Lipid Transport & Storage
BIOMEDICAL IMPORTANCE
• Fat
– Diet
– Synthesized
(liver & adipose tissue)
• Transported between the various tissues
– Utilization and storage
• Lipids are nonpolar
• Lipoproteins
• Abnormalities of lipoprotein metabolism
– hypo- or hyperlipoproteinemias
– Diabetes mellitus
• Lipids are transported in the plasma as
lipoproteins
• Four Major Lipid Classes Are Present in
Lipoproteins
– Triacylglycerols
– Phospholipids
– Cholesterol
– Cholesteryl esters
– free fatty acids (FFA), a much smaller fraction
Major Groups of Plasma Lipoproteins
Lipoproteins consist of a nonpolar core & a single surface layer of
amphipathic lipids
• The Distribution of Apolipoproteins Characterizes
the Lipoprotein
• Apolipoproteins roles
– form part of the structure of the lipoprotein
– they are enzyme cofactors
• C-II for lipoproteinlipase
• A-I for lecithin:cholesterol acyltransferase
• Enzyme inhibitors
– apo A-II and apo C-III for lipoprotein lipase
– apo C-I for cholesteryl ester transfer protein
• act as ligands
– apo B-100 and apo E for the LDL receptor
• apo E for the LDL receptor-related protein
(LRP), which has been identified as the
remnant receptor
• apo A-I for the HDL receptor
FREE FATTY ACIDS
• arise in the plasma from
– Lipolysis of triacylglycerol in adipose tissue
– action of lipoprotein lipase during uptake of plasma
triacylglycerols into tissues
– in combination with albumin
• Levels
– low in the fully fed condition
– Rise in
• the starved state
• diabetes mellitus
FREE FATTY ACIDS
• Oxidized
– (fulfilling 25–50% of energy requirements in
starvation)
• Esterified
– to form triacylglycerol in the tissues
• The free fatty acid uptake
– related directly to the plasma free fatty acid
concentration
– determined by the rate of lipolysis in adipose tissue.
FREE FATTY ACIDS
• membrane fatty acid transport protein
• fatty acid-binding proteins
TRIACYLGLYCEROL
• CHYLOMICRONS
– TRANSPORTED FROM THE INTESTINES IN
• VERY LOW DENSITY LIPOPROTEINS
– Transport of triacylglycerol from the liver to the
extrahepatic tissues
• Intestine and liver
– the only tissues from which particulate lipid is
secreted
• Apo B is essential for chylomicron and VLDL
formation
The formation and secretion of chylomicrons and VLDL
TRIACYLGLYCEROL
• Fatty acids originating from chylomicron
triacylglycerol are delivered mainly to adipose
tissue, heart, and muscle (80%), while about
20% goes to the liver
• Triacylglycerols of Chylomicrons & VLDL Are
Hydrolyzed by Lipoprotein Lipase
– Lipoprotein lipase
– Hepatic lipase
• Concerned with chylomicron remnant and HDL
metabolism
TRIACYLGLYCEROL
• Lipoprotein lipase
– Phospholipids and apo C-II
– apo A-II and apo C-III act as inhibitors
– Insulin
• The Action of Lipoprotein Lipase Forms Remnant
Lipoproteins
–
–
–
–
loss of approximately 90% of the triacylglycerol
loss of apo C
apo E, retained
enriched in cholesterol and cholesteryl esters
TRIACYLGLYCEROL
• The Liver Is Responsible for the Uptake of
Remnant Lipoproteins
• Uptake is mediated by
– A receptor specific for apo E
– and both the LDL (apo B-100, E) receptor
– and the LRP (LDL receptor-related protein)
Metabolic fate of chylomicrons
• VLDL is the precursor of IDL, which is then
converted to LDL
• Two possible fates await IDL
– It can be taken up by the liver directly via the LDL
(apo B-100, E) receptor
– or it is converted to LDL
LDL
• LDL IS METABOLIZED VIA THE LDL RECEPTOR
– LDL (B-100, E) receptor
– 30% of LDL is degraded in extrahepatic tissues
– 70% in the liver
• Correlation with coronary atherosclerosis
Metabolic fate of VLDL and production of low-density lipoproteins (LDL)
HDL
• Synthesized and secreted from
– both liver and intestine
• apo C and apo E are synthesized in the liver
and transferred from liver HDL to intestinal
HDL when the latter enters the plasma
• Function of HDL
– Repository for the apo C and apo E
• Required in the metabolism of chylomicrons and VLDL
– TRIACYLGLYCEROL & CHOLESTEROL METABOLISM
Metabolism of high-density lipoprotein (HDL) in reverse cholesterol transport
HDL
• the LCAT system is involved in the removal of
excess unesterified cholesterol from
lipoproteins and tissues.
• HDL receptor
– The class B scavenger receptor B1 (SR-B1)
• reverse cholesterol transport
– The smaller HDL3 accepts cholesterol from the
tissues via the ATP-binding cassette transporter-1
(ABC-1).
HDL
• HDL2
HDL3
– after selective delivery of cholesteryl ester to the
liver via the SR-B1
– or by hydrolysis of HDL2 phospholipid and
triacylglycerol by hepatic lipase.
• Preβ-HDL
– is the most potent form of HDL in inducing
cholesterol efflux from the tissues to form
discoidal HDL
• HDL concentrations
– Vary reciprocally with plasma triacylglycerol
concentrations
– Directly with the activity of lipoprotein lipase.
