404 - Lipid - ZC# 25-30
404 - Lipid - ZC# 25-30
404 - Lipid - ZC# 25-30
Why are TG
hydrolyzed in
intestinal lumen
only to be
resynthesized in
the mucosal
?
cell
Because TG is
too insoluble. TG
cannot diffuse
from a lipid
droplet or micelle
to the IBB.
For absorption, TG have
to be hydrolyzed to
products that are at least
slightly soluble in water.
404_25: Lipid transport in blood Dr. Abu Torab MA Rahim
✺ In Enterocytes, TG are
assembled into chylomicrons,
small fat droplets, 1μm.
✺ It also contain other dietary
lipids and a small amount of
ER-synthesized proteins.
Their assembly requires a
microsomal TG transfer
protein (MTP), & apoB-48
as its major protein
component.
✺ Intestinal capillaries of
endothelium has no
fenestrations, so
chylomicrons are collected by
the lymph rather than by the
blood from the extracellular
space.
404_25: Fate of TG Dr. Abu Torab MA Rahim
✺ While most tissues oxidize FA, only the liver converts FA to ketone bodies (KB) in the
mitochondria.
✺ The KB include the three biosynthetically related products:
⌗ Acetoacetate
⌗ β-hydroxybutyrate
⌗ Acetone
✺ KB are oxidized more easily than the fatty acids.
✺ In diabetic ketoacidosis, when KB are overproduced, acetone imparts a characteristic
smell to the patient’s breath.
✺ Brain covers part of its energy needs from KB during fasting, but it is unable to oxidize
FA.
✺ In theory, any substrate that is degraded to acetyl-CoA in the liver can be turned into KB.
✺ However, ketogenesis is associated with FA oxidation, long-term fasting, and insulin
deficiency.
Dr. Abu Torab MA
404_25: Cholesterol comes from both endogenously & dietary Rahim
✺ Metabolic acidosis Acetoacetate and beta-hydroxy butyrate are acids. When they
accumulate, metabolic acidosis results.
✺ Reduced buffers The plasma bicarbonate is used up for buffering of these acids.
✺ Kussmaul’s Patients will have typical acidotic breathing due to compensatory
respiration hyperventilation.
✺ Smell of acetone Acetone smell patient's breath.
✺ Osmotic diuresis Diuresis induced by ketonuria may lead to dehydration.
✺ Sodium loss The ketone bodies are excreted in urine as their sodium salt,
leading to loss of cations from the body.
✺ Dehydration. The sodium loss further aggravates the dehydration.
✺ Coma Dehydration and acidosis contribute to the lethal effect of
ketosis.
404_26: Structure of Lipoprotein Dr. Abu Torab MA Rahim
404_26: Classification of Lipoproteins Dr. Abu Torab MA Rahim
Synthesis of VLDL
⌗ Synthesised in the liver from glycerol & FA and incorporated into VLDL along with
hepatic cholesterol, apo-B-100, C-II and E.
⌗ Apo-B-100 is the major lipoprotein present in VLDL when it is secreted. Apo-E and C-II
are obtained from HDL in plasma.
Metabolism of VLDL
⌗ Half-life of VLDL in serum is only 1 to 3 hours.
⌗ When they reach the peripheral tissues, apo-C-II activates LPL which liberates FA that
are taken up by adipose tissue & muscle.
⌗ The remnant is now designated as IDL and contains less of TG and more of cholesterol
The major fraction of IDL further loses TG, so as to be converted to LDL. This
conversion of VLDL to IDL and then to LDL is referred to as lipoprotein cascade
pathway. A fraction of IDL is taken up by the hepatic receptors
Function of VLDL
⌗ VLDL carries endogenous TG from liver to peripheral tissues for energy needs
404_26: LDL: synthesis, metabolism & function Dr. Abu Torab MA Rahim
Synthesis of LDL
⌗ LDL transports cholesterol from liver to peripheral tissues. The only apoprotein
present in LDL is apo B100
⌗ Most of the LDL particles are derived from VLDL, but a small part is directly
released from liver. The half-life of LDL in blood is about 2 days.
Metabolism of LDL and LDL Receptors
⌗ LDL is taken up by peripheral tissues by receptor mediated endocytosis
⌗ LDL receptors are present on all cells but most abundant in hepatic cells. LDL
receptors are located in specialised regions called clathrin-coated pits
⌗ Binding of LDL to the receptor is by apo-B-100 and uptake of cholesterol from LDL
is a highly regulated process. When the apo-B-100 binds to the apo-B-100 receptor,
the receptor-LDL complex is internalised by endocytosis.
⌗ The endosome vesicle thus formed fuses with lysosomes. The receptor is recycled
and returns to the cell surface.
404_26: LDL: synthesis, metabolism & function Dr. Abu Torab MA Rahim
✺ Intestinal cells synthesise components of HDL and release into blood. The nascent HDL in plasma is
discoid in shape.
✺ Free cholesterol derived from peripheral tissue cells are taken up by the HDL. The apo-A-l of HDL
activates LCAT present in the plasma. LCAT then binds to the HDL disk. Cholesterol from the cell is
transferred to HDL by a cholesterol efflux regulator protein which is an ABC protein.
✺ Lecithin is a component of phospholipid bilayer of the HDL disk. The 2nd carbon of lecithin contains one
molecule of polyunsaturated fatty acid (PUFA). It is transferred to the 3rd -OH group of cholesterol to form
CE. The esterified cholesterol which is more hydrophobic, moves into the interior of the HDL disk.
