3. Introduction
• The French physician–scientist Michel Macheboeuf is acknowledged as the father
of plasma lipoproteins.
• Described horse serum lipoproteins, demonstrating the association of lipids and
proteins in plasma
• Large macromolecular complexes composed of neutral lipids, polar lipids, and
specialized proteins called apolipoproteins (apos).
• Facilitates the transport of poorly soluble lipids through body fluids to and from
tissues by associating nonpolar lipids (triacylglycerol and cholesteryl esters) with
amphipathic lipids (phospholipids and cholesterol) and proteins to make water-
miscible lipoproteins.
4. Structure of plasma lipoproteins
Major plasma lipids are:
• Tg- 16%
• Phospholipids- 30%
• Cholesterol- 14%
• Cholesterol ester- 36%
• small fraction of unesterified
Long chain FFAs- 4%
5. Classification
• Based on density and size
• Based on electrophoretic pattern
• Based on apolipoprotein content
6. Based on density and size
• Four major human plasma lipoproteins
• Density of lipoprotein decreases as the proportion of lipid to protein increases
7. Based on electrophoretic mobility
• Free fatty acid and albumin complex although not a lipoprotein is an important lipid fraction in serum and is the
fastest moving fraction.
• Chylomicrons remain at the origin since they have more lipid content.
• VLDLs with less protein content than LDL move faster than LDL, this is due to nature of apoprotein present.
8. Based on apolipoprotein content
• One or more apolipoproteins (proteins or polypeptides) are present in each
lipoprotein.
• The major apolipoproteins of HDL (α-lipoprotein) are designated A.
• The main apolipoprotein of LDL (β -lipoprotein) is apolipoprotein B (B-100),
which is found also in VLDL, synthesized in the liver.
• Chylomicrons contain a truncated form of apo B (B-48) and is synthesized in the
intestine
• Apo E is found in VLDL, HDL, Chylomicons, and chylomicron remnants.
10. Apolipoproteins
• The proteins associated with lipoproteins are referred to as apolipoproteins or
often just apoproteins.
• There are 2 major types of apolipoproteins distinguished by the secondary
structural motifs present in the proteins.
• The apolipoprotein A (apoA) proteins are composed primarily of alpha helices and
form reversible complexes with the lipids of lipoproteins.
• The apolipoprotein B (apoB) proteins are composed primarily of β-sheet
structures and form irreversible complexes with the lipids of lipoproteins.
• In addition to the apoA and apoB family of proteins, there are apoC, apoD, apoE,
apoF, apoH, apoL, apoM and apoa proteins.
11. Synthesis of apolipoproteins
• Apolipoprotein synthesis in the intestine is regulated principally by the
fat content of the diet.
• Apolipoprotein synthesis in the liver is controlled by a host of factors,
including dietary composition, hormones (insulin, glucagon, thyroxin,
estrogens, androgens) alcohol intake, and various drugs (statins, niacin,
and fibric acids).
• Apolipoprotein synthesis such as apoA4 in hypothalamus involves in the
integration of signals for regulation of food intake which is regulated by
vagal nerve and cholecystokinin
14. Apo-M
• 25-kDa protein is expressed in the liver and kidneys
• not found free in plasma but is predominantly associated with HDL.
• Like apo D, it is a member of the lipocalin family of proteins, which contain a
binding domain for small lipophilic ligands, and may therefore have a role in
transport of small lipid molecules.
• Although apo M is found in association with only 5% of HDL particles, where
it may potentiate the antioxidant effect of HDL, its concentration is positively
correlated with cholesterol concentration, suggesting that it may also have a role
in cholesterol metabolism
15. D-4F, an apolipoprotein A-I mimetic, inhibits TGF-β1 induced epithelial-mesenchymal transition in human alveolar epithelial cell
JiaYouab1JintaoWangc1LinshenXiedChengwenZhucJingyuanXiongab https://doi.org/10.1016/j.etp.2016.07.005
• Apolipoprotein A-I (Apo A-I) is the only known substance that can resolve established
pulmonary fibrotic nodules, and Apo A-I mimetic D-4F (a synthetic polypeptide consisting
of 18 amino acids) plays an inhibitory role in murine asthmatic model. However, cellular
mechanisms for such therapeutic effects of Apo A-I and D-4F remain to be elucidated.