• HDL2 concentrations
– Inversely related to the incidence of coronary
atherosclerosis
– reflect the efficiency of reverse cholesterol
transport
• THE LIVER plays a central role in lipid
transport & metabolism
– Facilitates the digestion and absorption of lipids
by the production of bile
• has active enzyme systems for
– synthesizing and
– oxidizing fatty acids
– and for synthesizing triacylglycerols and
– Phospholipids
• Converts fatty acids to ketone bodies
(ketogenesis)
• Plays an integral part in the synthesis and
metabolism of plasma lipoproteins
• Hepatic VLDL Secretion
– Dietary & Hormonal Status
• Hepatic triacylglycerol synthesis provides the
immediate stimulus for the formation and
secretion of VLDL.
• The fatty acids used are derived from two
possible sources
– Synthesis within the liver
– Uptake of free fatty acids from the circulation
• during starvation, the feeding of high-fat diets, or in diabetes
mellitus
• Factors that enhance both the synthesis of
triacylglycerol and the secretion of VLDL by the
liver include
–
–
–
–
–
the fed state rather than the starved state
the feeding of diets high in carbohydrate
high levels of circulating free fatty acids
ingestion of ethanol
high concentrations of insulin and low concentrations
of glucagon
• Enhance fatty acid synthesis and esterification and inhibit
their oxidation
CLINICAL ASPECTS
Metabolism of Acylglycerols
& Sphingolipids
CLINICAL ASPECTS
• Raised levels of plasma free fatty acids
– Mobilization of fat from adipose tissue
– Hydrolysis of lipoprotein triacylglycerol by
lipoprotein lipase in extrahepatic tissues
– Imbalance in the Rate of Triacylglycerol Formation &
Export
• Causing a fatty liver
• Starvation
• High-fat diets
• The ability to secrete VLDL may also be impaired
• Starvation
CLINICAL ASPECTS
• The second type of fatty liver
– Metabolic block in the production of plasma
lipoproteins
• Triacylglycerol accumulate
– Block in apolipoprotein synthesis
– Block in the synthesis of the lipoprotein from lipid
and apolipoprotein
– Failure in provision of phospholipids
– Failure in the secretory mechanism
Metabolism of adipose tissue.
• The Provision of Glycerol 3-Phosphate
Regulates Esterification
• Lipolysis Is Controlled by Hormone-Sensitive
Lipase
• Triacylglycerol is synthesized from acyl-CoA
and glycerol 3-phosphate
• Triacylglycerol undergoes hydrolysis by a
hormone sensitive lipase to form free fatty
acids and glycerol
• there is a continuous cycle of lipolysis and
reesterification within the tissue
• Glucose can take several pathways in adipose
tissue
– Oxidation to CO2 via the citric acid cycle
– Oxidation in the pentose phosphate pathway
– Conversion to long-chain fatty acid
– Formation of acylglycerol via glycerol 3-phosphate
• HORMONES REGULATE FAT MOBILIZATION
– Esterification
– Lipolysis
• by influencing the activity of the enzymes in the
pathways
– Hormone-sensitive lipase
• Insulin plays a prominent role in the regulation of
adipose tissue metabolism
• The sympathetic nervous system, through liberation of
norepinephrine in adipose tissue, plays a central role
in the mobilization of free fatty acids
Control of adipose tissue lipolysis
BROWN ADIPOSE TISSUE
• PROMOTES THERMOGENESIS
• responsible for diet-induced thermogenesis
• The tissue is characterized by a
– Well-developed blood supply
– High content of mitochondria and cytochromes
– Low activity of ATP synthase
• Oxidation and phosphorylation are not
coupled in mitochondria of this tissue
• Phosphorylation that does occur is at the
substrate level eg,
– at the succinate thiokinase step
– in glycolysis
• Oxidation produces much heat, and little free
energy is trapped in ATP
• Uncoupling protein, thermogenin, acts as a
proton conductance pathway dissipating the
electrochemical potential across the
mitochondrial membrane
Thermogenesis in brown adipose tissue.
Four major groups of lipoproteins
• Chylomicrons transport lipids resulting from
digestion and absorption.
• Very low density lipoproteins (VLDL)
– Transport triacylglycerol from the liver.
• Low-density lipoproteins (LDL)
– Deliver cholesterol to the tissues,
• High-density lipoproteins (HDL)
– Remove cholesterol from the tissues in the
process known as reverse cholesterol transport.
• Chylomicrons and VLDL are metabolized by
hydrolysis of their triacylglycerol
• Lipoprotein remnants are left in the
circulation.
• These are taken up by liver
• Some of the remnants (IDL) resulting from
VLDL form LDL
• LDL is taken up by the liver and other tissues
via the LDL receptor.
Apolipoproteins
• the protein moiety of lipoproteins
• act as
– enzyme activators (eg, apo C-II and apo A-I)
– as ligands for cell receptors (eg, apo A-I, apo E,
and apo B-100).
• Triacylglycerol
– The main storage lipid in adipose tissue
– Upon mobilization, free fatty acids and glycerol are
released.
– Free fatty acids are an important fuel source.
• Brown adipose tissue
– Present in small quantity in humans.
– the site of “nonshivering thermogenesis
– Presence of an uncoupling protein, thermogenin, in
the inner mitochondrial membrane.