Lipid metabolism - PowerPoint by 740aZAUw

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									Lipid metabolism




  Pavla Balínová
                         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
                     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/Triacylglycerol
                           Fatty acids (FA)




The figure was adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition
       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/mwking/fatty-acid-oxidation.html
      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 ---> Acyl-CoA + PPi + AMP
      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/mwking/fatty-acid-oxidation.html
        β-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
                        Summary
For complete degradation of palmitic acid 7 cycles are
required.
Degradation of palmitic acid (16 C) gives 106 ATP in total.

Regulation of β-oxidation of FA:
Regulatory enzyme is carnitine acyltransferase I – it is
inhibited by malonyl-CoA (intermediate of FA synthesis).
           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 → β-oxidation of FA → excess of
acetyl-CoA → ↑ ketogenesis
                   Synthesis of ketone bodies
                         (ketogenesis)




Figure is found at http://themedicalbiochemistrypage.org/fatty-acid-oxidation.html#ketogenesis
        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
                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://themedicalbiochemistrypage.org/fatty-acid-oxidation.html#ketogenesis
               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
         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
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.
    FA synthesis is performed through a cycle of four
                                     reactions:




Figure is found on http://138.192.68.68/bio/Courses/biochem2/FattyAcid/FASynthesis.html
                           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/mwking/lipid-synthesis.html#phospholipids
                     Complex lipids
   (phospholipids, sphingophospholipids, glycolipids)
Phospholipids
= glycerol + 2 FA + phosphate group + hydrophilic compound

Phosphatidylethanolamine (cephalin)
Phophatidylinositol
Phosphatidylcholine (lecithin)



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




acyl residue
Glycolipids
= sphingosine + FA + sugar or oligosaccharide residue
The phosphate group is absent.
Galactocerebroside
                 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/mwking/lipid-synthesis.html#phospholipids
                     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 body´s cholesterol pool


Cholesterol is a constituent of cellular
membranes and it is present in all animal
tissues.
      Biosynthesis of isoprenoids and steroids




Figure is found on http://web.indstate.edu/thcme/mwking/cholesterol.html
         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.
                               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 body´s tissues and brings it back to the liver


Figure was assumed from http://http://www.britannica.com/EBchecked/topic-
art/720793/92254/Cutaway-view-of-a-low-density-lipoprotein-complex-The-LDL
Metabolism of lipoproteins




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