in need
FA
FA
FA
FA
FA
FA
perifer
cell
perifer
cell
storage
Lipoprotein lipase
Tissue
CH
TAG transport
• chylomikrone formed in enterocytes provide TAG for muscle (=energy substrate) and
adipose tissues (= storage)
• FFA are released from lipoprotein’s TAG; – by LPL (enzyme bound to endothelium of
blood vessels esp. in adipose tissue, muscles, myocardium),
– by hepatic lipase in hepatocytes
• FFA are utilised by either β-oxidation to provide immediate energy (glycerol is used for
gluconeogenesis in liver) or for re-synthesis of TAG for storage
• storage TAG (adipose tissue) can provide FFA upon hydrolysis by hormone-sensitive
lipase (HSL)
• above mentioned processes are regulated by hormones: – inzulin activates LPL and
inhibits HSL, – catecholamines and glucocorticoids activate HSL
• chylomicrons deprived of dietary TAG form chylomikron remnants carrying remaining
dietary cholesterol; remnants are taken up by liver, – binding to the receptor for
chylomicron remnants via apoB-48
• liver form VLDLs from:– (1) TAG synthesized de novo from acetyl-Co A from surplus of
saccharides (after replenishing the liver glycogen), – (2) remaining dietary TAG s CH,
– (3) remaining circulating FFA, – (4) de novo synthesized CH
• VLDLs circulate and are - similarly to chylomicrons - source of TAG for peripheral
tissues (LPL), gradually transforming into IDL and LDL
• PPARα regulated genes:
• - Activation of fatty acid oxidation
• - Reduction of plasma TAG levels
• - Reduction of plasma level of CH
Cholesterol (CH)
CH transport – to the periphery
Overview of CH metabolism
Insuline has important efect on: fat metabolism,
especially:- activation of LPL,- inhibition of HSL
Inhibition of MK oxidation (+ ketogenesis) a
formation of TAG and VLDL in the liver
In diabetes due to a deficiency insulin (T1DM) or
resistence (T2DM) this effect is missing, respectively.
disorder and lipid metabolism
- primarily TAG, - Secondarily also CH overproduction
VLDL (and thus LDL) and increase catabolism HDL
and secondarily further deterioration use of glucose
because of metabolism of sugars and fats together
closely related: competitions of Glc and MK at level
intermediary metabolism
diabetic dyslipidemia is therefore
- atherogenic because it increases supply CH and worsens
reverse transport CH
- pro-diabetic, because it worsens
sensitivity to insulin
fat metabolism, especially. - activation of LPL - inhibition of HSL Inhibition of MK oxidation (+ ketogenesis) a formation of TAG and VLDL in the liver In diabetes due
fat metabolism, especially. - activation of LPL - inhibition of HSL Inhibition of MK oxidation (+ ketogenesis) a formation of TAG and VLDL in the liver In diabetes
fat metabolism, especially. - activation of LPL - inhibition of HSL Inhibition of MK oxidation (+ ketogenesis) a formation of TAG and VLDL in the liver In diabete
Abetalipoproteinemia- AR rare hereditary DMP, completely lacking lipoprotein particles
containing ApoB (chylomicrons, VLDL), the overall level of CHOL and TAG are low, fat malabsorption,
steatorrhoea, stunted growth later formed retinitis pigmentosa and cerebellar
Ataxia is typical acanthocytosis (stratum erythrocytes) deficit of fat-soluble vitamins, impaired
cortisol lipids accumulate in the epithelium, gut - vakuoalizace, the body lacks essential MK (linoleic
acid)
Analfalipoproteinemie (Tangier disease) decreased levels of HDL and ApoA-I, also lower LDL
and total CHOL, HDL does not pass ApoCII → just VLDL, CHOL esters accumulation in tissues,
yellowish enlarged tonsils, hepatosplenomegaly and corneal infiltration, higher incidence of the AT
Familial hypolipoproteinemia associated with longevity, probably for the low incidence of
myocardial infarction. It is still considered a rare genetic, abnormality, probably with autosomal
dominant inheritance. LDL cholesterol levels are reduced below 5 th percentile threshold normal
range.
familial hypoalphalipoproteinemia
It is a genetic lipoprotein abnormalities associated with the occurrence of longevity in the family (about
8 to 12 years compared to the average in the population); expected form of inheritance is autosomal
dominant. Familial forms, however, be distinguished from forms obtained (secondary) eg. when you
abuse alcohol or use contraceptive preparations or preparations based estrogens. The syndrome is
characterized by significant increasing the HDL cholesterol-1 lipoprotein to ELFO), mild to moderate
increase celkového (increased cholesterol in plasma and normal concentrations of S-triglycerides.
