Transcript Lipid Metabolism

Lipid Metabolism
Sara M.Abuel Gassim
January 2010
INTRODUCTION
•Lipids, such as cholesterol and triglycerides, are insoluble in plasma and
circulating lipid is carried in lipoproteins that transport the lipid to various
tissues for energy utilization, lipid deposition, steroid hormone production, and
bile acid formation.
•The lipoprotein consists of esterified and unesterified cholesterol, triglycerides,
phospholipids, and protein.
• The protein components of the lipoprotein are known as apolipoproteins (apo)
or apoproteins.
•The different apolipoproteins serve as cofactors for enzymes and ligands for
receptors.
Classification of lipoproteins
There are five major lipoproteins, each of which has a different function.
•Chylomicrons are very large particles that carry dietary lipid. They are
associated with a variety of apolipoproteins.
•Very low density lipoprotein — (VLDL) carries endogenous triglycerides
and to a lesser degree cholesterol.
•Intermediate density lipoprotein.
•Low density lipoprotein.
•High density lipoprotein.
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Lipids
•Are groups of heterogeneous compounds characterized by their solubility
properties.
•They are insoluble in water, but are soluble in organic solvents such as ether
chloroform, and benzene.
Classification of lipids
1. Simple Lipids
a. Fats
b. Waxes
2. Complex Lipids
a. Glycerophospholipids
b. Sphingolipids
c. Sterols
3. Derived lipids or lipids with specific biological activity
Simple lipids
They are esters of fatty acids with alcohols. Two types:
•Fats, oils, acylglycerols, neutral lipids; these are esters of fatty acids with glycerol
eg. Triacyl glycerol
•Waxes are esters of fatty acids with long chain monohydric alcohol
Fatty Acids
CH3(CH2)nCH2CO 2H
O
O
CH3(CH2)nCH2C-OH
H-O-R
CH3(CH2)nCH2C-OH
O
O
CH3(CH2)nCH2C-O-R
Ester
H-S-R
CH3(CH2)nCH2C-S-R
Thioester
Complex lipids
• glycerophospholipids
• sphingolipids
A- phosphosphingolipids
B- glycosphingolipids
•Sterols (cholesterol)
Fats or oils or Acylglycerols
• Esters of fatty acids with glycerol; mono-di- or triacylglycerol (TAG).
• The main storage form of fuel in animals is TAG.
• It is stored in adipose tissues.
• It is hydrophobic molecule, therefore it is transported in blood by the
lipoprotein particles mainly chylomicrons and very low density
lipoprotein (VLDL).
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•Transported in blood bound to albumin
•Can be oxidized by various tissues (β-oxidation) to generate metabolic
energy.
•Some are not synthesized in animal body, thus are dietary essential e.g.
(linoleic, and linolenic acids)
Dietary Fatty Acids
• Triacylglycerols, phospholipids, sterol esters
• Principal sources: dairy products, meats
Digestion of Dietary Triacylglycerols
• Occurs in duodenum
• Facilitated by
• Bile salts (emulsification)
• Alkaline medium (pancreatic juice)
Pancreatic
lipases
OH
OH
TAG
MAG
Intestinal
lipases
Glycerol
+
Fatty Acids
Epithelial Cell (Intestinal Wall)
MAG Glycerol Fatty Acids
Intestinal lumen
Lipoprotein
TAG
Lymphatics
Blood (bound to albumin)
Chylomicrons
Adipose Tissue
And Muscle
Adipocytes
Fat Storage
• Mainly as triacylglycerols (triglycerides) in adipose cells
• Constitute 84% of stored energy
• Protein - 15%
• Carbohydrate (glucose or glycogen) - <1%
Processing of Lipid Reserves: Overview
1. Lipid Mobilization:
In adipose tissue TAGs hydrolyzed to fatty acids plus glycerol
2.
Transport of Fatty Acids in Blood To Tissues
3.
Activation of Fatty Acids as CoA Ester
4.
Transport into Mitochondria
5.
Metabolism to Acetyl CoA
Release of Fatty Acids from Triacylglycerols
O
CH 2OC-R1
O
CH 2OH
Lipases
CHOC-R 2
CHOH
O
CH 2OC-R3
CH 2OH
Triacylglycerol
Glycerol
+
O
O
O
HOC-R 1
HOC-R 2
HOC-R 3
Lipolysis
•Lipolysis is the hydrolysis of lipids . Metabolically it is the breakdown of
triglycerides into free fatty acids within cells.
•When fats are broken down for energy the process is known as beta oxidation.
•Ketones are produced, and are found in large quantities in ketosis.