• apoA-I with its ability to directly bind and neutralize LPS, which is derived from the cell
walls of GNB, as well as LTA, which is a cell wall component of gram-positive bacteria
• Similarly HDL have been found to attenuate the emphysema caused by alpha 1 anti trysin
deficiency
17. Assembly of chylomicrons in intestine and VLDL in the liver
• ARF-1- ADp-ribosylation factor-1;
• Ffa-free fatty acids;
• Mtp- microsomal triacylglycerol
transfer protein
• PA-phosphatidic acid
• PL- phospholipid
• PLD- phospholipase D
18. Regulation of VLDL formation in the liver
• Factors that enhance both the synthesis of triacylglycerol and the secretion of
VLDL by the liver includes:
1) fed state rather than the starved state
2) high carbohydrate diet (sucrose or fructose), leading to high rates of lipogenesis and
esterification of fatty acids;
3) high levels of circulating FFA
4) ingestion of ethanol
• Factors which are known to inhibit or prevent VLDL assembly in the liver
includes:
1. antibiotic brefeldin A, which inhibits the action of ARF-1
2. Sulfonylurea hypoglycemic drug, tolbutamide, dietary ω3 fatty acids and orotic acid
decrease the rate of TG lipolysis;
3. defect in the MTP gene.
20. High density lipoprotein (HDL)
Synthesis of HDL
• synthesized de novo in the liver and small intestine, as
primarily protein-rich disc-shaped particles and this nascent
HDL consists of phospholipid bilayer containing apo
A(70% of total protein mass) and free cholesterol.
• apo C and apo E are synthesized in the liver and transferred
from liver HDL to intestinal HDL when the latter enters the
plasma.
• Hence, the primary apoproteins of HDLs are apoA-I,
apoC-I, apoC-II, and apoE.
• A major function of HDL is to act as a repository for the
apo C and apo E required in the metabolism of
chylomicrons and VLDL.
21. Metabolism of HDL in reverse cholesterol transport
• Role of LCAT
• Reverse cholesterol transport
- class B scavenger receptor
B1 (SR-B1)
- ATP-binding cassette
transporter A1 (ABCA1).
HDL Cycle
lysolecithin to plasma albumin
22. • These lipoproteins are similar to the particles found in the plasma of patients with a
deficiency of the plasma enzyme lecithin:cholesterol acyltransferase (LCAT) and
in the plasma of patients with obstructive jaundice.
• LCAT—and the LCAT activator apo A-I—bind to the discoidal particles, and the
surface phospholipid and free cholesterol are converted into cholesteryl esters and
lysolecithin.
• The nonpolar cholesteryl esters move into the hydrophobic interior of the bilayer,
whereas lysolecithin is transferred to plasma albumin.
• Thus, a nonpolar core is generated, forming a spherical, pseudomicellar HDL
covered by a surface film of polar lipids and apolipoproteins and aids the removal
of excess unesterified cholesterol from lipoproteins and tissues
23. Antioxidant and Anti-inflammatory activities of HDL
• Apolipoprotein A-I: can remove oxidized phospholipids from oxidized LDL
(oxLDL) and from cells. Specific methionine residues of apoA-I have been
shown to directly reduce cholesterol ester hydroperoxides and
phosphatidylcholine hydroperoxides.
• Apolipoprotein A-II: ApoA-II–enriched HDLs support highly effective RCT
from macrophages and also protect VLDL from oxidation more efficiently than
apoA-II–deficient HDL.
• Apolipoprotein A-IV: Besides RCT ApoA-IV play an important role in the
control of feeding behaviors, antioxidant, anti-inflammatory, and
antiatherosclerotic actions.
24. • Paraoxonases 1 and 3:
synthesized in the liver and is carried in the serum by HDL and hydrolyze
organophosphates
possesses antioxidant properties(prevents the oxidation of LDL), enhances
cholesterol efflux from macrophages by promoting HDL binding mediated by
ABCA1
pathological conditions associated with oxidative stress, such as rheumatoid
arthritis and Alzheimer disease, are associated with reduced activity of PON1
25. Clinical significance of lipoprotein metabolism
Fatty Liver
• abnormal accumulation of certain fats (triglycerides) inside liver cells.
• Hepatic triacylglycerol synthesis provides the immediate stimulus for the
formation and secretion of VLDL.
• Impaired VLDL formation or secretion leads to nonmobilization of lipid
components from the liver, results in fatty liver.
