404_25: Absorption & Transport of Dietary Fat Dr.

Abu Torab MA Rahim

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

⌗ Triglycerides in chylomicrons are utilized by adipose tissue, heart, skeletal

muscle, lactating mammary glands and, to a lesser extent, by spleen, lungs,
kidneys, endocrine glands, and aorta.
⌗ These tissues (but not liver and brain) possess lipoprotein lipase (LPL), an
enzyme that is attached on the surface of the capillary endothelium.
⌗ As the chylomicrons pass through the capillaries, they bind to LPL. Their TG are
hydrolyzed to free fatty acids, which are taken up by the cells.
⌗ LPL expression is regulated. Feeding raises LPL activity in adipose tissue but
reduces it in skeletal muscle and myocardium. In consequence, dietary fat is
redirected to adipose tissue in the well-fed state.
⌗ During lactation, LPL activity declines in adipose tissue but rises massively in the
mammary gland. These effects are orchestrated by hormones, including insulin,
epinephrine, glucocorticoids, and prolactin.
404_25: Adipose tissue is specialized for storage of TG Dr. Abu Torab MA Rahim

⌗ Adipocytes are specialized for fat synthesis and storage.

⌗ After a mixed meal, adipocytes obtain most of the FA for fat synthesis from the
action of LPL on chylomicron TG. These FA are transported into the adipocytes
where they are activated to their CoA-thioesters.
⌗ Unlike liver and intestine, adipose tissue releases lipid not in the form of
lipoproteins but as “free” (unesterified) fatty acids.
⌗ These FA are transported to distant sites in reversible binding to serum albumin.
The albumin-bound FA have a plasma half-life of only 3 minutes.
⌗ Other product of fat breakdown, glycerol, is used for gluconeogenesis by the liver.
⌗ ~ 40% of the FA released by lipolysis during fasting does not leave the tissue but is
resynthesized into storage TG.
⌗ This futile cycling consumes ~ 3% of the energy in the TG, but it permits better
regulation of lipolysis by controlling both the lipases and the enzymes that convert
them back into TG.
404_25: FA are transported into Mitochondria Dr. Abu Torab MA Rahim

✺ Carnitine-palmitoyl transferase reaction is freely reversible.

✺ 2 carnitine-palmitoyl transferases on the 2 sides of the membrane catalyses the
reversible reaction.
✺ FA with a chain length of <13 C do not depend on carnitine. They diffuse passively
across the membrane and subsequently are activated in the mitochondrion.
 404_25: Liver converts excess FA to Ketone bodies 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

✺ All nucleated cells can synthesize cholesterol.

✺ Most cholesterol in the human body is derived from endogenous synthesis rather than the diet.
✺ Endogenous synthesis amounts to 0.6 to 1 g/day, depending on the dietary supply.
✺ Endocrine glands including adrenal cortex & corpus luteum, have the highest rates of cholesterol
biosynthesis on a per-weight basis.
✺ The dietary supply is variable, but most people in modern societies eat 0.5-1g of cholesterol/d.
✺ In the presence of bile salts, ~ 50% of this is absorbed in the intestine.
✺ Cholesterol absorption requires not only the import carrier NPC1L1 (Niemann Pick–type C1-like
1), which transports preferentially cholesterol, but also phytosterols to some extent.
✺ Some of the absorbed cholesterol is resecreted into the intestine by the export carriers ABCG5 &
ABCG8 (ATP-binding cassette G5 and G8).
 404_25: Cholesterol Nutrition Dr. Abu Torab MA Rahim