Lipolysis
Hormone
(Adrenalin, Glucagon, ACTH)
Receptor (7TM)
Activates
ATP
Insulin
blocks this
step
Adenylyl
Cyclase
c-AMP
Activates lipase
Triacylglycerols
Glycerol +
Fatty acids
Adipose Cell
Blood
Adenylyl cyclase
ATP
Phosphodiesterase
c-AMP
AMP
Enhanced by glucagon
Enhanced by insulin
Inactive Kinase
Activated Kinase
P
Inactive Lipase
Activated Lipase
Phosphatase
Insulin favors formation
of the inactive lipase
Triacylglycerol
(Hormone-sensitive
Lipase)
Glycerol +
Fatty Acids
Acylglycerol Lipases
Diacylglycerol (DAG)
Triacylglycerol
Lipase
OH
Triacylglycerol (TAG)
OH
OH
OH
Glycerol
Monoacylglycerol
Lipase
Diacylglycerol
Lipase
OH
OH
Monoacylglycerol
(MAG)
Fate of Glycerol
Pyruvate
In Liver:
OH
OH
OH
Glycolysis
Dihydroxyacetone
Phosphate
Gluconeogenesis
Glycerol
Glucose
Beta Oxidation
• Cleavage of fatty acids to acetate in tissues
• Occurs in mitochondria
[O]
[O]
[O]
[O]
[O]
[O]
[O]
[O]
CO2 H
9 CH3COSCoA
Steps in Beta Oxidation
• Fatty Acid Activation by Esterification with CoASH
• Membrane Transport of Fatty Acyl CoA Esters
• Carbon Backbone Reaction Sequence
• Dehydrogenation
• Hydration
• Dehydrogenation
• Carbon-Carbon Cleavage (Thiolase Reaction)
Beta Oxidation
Reaction Sequence
Acyl CoA
H
Dehydrogenase
R-CH2 -C-C-COSCoA
R-CH2 -C=C-COSCoA
H H
H H
FAD
FADH2
L--Hydroxyacyl
CoA
Dehydrogenase
-Ketoacyl CoA
H
NADH
+ H+
CoASH
trans- 2 -enoyl CoA
H2 O
Enoyl CoA Hydratase
H H
R-CH2 -C-C-COSCoA
R-CH2 -C-C-COSCoA
OH
H
NAD+
HO H
L--Hydroxyacyl CoA
Thiolase
(-ketothiolase)
R-CH2 -C-SCoA
O
+
Occurs in Mitochondria
CH 3 -C-SCoA
O
Repeat Sequence
Ketone Bodies As Energy Sources
In liver
-Hydroxybutyrate
Acetoacetate
Acetoacetate is major energy
source in cardiac muscle and
renal cortex; also in brain in
starvation and diabetes
Succinyl CoA
-Ketoacyl CoA
transferase
Not found in liver
Thiolase
2 Acetyl CoA
Combines with
oxaloacetate
TCA Cycle
Acetoacetyl CoA
Succinate
Fatty Acid Synthesis vs. Degradation
Synthesis
Degradation
Intermediates
Linked to SH in
Proteins
(Acyl Carrier Proteins)
Linked to CoASH
Site
Cytosol
Mitochondria
Enzymes
Components of
Single Peptide
Redox
Coenzymes
NADP+ / NADPH
Separate Polypeptides
NAD+ / NADH
Fatty Acid Biosynthesis
• Occurs in cytosol
• Starts with acetyl CoA
• Problem:
» Most acetyl CoA produced in mitochondria
» Acetyl CoA unable to traverse mitochondrial
membrane.
Citrate As Carrier of Acetate Groups
Cytosol
Glucose
Mitochondria
Pyruvate
Pyruvate
Acetyl CoA
Pyruvate
Dehydrogenase
Malic enzyme
Malate
Malate
dehydrogenase
Citrate
Acetyl CoA
Oxaloacetate
Oxaloacetate
ATP-Citrate
Lyase
Note: Acetyl CoA
cannot be converted
to glucose
Citrate
Mitochondrial
membrane
Respiratory Distress Syndrome
•Most frequently seen in premature infants
•Also called hyaline membrane disease
•Failure to produce sufficient dipalmitoyl phosphatidylcholine,
which normally is found in the extracellular fluid surrounding
alveoli; decreases surface tension of fluid to prevent lung
collapse.
Tay-Sachs Disease
•GM2 (a ganglioside):
•Ceramide - O - Glucose - Galactose - N-Acetylgalactose
•Hexoseaminidase A
catalyzes cleavage of this
glycoside linkage
•Autosomal recessive disorder characterized by deficiency
of hexoseaminidase A; accumulation of gangliosides in brain
•Most prevalent in Jews from Eastern Europe
Metabolite Regulation of Fatty Acid Synthesis and Breakdown
Glucose
Citrate
Stimulates
Blocks
Pyruvate
Acetyl CoA
Malonyl CoA
Inhibits
Palmitoyl CoA
Beta
Oxidation
Hormonal Regulation of Fatty Acid Synthesis and Breakdown
Phosphodiesterase
Adenylyl cyclase
ATP
cAMP
Stimulates
Glucagon and
epinephrine
Inhibition of
fatty acid
synthesis
AMP
Stimulates
Insulin
Activates Protein Kinase
Inactivates ACC by
phosphorylation
Inactivates
lipase
Activates triacylglycerollipase
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