Lipid metabolism

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Lipid metabolism

• Pavla Balínová

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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

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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
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Fatty acids (FA)
The figure was adopted from J.Koolman, K.H.Röhm
/ Color Atlas of Biochemistry, 2nd edition
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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
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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

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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

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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

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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).

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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

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Synthesis of ketone bodies (ketogenesis)
Figure is found at http//themedicalbiochemistrypa
ge.org/fatty-acid-oxidation.htmlketogenesis
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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

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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
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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

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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

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• 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.

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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

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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

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Complex lipids(phospholipids, sphingophospholipid
s, glycolipids)

• Phospholipids
• glycerol 2 FA phosphate group hydrophilic
  compound
• Phosphatidylethanolamine (cephalin)
• Phophatidylinositol
• Phosphatidylcholine (lecithin)

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

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

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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

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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.
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Biosynthesis of isoprenoids and steroids

• Figure is found on http//web.indstate.edu/thcme/m
  wking/cholesterol.html

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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.
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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

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Metabolism of lipoproteins
Figure was assumed from www.media-2.web.britannica
.com/eb-media/42/96842-...
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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.