✺ Human body contains about 140 g of cholesterol, most in

the form of “free” (unesterified) cholesterol in cellular
membranes.
✺ Concentration of free cholesterol in plasma is 300 x
higher than this value.
✺ Most abundant in tissues, especially in nervous system.
So brain is considered an unhealthy kind of food.
✺ Cholesterol is poorly soluble in water. Only 0.2 mg
dissolves in 100 mL of water at 250C. Therefore
cholesterol can be transported only as a constituent of
lipoproteins.
✺ However, only 30% of the “cholesterol” that is present in
human plasma lipoproteins and is measured as such in
clinical laboratories is free cholesterol.
404_25: Determinants of Hyperlipidemia & Atherosclerosis Dr. Abu Torab MA Rahim
404_25: Anti-hyperlipidemic drugs Dr. Abu Torab MA Rahim
 Dr. Abu Torab MA
404_25: Effect of various manipulation BP level & risk of CHD Rahim
404_25: Most plasma lipids are components of Lipoproteins Dr. Abu Torab MA Rahim
404_26: Summary of Ketosis Dr. Abu Torab MA Rahim
404_26: Consequences of Ketosis Dr. Abu Torab MA 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

⌘ Depending on the density (by ultra centrifugation)or on the electrophoretic

mobility, the lipoproteins in plasma are classified into five major types:
✺ Chylomicrons. Contains apoprotein B-48.
✺ Very low density lipoproteins (VLDL) or pre-beta lipoproteins. Main apoprotein
is B-100.
✺ Intermediate density lipoproteins (IDL) or broad-beta lipoproteins
✺ Low density lipoproteins (LDL) or beta-lipoproteins. Major apoprotein in LDL
is B-100.
✺ High density lipoproteins (HDL) or alpha-lipoproteins. Major apoprotein in HDL
is apo-A. Free fatty acids (FFA) or non esterified fatty acids (NEFA) are
complexed with albumin. FFAs are not generally included in the classification
of lipoproteins, because they are loosely bound to the protein.
404_26: Apoprotein types & functions Dr. Abu Torab MA Rahim
404_26: Chylomicron structure & metabolism Dr. Abu Torab MA Rahim
404_26: VLDL: synthesis, metabolism & function 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

⌗ The LDL particle, along with

apoproteins and cholesterol ester are
hydrolysed by lysosomal hydrolases,
forming amino acids and free
cholesterol.
⌗ The free receptors can now return
to the membrane surface to bind
further LDL molecules
⌗ Approximately 70% of LDL is
degraded in the liver, and the
rest in extra-hepatic tissues. For
their work on LDL receptors.
 404_27: HDL metabolism 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

✺ When the HDL3 remains in circulation, the

cholesterol ester from HDL is transferred to
VLDL, IDL and LDL by a Cholesterol Ester
Transfer Protein (CETP). This will help to
relieve product inhibition of LCAT so that
more cholesterol can be taken up.
✺ TAG from VLDL, IDL and LDL is transferred
to HDL in exchange for the cholesterol ester.
The HDL particles that are rich in triacyl
glycerol and spherical are called HDL2. These
particles are first acted upon by hepatic
triglyceride lipase (HTGL) before being taken
up by scavenger B1 receptors in liver.
✺ The efflux of cholesterol from peripheral cells
to HDL is mediated by the ABC transporter
protein. The reverse cholesterol transport to
liver through HDL needs the activity of
LCAT, CETP and Apo-D.
 404_27: Reverse Cholesterol Transport 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

⌗ VLDL mainly transport & deliver TG

⌗ LDL & IDL transport & deliver
Cholesterol
⌗ Chylomicrons carry dietary lipids from
Intestine to Liver & release some TG
during the route
⌗ VLDL carry both exogenous &
endogenous lipids to other cells
⌗ LDL deliver both dietary and liver-
made cholesterol from Liver to other
tissues
⌗ Under certain conditions, LDL deposit
cholesterol in arterial wall to promote
atherogenesis. What is that condition?
404_27: Oxidative Hypothesis of Atherosclerosis. Dr. Abu Torab MA Rahim
404_27: Lipid hydrogenation & Trans fat 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

⌗ Body cannot use trans-bonded FA properly because incorporation into

TG is very difficult.

⌗ Trans-FA creates problem in cell membrane permeability.

⌗ Trans-FA are highly atherogenic than SFA itself.

⌗ Trans-FA decreases the HDL-cholesterol-to-LDL-cholesterol ratio

▷ Worsen situation.

⌗ Trans-FA increases the inflammation condition.