Are multiplied HDL particles containing only ApoAI not containing particles as ApoAI and ApoAII
[LPA I And II]. Abnormality is probably due to increased synthesis of apo AI. There is a reduced risk
of cardiovascular disease
induced atherosclerosis.
Hypolipoproteinemia
FA
FA
FA
FA
FA
FA
perifer
cell
perifer
cell
storage
Lipoprotein lipase
Tissue
CH
FA
FA
FA
FA
FA
FA
perifer
cell
perifer
cell
storage
Lipoprotein lipase
Tissue
CH
Hyperlipoproteinaemia
Fredrickson(WHO)
classification
Type I Hyperlipoproteinemia
Type I
Lipoprotein
lipase deficency
Chylomicron
Triacylglycerol
Type IIa Hyperlipoproteinemia
Most common
Familial hypercholesterolemia
Defective LDL receptors
Plasma LDL & cholesterol level are
elevated
Type IIb Hyperlipoproteinemia
Excess of apo-B
↑Pre-beta & beta (VLDL &
LDL)
↑Total cholesterol, LDL, VLDL
& TG
Type III Hyperlipoproteinemia
Abnormal apo-E
‘Broad beta' band (IDL)
↑Total cholesterol & TG
Type IV Hyperlipoproteinemia
Overproduction of VLDL
Pre-beta (VLDL)
↑Triacylglycerol
Type V Hyperlipoproteinemia
Secondary to other causes
Pre-beta (VLDL) plus
chylomicrons
↑Total cholesterol & TG
Eruptive xanthoma Eruptive xanthoma
Palmar xanthoma Tendon xanthoma
Abetalipoproteinemia- AR rare hereditary DMP, completely lacking lipoprotein particles
containing ApoB (chylomicrons, VLDL), the overall level of CHOL and TAG are low, fat malabsorption,
steatorrhoea, stunted growth later formed retinitis pigmentosa and cerebellar
Ataxia is typical acanthocytosis (stratum erythrocytes) deficit of fat-soluble vitamins, impaired
cortisol lipids accumulate in the epithelium, gut - vakuoalizace, the body lacks essential MK (linoleic
acid)
Analfalipoproteinemie (Tangier disease) decreased levels of HDL and ApoA-I, also lower LDL
and total CHOL, HDL does not pass ApoCII → just VLDL, CHOL esters accumulation in tissues,
yellowish enlarged tonsils, hepatosplenomegaly and corneal infiltration, higher incidence of the AT
Familial hypolipoproteinemia associated with longevity, probably for the low incidence of
myocardial infarction. It is still considered a rare genetic, abnormality, probably with autosomal
dominant inheritance. LDL cholesterol levels are reduced below 5 th percentile threshold normal
range.
familial hypoalphalipoproteinemia
It is a genetic lipoprotein abnormalities associated with the occurrence of longevity in the family (about
8 to 12 years compared to the average in the population); expected form of inheritance is autosomal
dominant. Familial forms, however, be distinguished from forms obtained (secondary) eg. when you
abuse alcohol or use contraceptive preparations or preparations based estrogens. The syndrome is
characterized by significant increasing the HDL cholesterol-1 lipoprotein to ELFO), mild to moderate
increase celkového (increased cholesterol in plasma and normal concentrations of S-triglycerides.
Are multiplied HDL particles containing only ApoAI not containing particles as ApoAI and ApoAII
[LPA I And II]. Abnormality is probably due to increased synthesis of apo AI. There is a reduced risk
of cardiovascular disease
induced atherosclerosis.
