Lipids are digested and absorbed in the stomach and small intestine. Lingual and gastric lipases begin digestion in the stomach. Co-lipase and pancreatic lipase work together to further digest triglycerides in the small intestine. Absorbed fatty acids are packaged into chylomicrons for transport. The liver regulates lipid metabolism through synthesis and breakdown of triglycerides and cholesterol. Excess lipids are stored as triglycerides or converted to ketone bodies.

1. Digestion and absorption of
Lipids
Dr. Jaswant kaur

6. Digestion in Stomach
• The lingual lipase from the mouth enters stomach along with the food.
• It has an optimum pH of 2.5 – 5.
• The enzyme therefore continues to be active in the stomach.
• It acts on short chain triglycerides (SCT).
• SCTs are present in milk, butter and ghee.
• The action of lingual lipase is observed to be more significant in the
newborn infants.
• Gastric lipase is acid stable, with an optimum pH about 5.4.
• It is secreted by Chief cells, the secretion is stimulated by Gastrin.
• Up to 30% digestion of triglycerides occurs in stomach.

19. Co- lipase
•Binding of co-lipase to the TG molecules at oil
water interface is obligatory for the action of
lipase .
•The co -lipase is secreted by the pancreas as an
inactive Zymogen . It is activated by trypsin .

32. •It may be due to bile salt deficiency occur in liver disease
or obstruction of bile duct.
•abetalipoproteinemia :-defective synthesis of
chylomicron congenital .

39. What is the importance of carnitine ?
• Fatty acids are activated in the cytoplasm; but beta oxidation is in
mitochondria.
• So transport of fatty acids through the mitochondrial membrane is
essential.
• The long chain fatty acyl-CoA cannot pass through the inner
mitochondrial membrane.
• Therefore a transporter, carnitine is involved in transfer of fatty acids.
• Carnitine is β-hydroxy-γ-trimethyl ammonium butyrate:
• (CH3)3–N+–CH2–CHOH–CH2–COOH.

41. Mcqs
1. Medium chain and short chain fatty acids do not require carnitine for
transport across the inner mitochondrial membrane. So, medium chain
and short chain fatty acids are easily oxidized.
2. Carnitine deficiency is reported in preterm infants, in whom impaired
fatty acid oxidation is noticed. So more glucose is utilized, resulting in
episodes of hypoglycaemia.
3. Acetyl-CoA is the combination of acetate or acetic acid (2 carbon units)
with coenzyme
4. Acyl-CoA means acyl group (any fatty acid, C4 to C26 in length)
combined with coenzyme A.

47. β-oxidation of
palmitic acid (16 C).
It undergoes 7
cycles, which give
rise to 8 molecules of
acetyl-CoA

49. • Net yield = 108 - 2 =106 ATP
• (In the initial activation reaction, the equivalents of 2 high energy
bonds are utilized).
• The efficiency of beta oxidation is about 33%.

53. Alpha oxidation :-
• It is a process by which fatty acids are oxidized by removing carbon
atoms, one at a time, from the carboxyl end.
• The process is important in brain.
• The fatty acid does not need activation.
• Hydroxylation occurs at the alpha-carbon atom.
• It is then oxidized to alpha-keto acid.
• The keto acid then undergoes decarboxylation yielding a molecule of
CO2 and a fatty acid with one carbon atom less.
• This process occurs in the endoplasmic reticulum, does not require
CoA, but does not generate energy.
• Some fatty acids undergo alpha oxidation in peroxisomes also.

54. • Alpha-oxidation is mainly used for fatty acids that have a
methyl group at the beta-carbon, which blocks beta-
oxidation.
• A major dietary methylated fatty acid is phytanic acid.
• It is derived from phytol present in chlorophyll, milk and
animal fats.

55. Refsum’s Disease
• It is a metabolic error due to lack of alpha-hydroxylase (phytanic acid
oxidase) so that alpha oxidation does not occur and phytanic acid
accumulates in the tissues.
• The patient presents with severe neurological symptoms,
polyneuropathy, retinitis pigmentosa, nerve deafness and cerebellar
ataxia.
• Regression of symptoms is observed with restricted dietary intake of
phytanic acid.
• Milk is a good source of phytanic acid, which may be avoided.

56. Infantile Refsum disease
•It is a peroxisomal disorder, similar to Zellweger
syndrome and adrenoleukodystrophy.
•Hence phytanic acid accumulates along with VLCFA.
•Children do not survive long.