⌗ So SFA ▷ BAD and Trans FA ▷ Worst

 404_29: Eicosanoids Dr. Abu Torab MA Rahim

✺ Greek εíκoσα meaning “20”.

Eicosanoids are derived from PUFA
carbon-20.
✺ The 3 FA can be used as a
precursor, but arachidonic acid is
most important because it is far
more abundant than the others.
✺ In cell, these FA of membrane
phosphoglycerides are encountered
in position 2, by the action of
phospholipase A2 to release them.
✺The cyclooxygenase pathway
produces prostaglandins,
prostacyclin, and thromboxane, and
lipoxygenase pathway produces
leukotrienes.
 404_29: Prostaglandins, the biologically active lipid Dr. Abu Torab MA Rahim

✺ These biologically active lipids are not

only mediators of inflammation. They
participate in the regulation of many
normal functions, not as hormones, but
as paracrine and autocrine messengers in
the tissues in which they are formed.

✺ PGs, in particular, are formed by nearly

all cells in the human body. For
example, as regulators of platelet
activation.
✺ Most of the known effects of PGs and
other eicosanoids are mediated by
G-protein–coupled receptors.
 404_29: PG synthesis precursors Dr. Abu Torab MA Rahim

⌘ Prostaglandins are synthesized in all tissues

✺ PGE1 is
⌗ The key enzyme of PG synthesis is microsomal synthesized
cyclooxygenase complex, which consists of from
cyclooxygenase and peroxidase components. eicosatrienoi
⌗ It uses molecular O2 as an oxidant and that it c acid
creates a ring structure in its substrate.
⌗ Cyclooxygenase 1 (COX-1) is a constitutive ✺ PGE2 from
enzyme that is present in all cells except arachidonic
erythrocytes. acid
⌗ Cyclooxygenase 2 (COX-2) is an inducible
enzyme produced mainly by white blood cells but
to some extent by many other cell types as well.
✺ PGE3
⌗ COX-2 is induced by cytokines and other from
proinflammatory stimuli. eicosapent
aenoic
acid
 404_29: Functions of Prostaglandins Dr. Abu Torab MA Rahim

⌘ PG participate in physiological processes

⌗ Aggregating platelets release thromboxane A2 (TXA2).

⌗ Prostaglandin E2 (PGE2) and PGI2 are vasodilators that are formed by

endothelial cells.

⌗ Prostaglandin E2, formed by the gastric mucosa, stimulates mucus secretion and
suppresses gastric acid secretion.

⌗ PGE2 and prostaglandin F2α (PGF2α), synthesized in the endometrium,

induce uterine contraction.
⌗ PGE2 and TXA2 are formed by white blood cells as mediators of inflammation.

⌗ Fever is mediated by the cytokine interleukin-1 (IL- 1)

404_29: A Dr. Abu Torab MA Rahim
404_29: ⍹-3 / ⍹-6 Balance Dr. Abu Torab MA Rahim

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

⍹-3 Effect PG ⍹-6 Effect PG

404_30: Summary of Lipid Function in Human Dr. Abu Torab MA Rahim
 Fat Consumption Pattern in Bangladesh
Daily Per Capita Nutrient Intake (Nutrition Survey conducted by INFS)
Rural Urban Rural Urban Rural Urban Rural Urban
Calorie 2251 Kcal 1732 kcal 2094 kcal 1943 kcal 1892 kcal 1779 kcal

Protein 57.5 g 49.5 g 58.5 g 48.4 g 46.4 g 49.0 g

Fats 17.7 g 25.0 g 12.2 g 9.8 g 14.2 g 22.5

CHO 476 g 327 g 439 g 412 g 394.5 g 344.8 g

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

Fats & Oils 6.7 g 13.7 g 3.0 g 3.0 g 6.0 g 13.0 g

404_30: Summary of Lipid Function in Human Dr. Abu Torab MA Rahim
404_30: Summary of Lipid Function in Human Dr. Abu Torab MA Rahim
404_30: Summary of Lipid Function in Human Dr. Abu Torab MA Rahim
404_30: Summary of Lipid Function in Human Dr. Abu Torab MA Rahim