Transcript Lipid metabolism

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 acylCoA-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/topicart/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.