1. Lipid Transport & Storage

2. 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

3. 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

4. Major Groups of Plasma Lipoproteins

5. Lipoproteins consist of a nonpolar core & a single surface layer of amphipathic lipids

6. 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

7. apo A-I for the HDL receptor
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

8. FREE FATTY ACIDS arise in the plasma from Levels
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

9. FREE FATTY ACIDS Oxidized Esterified The free fatty acid uptake
(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.

10. FREE FATTY ACIDS membrane fatty acid transport protein
fatty acid-binding proteins

11. TRIACYLGLYCEROL CHYLOMICRONS VERY LOW DENSITY LIPOPROTEINS
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

12. The formation and secretion of chylomicrons and VLDL

14. 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

15. 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

16. 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)

17. Metabolic fate of chylomicrons

18. 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

19. 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

20. Metabolic fate of VLDL and production of low-density lipoproteins (LDL)

21. 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

22. Metabolism of high-density lipoprotein (HDL) in reverse cholesterol transport

23. 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).

24. HDL
HDL 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

25. HDL concentrations HDL2 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

26. 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

27. Converts fatty acids to ketone bodies (ketogenesis)
Plays an integral part in the synthesis and metabolism of plasma lipoproteins

28. 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

29. 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

30. CLINICAL ASPECTS

31. Metabolism of Acylglycerols & Sphingolipids

32. CLINICAL ASPECTS Raised levels of plasma free fatty acids Starvation
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

33. 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

34. Metabolism of adipose tissue.

35. 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

36. Glucose can take several pathways in adipose tissue
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

37. 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

38. Control of adipose tissue lipolysis

39. 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

40. 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

41. Thermogenesis in brown adipose tissue.

42. 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.

43. 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.

44. 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).

45. Triacylglycerol Brown adipose tissue
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.