• Fatty livers fall into two main categories
A) raised levels of plasma free fatty acids : due to mobilization of fat
from adipose tissue or from the hydrolysis of lipoprotein triacylglycerol
by lipoprotein lipase in extrahepatic tissues.
26. B) Metabolic block in the production of plasma lipoproteins
• usually due to a metabolic block in the production of plasma lipoproteins, thus
allowing triacylglycerol to accumulate.
• The lesion may be due to
(1)A block in apolipoproteins synthesis
a) Protein energy Malnutrition
b) Impaired absorption
c) Presence of inhibitors of endogenous protein synthesis e.g.- Carbon tetra
chloride, Puromycin, Ethionine , Heavy metals etc.
d) Hypobetalipoproteinemia- Defective apo B gene can cause impaired synthesis
of apo B protein.
27. 2) A failure in provision of phospholipids that are found in lipoproteins
• A deficiency of choline, a lipotropic factor can cause impaired formation of
phosphatidyl choline (Lecithin),a glycerophospholipid
• Methionine deficiency can also cause impaired choline synthesis
• Deficiency of essential fatty acids can also cause impaired PL synthesis
3)Impaired Glycosylation
Orotic acid also causes fatty liver; it interferes with glycosylation of the lipoprotein,
thus inhibiting release, and may also impair the recruitment of triacylglycerol to the
particles.
4) a failure in the secretory mechanism itself: oxidative stress is a common cause
for membrane disruption of lipoproteins.
28. Alcoholic fatty liver
• Alcoholism leads to fat accumulation in the liver, hyperlipidemia, and ultimately
cirrhosis.
• Excessive alcohol consumption inhibits hepatic oxidation of free fatty acids, thus
promoting hepatic TG synthesis and VLDL secretion
Coronary heart disease
• Increased LDL cholesterol, chylomicron remnants, IDL promote atherosclerosis
• A scavanger cell receptor which provides a mechanism for entry of chylomicrons
remnants in the arterial wall have been identified.
• Decrease in the concentrations of apo A-I and increased concentration of apo B-
100 leads to CHD (apoB-100/A-I ratio for determining risk of CHD)
29. Disorderof lipoprotein metabolism
• Disorder of lipoprotein metabolism are collectively reffered as ‘Dyslipidemias’
• Characterised clinically by increased plasma levels of cholesterol, TG, or both,
variably accompained by reduced levels of HDL-C
• Majority of patients have genetic predisposition(often polygenic) and environmental
contribution(life style, medical condition, or drug)
• Many but not all are at increased risk for ASCVD
• Patients with substantially elevated levels of tg may be at risk for acute pancreatitis
30. • provide an evidence based algorithm to summarize the approach to the etiology of
hypertriglyceride-induced pancreatitis.
• It may be secondary to rapid accumulation of chylomicrons in the pancreatic vasculature
and as Chylomicrons are the largest lipid-transporting lipoprotein it can form a thrombus
plug and obstruct the pancreatic circulation
• Another hypothesis is that it may be secondary to the release of free fatty acids from
triglycerides by pancreatic lipase. These pro-inflammatory free fatty acids can induce free
radical formation and damage to the pancreas or may in fact cause direct injury through
chemical irritation together with lisolecithin
• retrospective cohort study
• patients who presented with hypertriglyceridemia-induced pancreatitis had a mean age of
54.2 ± 11.9 years. Three fourths of which are male and a great majority (78.9%) are
Caucasians.
• accounts for 1.3 to 3.8 percent of pancreatitis cases
April 20, 2016
31. • Discrete “nodes” or pathways that regulate lipoprotein metabolism and are
dysfunctional in specific dyslipidemias includes:
1. assembly and secretion of TG-rich VLDLs by the liver;
2. lipolysis of TG-rich lipoproteins by LPL;
3. receptor-mediated uptake of apoB-containing lipoproteins by the liver;
4. cellular cholesterol metabolism in the hepatocyte and the enterocyte;
5. neutral lipid transfer and phospholipid hydrolysis in the plasma.
32. Dyslipidemias caused by excessive hepatic secretion of VLDL
• Individuals with excessive hepatic VLDL production usually have elevated fasting
TGs and low levels of HDL cholesterol (HDL-C), with variable elevations in LDL
cholesterol (LDL-C) but usually elevated plasma levels of apoB.