✺ This reaction continues till HDL becomes spherical with a lot of cholesterol esters are formed. This HDL
particle designated as HDL3. Mature HDL spheres are taken up by liver cells by apo-A-l mediated receptor
mechanism. HDL is taken up by hepatic scavenger receptor B1. Hepatic lipase hydrolyses HDL
phospholipid and TAG, and cholesterol esters are released into liver cells. The cholesterol that reaches the
liver is used for synthesis of bile acids or excreted as such in bile.
✺ The scavenger receptor B1 (SR-B1) is identified as an HDL receptor with dual role in HDL metabolism. In
liver and steroidogenic tissues, it delivers cholesteryl ester to tissues whereas in the tissues it is involved in
reverse cholesterol transfer.
404_27: HDL metabolism Dr. Abu Torab MA Rahim
✺ Functions of HDL
⌗ HDL is the main transport form of
cholesterol from peripheral
tissue to liver, which is later
excreted through bile. This is
called reverse cholesterol
transport by HDL.
⌗ The only excretory route of
cholesterol from the body is the
bile.
⌗ Excretion of cholesterol needs
prior esterification with PUFA.
Thus PUFA will help in
lowering of cholesterol in the
body, and so PUFA is anti-
atherogenic.
404_27: Clinical Significance of HDL Dr. Abu Torab MA Rahim
✺ Functions of HDL
⌗ The level of HDL in serum is inversely related to the incidence of myocardial infarction. As it is
“anti-atherogenic” or “protective” in nature, HDL is known as “good cholesterol” in common
parlance.
⌗ It is convenient to remember that "H" in HDL stands for "Healthy". HDL level below 35 mg/dl
increases the risk, while level above 60 mg/dl protects the person from coronary artery diseases.
⌗ The accumulation of cholesterol in beta cells causes perturbations in glucose metabolism, reduces
insulin secretion and can be associated with a diabetic phenotype. Cholesterol is also a key
determinant of beta cell membrane organization and cell survival.
⌗ The ATP-binding cassette transporter A1, which effluxes cholesterol to lipid-free/lipid-poor
apolipoprotein A-I, the principal apolipoprotein in HDLs, is crucial for maintaining beta-cell
cholesterol homeostasis and function.
⌗ The maintenance of beta-cell cholesterol homeostasis, therefore, is important for preventing the
onset of insulin resistance and the development of type 2 diabetes.
404_27: Atherosclerosis: Plaque formation Dr. Abu Torab MA Rahim
✺ The characteristic lesion of atherosclerosis is the atheromatous plaque in the intima of the artery.
Typical plaques contain a core of cholesterol esters surrounded by an area of fibrosis, often with
calcification.
✺ The plaque impairs blood flow by narrowing the lumen of the artery, and it can lead to haemorrhage
into the plaque and thrombosis.
✺ The process starts with the accumulation of CE in subendothelial macrophages, which take up lipoproteins through
their scavenger receptors.
✺ The resulting fatty streaks initially are reversible. They are seen even in children, and most regress spontaneously.
✺ When lipid-laden macrophages, known as foam cells, die, the lipid becomes extracellular.
404_28: Summary of Fate of Lipoproteins Dr. Abu Torab MA Rahim
404_27: LDL cholesterol delivery to peripheral cells Dr. Abu Torab MA Rahim
404_27: Summary of Lipoprotein Functions Dr. Abu Torab MA Rahim
✺ Existing Axiom
⌗ Vegetable fat are good
⌗ Animal fats are bad
✺ In reality
⌗ Butter is rich SFA ▷ SFA gives these products unique texture & flavour ▷ USFA can’t do
⌗ Palm oil is rich in SFA ▷ SFA gives technological properties like solidness at RT.
⌗ USFA in these oils cause problems in bakery items ▷ Causing self life problem
✺ Problems salved by Food industry
⌗ Vegetable oils ▷ Hydrogenation of USFA under pressure ▷ More SFA produced which solidifies
the oil ▷ Margarine
✺ Human health concern
⌗ Body can not differentiate SFA from animal & SFA from plant
⌗ Hydrogenation under pressure may result in Partial Hydrogenation
404_28: Partial hydrogenation produces Trans fat Dr. Abu Torab MA Rahim
404_28: Partial hydrogenation produces Trans fat Dr. Abu Torab MA Rahim
404_28: Problem of the body with Trans fat Dr. Abu Torab MA Rahim
⌗ Prostaglandin E2, formed by the gastric mucosa, stimulates mucus secretion and
suppresses gastric acid secretion.
Effect PG Effect PG
Platalete
Blood pressure ⇪ Prostacyclene (PC) aggrigation & ⇪ Tromboxine (Tx)
control
Vasodialation ⇪ PC Vasoconstriction ↓ Tx
Immuno
supression ⇪ Bad Ecosonoids Immunity ⇪ Good Ecosonoids
Anti-
inflamation ↓ Inflamation needed
when antigen attack
Pro-inflamation ⇪
Pain
Pain inhibition ⇪ Transmission ⇪
404_29: Eicosanoids Dr. Abu Torab MA Rahim
Pain
Pain inhibition ⇪ Transmission ⇪
Cell
Cell
proliferation
proliferation
Inhibition
Less stomach More stomach
secretion secretion
Nutrition Survey of East Pakistan Nutrition Survey of Rural Nutrition Survey of Rural Bangladesh National Nutrition
1962-64 Bangladesh 1975-76 Bangladesh 1981-82 Survey 1995-96