Hypolipoproteinemia
Hypolipoproteinemia
Abetalipoproteinemia
• Defect in synthesis
of apo-B
Familial lipoprotein
deficiency[Tangier
disease]
• Defect in synthesis
of apo-A
Abetalipoproteinemia
• ↓Apo-B
Defect
• ↓CM VLDL,
LDL
↓Synthesis
• Fat soluble
vitamins are
not absorbed
Malabsorption
• Mental &
physical
retardation
Leads to
Familial α-lipoprotein
deficiency[Tangier disease]
Defect
ABC-1
Decreased
↓↓HDL, A-I
Risk of
CAD
Storage disorders cholesterol
Wolman disease - rare AR deposition of cholesterol esters and triacylglycerols in the liver
cells, kidney, adrenals, hematopoietic system and thin intestines. It is caused by the lack of lysosomal
acid lipase., Accumulation of cholesterol esters in lysosomes of cells of the affected tissues
hepatosplenomegaly, repeated vomiting, persistent diarrhea with steatorrhoea, bilateral adrenal
calcification. fatal.
Familiar deficit of lecithin: cholesterol acyltransferase (LCAT)
It goes into making the deficit a key enzyme in cholesterol esterification. AR levels are elevated
triglycerides and the level of cholesterol is variable; but lacking cholesterol esters (3-30% vs. 75-70%).
Leads to lipid deposition in the cornea (opalescent) in glomerular membrane (proteinuria) in bone marrow
and spleen (Sea Blue histiocytes) in erythrocytes (anemia) in the vascular wall (atheromas). They are
changes in the plasma lipoproteins: triacylglycerolemie 2, 26-11, 3 mmol / l. Most classes have abnormal
lipoprotein
character
Sphingolipidoses inborn errors of metabolism of membrane lipids (sphingolipids) - the
accumulation of these lipids in the relevant bodies.
Gangliosidosis - Norman-Landigova disease -mental retardation, degeneration of
the nervous system, Tay-Sachs gangliosido- Gaucher disease, Scholzová disease, mental retardation,
degeneration of the central and peripheral nervous system-Fabry disease
Gaucher disease - defect lyzosomové B glucozocerebrosidase,
glukózocerebrosid accumulate in the spleen, liver and bone marrow
Niemanova and Pick disease –stogage sphingomyelin and cholesterol
Disorders of β-oxidation of fatty acids
beta-oxidation contributes significantly to ensuring the energy needs in a period of fasting; it is a direct
source of energy for heart and muscle
tissue and source of ketone bodies for about 20 CNSje known disorders are the most common AR
inherited disorder include MCAD (Medium-Chain-acyl
CoA dehydrogenase) and LCHAD (Long Chain 3-OH-acyl-CoA dehydrogenase)
Fatty liver
Excessive accumulation of fat
in the liver parenchymal cells
Liver is not a storage organ for fat
Liver contains about 5% fat
Fatty liver
Accumulation of
fat in the liver
Fibrotic
changes
Cirrhosis
FATTY LIVER: CAUSES
DECREASED
Secretion of
VLDL
INCREASED
Hepatic TG
synthesis
Conditions that cause FATTY LIVER
High fat diet
Starvation
Uncontrolled diabetes
Alcoholism
High cholesterol diet
Dietary deficiency of
Conditions that cause FATTY LIVER
Lipotropic
factors
Essential
fatty acids
Essential
amino acids
Vitamin E
and
selenium
Dietary
deficiency
of
LIPOTROPIC FACTORS
Substances
that prevent
the
accumulation
of fat in the
liver
Choline
Methionine
Betain
Vitamin B12
Folic acid
Regulation of the balance between lipid
storage and mobilization in adipocytes
• the balance (ratio between lipogenesis and lipolysis) is a product of
continuous neurohumoral regulation reflecting feeding/fasting cycling
and immediate
• energy requirements of the body
• 􀂃 (a) normal adipocytes in a fed
• (postprandial) state
• – glucose is taken up by adipocytes via
• GLUT4 stimulated by insulin
• – FFA are released from TAG rich
• lipoproteins (mainly chylomicrons) by the
• action of LPL stimulated by insulin
• – surplus of glucose is the main source for
• TAG production
• 􀂃 (b) normal adipocytes in a fasted state