• Primary (Genetic) causes includes: Familial combined hyperlipidemia(FCHL),
Lipodystrophy
• Secondary causes of VLDL overproduction includes :
High carbohydrate diet
Alcohol
Obesity and insulin resistance
Nephrotic syndrome
Cushing’s syndrome
33. Impaired lipolysis of tg TG-rich lipoproteins by LPL
• Individuals with impaired LPL activity, whether secondary or due to a primary
genetic disorder, have elevated fasting TGs and low levels of HDL-C, usually
without elevation in LDL-C or apoB
• Primary(genetic) causes includes: familial chylomicronemia syndrome, LPL
deficiency, apoA-V deficiency, familial hypertriglyceridemia
• Secondary causes includes: obesity and insulin resistance
Impaired hepatic uptake of apoB-containing lipoproteins by the liver
• Impaired uptake of LDL and remnant lipoproteins by the liver due to down-
regulation of LDL receptor activity or genetic variation leads to dyslipidemia.
• Hypothyroidism, estrogen deficiency, chronic kidney disease, familial
hypercholesterolemia, familial defective apoB-100, sitosterolemia,
34. Primary Disorders of plasma lipoproteins
• Inherited defects in lipoprotein metabolism lead to the primary condition of
either hypo- or hyperlipoproteinemia .
• In addition, diseases such as diabetes mellitus, hypothyroidism, nephrotic
syndrome are associated with secondary abnormal lipoprotein patterns that
are very similar to one or another of the primary inherited conditions.
• All of the primary conditions are due to a defect at a stage in lipoprotein
formation, transport, or degradation.
35.
36.
37. Caused by mutations in ABCA1
gene on chr no 9q31
Apo -1 deficiency
mutations in the gene encoding MTP
deficient in vitamin E
38. Familial Combined Hypolipidemia
• low plasma levels of all three major lipid fractions: TG, LDL-C, and HDL-C
• mutations in both alleles of the gene Angiopoietin-like 3
• ANGPTL3 is a protein synthesized by the liver and secreted into the
bloodstream.
• It inhibits LPL, thus delaying clearance of TRLs from the blood and
increasing TRL blood concentrations.
• Deficiency of ANGPTL3, raises LPL activity and predominantly lowers blood
TG.
• ANGPTL3 deficiency is associated with a reduced risk for CHD.
39. Primary Hypoalphalipoproteinemia
• low plasma levels of HDL-C below the tenth percentile in the setting of
relatively normal cholesterol and TG levels
• no apparent secondary causes of low plasma HDL-C
• no clinical signs of LCAT deficiency or Tangier disease.
• Often referred to as isolated low HDL
• cause: accelerated catabolism of HDL and its apolipoproteins.
43. References
• www.uptodate.com/.../lipoprotein-classification-metabolism-and-role-in-atherosclerosis
• www.namrata.co/general-structure-and-classification-of-lipoproteins/
• Principles of internal medicine. Harrison 20th edition
• Burtis CA, Ashwood ER, Burns DE. Tietz Textbook of Clinial Chemistry and Molecular
Diagnostics. 5th ed. United Stated of America: Elsevier; 2012.
• Harvey R, Ferrier D. Lippincott’s Illustrated Review: Biochemistry. 5th ed. Harvey RA, editor.
Philadelphia: Lippincott Williams and Wilkins; 2008.
• Vasudevan DM, S S, Vaidyanathan K. Textbook of Biochemistry for Medical Student. 6th ed. New
Delhi: Jaypee Brothers Medical Publisher(P) Ltd; 2011.
• Murray RK, Granner DK, Mayes PA, Rodwell VW. Harper's Illustrated Biochemistry. twenty-sixth
ed. New York: Lange Medical Books/McGraw-Hill; 2003.
ApoB is an integral apoprotein whereas the others are peripheral apoproteins.
form irreversible complexes with the lipids of lipoproteins.
ileal peptide protein tyrosine tyrosine (PYY). Hypothalamic expression of Apo A-IV indicated that ApoA-IV exerts effects on appetite
Carbohydrate residues are added in the golgi apparatus and released from the cell by reverse pinocytosis
Mtp – transfers the lipids in nascent chylomicrons and VLDL
antibiotic brefeldin A, - antiviral drug
Estrogen decreases the hepatic lipase activity so high conc of HDL2 in women while androgens increases the activity
Hypothyroidism – decreased hepatic ldl receptor and delayed clearance of LDL and ldl-c increases