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Lipid metabolism

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Title: Lipid metabolism


1
Lipid metabolism
  • Pavla Balínová

2
Lipids
  • Lipids dissolve well in organic solvents but they
    are insoluble in water.
  • Biological roles of lipids
  • ? lipids are important source of energy they
    serve as metabolic fuel
  • ? amphipathic lipids are building blocks of
    cellular membranes
  • ? some of them are substrates for synthesis of
    other compounds (eicosanoids, bile acids)
  • ? lipids are excellent insulators

3
Classification of lipids
  • I. Simple lipids
  • ? Triacylglycerols TAG (fats)
  • ? Waxes
  • II. Complex lipids
  • ? Phospholipids
  • ? Sphingophospholipids
  • ? Glycolipids
  • III. Isoprenoids and steroids
  • Isoprenoids vitamins A, D, E, K
  • Steroids sterols, bile acids, steroid hormones

Figure is found on http//en.wikipedia.org/wiki/Tr
iacylglycerol
4
Fatty acids (FA)
The figure was adopted from J.Koolman, K.H.Röhm
/ Color Atlas of Biochemistry, 2nd edition
5
Degradation of fats in adipose tissue
  • Adipose tissue (fat cells) fat storage
  • Degradation of TAG in adipose tissue (lipolysis)
    is catalyzed by hormone sensitive lipase (HSL).
  • This enzyme is activated by epinephrine and
    glucagon and inhibited by insulin.

Figure is found on http//web.indstate.edu/thcme/m
wking/fatty-acid-oxidation.html
6
Utilization of FA within the cell
  • Tissues take up FA from the blood to rebuild fats
    or to obtain energy from their oxidation.
  • Metabolism of FA is especially intensive in the
    liver.
  • Free fatty acids (FFA) are transferred with
    albumin in the blood.
  • FA in blood ? enter to the cell ? in the
    cytoplasm FA are converted to their CoA
    derivatives by enzyme acyl-CoA-synthetase (ATP is
    consumed) ? acyl-CoAs
  • Fatty acid ATP CoA ---gt Acyl-CoA PPi AMP

7
Transfer of acyl-CoAs from cytoplasm to the mit.
matrix is performed by a carnitine transporter
  • Figure is found on http//web.indstate.edu/thcme/m
    wking/fatty-acid-oxidation.html

8
ß-oxidation of fatty acids
  • substrate acyl-CoA
  • product n acetyl-CoA, n NADH H, n FADH2
  • function gain of energy from fatty acids
  • subcelullar location matrix of mitochondria
  • organ location liver, skeletal muscles and other
    tissues with expection to CNS
  • regulatory enzyme carnitine acyltransferase I

9
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10
Summary
  • For complete degradation of palmitic acid 7
    cycles are required.
  • Degradation of palmitic acid (16 C) gives 106 ATP
    in total.
  • Regulation of ß-oxidation of FA
  • Regulatory enzyme is carnitine acyltransferase I
    it is inhibited by malonyl-CoA (intermediate of
    FA synthesis).

11
Synthesis of ketone bodies (ketogenesis)
  • substrate acetyl-CoA
  • product acetoacetate, 3-hydroxybutyrate,
    acetone
  • function energy substrate for extrahepatal
    tissues
  • subcelullar location matrix of mitochondria
  • organ location liver
  • Excessive production of ketone bodies is typical
    during starvation or diabetes mellitus
  • ? lipolysis ? ? FA ? ß-oxidation of FA ? excess
    of acetyl-CoA ? ? ketogenesis

12
Synthesis of ketone bodies (ketogenesis)
Figure is found at http//themedicalbiochemistrypa
ge.org/fatty-acid-oxidation.htmlketogenesis
13
Use of ketone bodies by the extrahepatal tissues
  • acetoacetate and 3-hydroxybutyrate are
    reconverted to acetyl-CoA (? citric acid cycle)
  • is located in matrix of mitochondria of the
    peripheral tissues
  • is significant in skeletal muscles, heart and
    also in the brain if lack of Glc occurs

14
Use of ketone bodies by the extrahepatal tissues
Liver lacks this enzyme therefore is unable to
use ketone bodies as fuel
Figure is found at http//themedicalbiochemistrypa
ge.org/fatty-acid-oxidation.htmlketogenesis
15
Fatty acid synthesis
  • substrate acetyl-CoA, NADPH H
  • product palmitate ( endproduct of FA synthesis)
  • function de novo synthesis of FA which are
    stored as TAG
  • subcelullar location cytosol
  • organ location mainly liver and adipose tissue
    and also other tissues
  • regulatory enzyme acetyl-CoA carboxylase

16
The committed step in FA synthesis
  • Formation of malonyl-CoA from acetyl-CoA and
    HCO3- is catalyzed by enzyme acetyl-CoA
    carboxylase (a key regulatory enzyme). Citrate is
    an allosteric stimulator and palmitoyl-CoA
    inhibits this enzyme.
  • Hormonal regulation glucagon and epinephrine -
    inhibition insulin - stimulation

17
  • The growing fatty acids are linked to a
    phosphopantetheine group of an acyl carrier
    protein (ACP) of FA synthase.
  • Acetyl-CoA is carboxylated by HCO3- to yield
    malonyl-CoA ? condensation between the acetyl-ACP
    and the malonyl-ACP ? acetoacetyl-ACP is formed.

18
FA synthesis is performed through a cycle of four
reactions
  • Figure is found on http//138.192.68.68/bio/Course
    s/biochem2/FattyAcid/FASynthesis.html

19
Biosynthesis of TAG
  • Biosynthesis of TAG occurs in cytoplasm and ER of
    liver and fat cells but also in other tissues.
  • Figure is found on http//web.indstate.edu/thcme/m
    wking/lipid-synthesis.htmlphospholipids

20
Complex lipids(phospholipids, sphingophospholipid
s, glycolipids)
  • Phospholipids
  • glycerol 2 FA phosphate group hydrophilic
    compound
  • Phosphatidylethanolamine (cephalin)
  • Phophatidylinositol
  • Phosphatidylcholine (lecithin)

choline
21
  • Sphingophospholipids
  • sphingosine FA phosphate residue amino
    alcohol or sugar alcohol
  • Ceramide sphingosine fatty acid
  • Sphingomyelin

acyl residue
22
  • Glycolipids
  • sphingosine FA sugar or oligosaccharide
    residue
  • The phosphate group is absent.
  • Galactocerebroside

23
Degradation of phospholipids
  • Phospholipases are divided according to the type
    of the bond which is cleaved.
  • Figure is found on http//web.indstate.edu/thcme/m
    wking/lipid-synthesis.htmlphospholipids

24
Synthesis of cholesterol
  • substrate acetyl-CoA
  • product cholesterol
  • function de novo synthesis of endogenous
    cholesterol
  • subcelullar location cytosol and endoplasmic
    reticulum
  • organ location liver, intestine, adrenal cortex,
    ovaries, testes and placenta make the largest
    contributions to the bodys cholesterol pool

Cholesterol is a constituent of cellular
membranes and it is present in all animal
tissues.
25
Biosynthesis of isoprenoids and steroids
  • Figure is found on http//web.indstate.edu/thcme/m
    wking/cholesterol.html

26
Regulation of cholesterol synthesis
  • reduction of HMG-CoA to mevalonic acid is
    catalyzed by HMG-CoA reductase rate-limiting
    and key regulatory step
  • expression of HMG-CoA
  • reductase gene is inhibited
  • by cholesterol
  • ? activity of HMG-CoA
  • reductase is increased
  • by insulin and thyroxine
  • but glucagone has the opposite effect

Figure was adopted from textbook T. M. Devlin et
al. Textbook of Biochemistry With Clinical
Correlations, 4th ed.
27
Lipoproteins
  • ? Chylomicrons carry TAG (fat) from the
    intestine to the liver and adipose tissue
  • ? VLDL carry (newly synthesized) TAG from the
    liver to peripheral tissues
  • ? IDL are intermediate between VLDL and LDL
  • ? LDL carry cholesterol from the liver to cells
    of the body
  • ? HDL collects cholesterol from bodys tissues
    and brings it back to the liver
  • Figure was assumed from http//http//www.britanni
    ca.com/EBchecked/topic-art/720793/92254/Cutaway-vi
    ew-of-a-low-density-lipoprotein-complex-The-LDL

28
Metabolism of lipoproteins
Figure was assumed from www.media-2.web.britannica
.com/eb-media/42/96842-...
29
Enzyme lipoprotein lipase (LPL)
  • is present on the surface of the vascular
    endothelia. This enzyme hydrolyses TAG in
    chylomicrons ? chylomicrons remnants ? liver
  • LPL also catalyzes cleavage of TAG in VLDL ? IDL.
  • LPL synthesis is stimulated by insulin.
  • Enzyme lecithin cholesterol acyltransferase
    (LCAT) catalyzes esterification of cholesterol
    with acyl. It is included in HDL formation.

Figure was adopted from textbook T. M. Devlin et
al. Textbook of Biochemistry With Clinical
Correlations, 4th ed.
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