57. Omega oxidation :-
• It is a minor pathway taking place in microsomes, with the help
of hydroxylase enzymes involving NADPH and cytochrome P-
450.
• The CH3 group is converted to CH2OH and subsequently
oxidized with the help of NAD+ to a COOH group to produce
dicarboxylic acids.
• ω-oxidation becomes important when β-oxidation is defective
and dicarboxylic acids (6C and 8C acids) are excreted in urine
causing dicarboxylic aciduria

58. Oxidation of odd chain fatty acid
• The odd chain fatty acids are oxidized exactly in the same
manner as even chain fatty acids.
• However, after successive removal of 2-carbon units, at the
end, one 3 carbon unit, propionyl-CoA is produced

59. Propionate is gluconeogenic
• Ordinary fatty acids are cleaved to acetyl-CoA units which on entering
the Krebs cycle are completely oxidized to CO2, and hence as a
general rule, fatty acids cannot be used for gluconeogenesis.
• However, propionate is entering into the citric acid cycle at a point
after the CO2 elimination steps, so propionate can be channelled to
gluconeogenesis.
• Thus 3 carbon units from odd carbon fatty acids are
gluconeogenic.
• Cow's milk contains significant quantity of odd chain fatty acids.

60. Fate of propionyl CoA / Odd chain fatty acid

61. De novo Fatty acid synthesis
• It is not a reversal of oxidation.
• This pathway operates in the cytoplasm.
• The major fatty acid synthesized - palmitic acid, the 16C
saturated fatty acid.
• Site:- liver, adipose tissue, kidney, brain, and mammary
glands.

62. Important points
• To attach a two-carbon acetate unit at end of every cycle
• Acetyl CoA is the initiator and malonyl-CoA is the chain elongator
• Growing chain undergoes reduction
• Methyl end are synthesized first
• Proceeds towards the carboxylic acid end

64. Stages
• Three stages
• Production of acetyl CoA and NADPH
• Conversion of acetyl CoA to malonyl CoA
• Reactions of fatty acid synthase complex
• Two main enzymes :- Coenzyme
• Acetyl CoA carboxylase NADPH, Biotin, Mn,Mg
• Fatty acid synthase

74. Summary
• The net reaction of de novo synthesis of fatty acid may be as:
• 1 Acetyl-CoA +7 Malonyl-CoA +14 NADPH +14 H+ →
1 Palmitate + 7 CO2 +14 NADP+ + 8 CoA+ 6 H2O.

79. Glucagon inhibit lipogenesis
• Glucagon and epinephrine are lipolytic.
• They inhibit acetyl-CoA carboxylase by keeping the enzyme in the
inactive phosphorylated state.
• These hormones are secreted when the energy charge is low and AMP
levels are high.

81. Cholesterol structure

82. • Cholesterol has a total of 27 carbon atoms.
• One hydroxyl group at third position
of all sterols. The OH group is beta oriented, projecting
above the plane of ring.
• There is a double bond between carbon atoms 5 and 6.
• Further, there is an eight carbon side chain, beta-oriented
attached to 17th carbon

83. Function:-
1. Cell membranes: Cholesterol is a component of
membranes.
2. Nerve conduction: Cholesterol has an insulating effect on nerve fibers.
3. Bile acids and bile salts are derived from cholesterol. Bile salts are
important for fat absorption.
4. Steroid hormones: Glucocorticoids, androgens and estrogens are from
cholesterol.
5. Vitamin D3 is from 7-dehydrocholesterol.
6. Esterification: The OH group of cholesterol is esterified to fatty acids to
form cholesterol esters. This esterification occurs in the body by transfer of
a PUFA moiety by lecithin-cholesterol acyl-transferase.

90. Regulation

98. Synthesis of TG (Triacylglycerol) : Lipogenesis
• Major site :-Liver and adipose tissue are the major sites of
triacylglycerol (TAG) synthesis.
• TAG synthesis in adipose tissue is for storage of energy.
• But liver TAG is secreted as VLDL and is transported
• The TAG is synthesized by esterification of fatty acyl-CoA with either
glycerol-3-phosphate or dihydroxy acetone phosphate (DHAP).
• The glycerol part of the fat is derived from the metabolism of glucose.
• DHAP is an intermediate of glycolysis.
• Glycerol-3-phosphate may be formed by phosphorylation of glycerol or
by reduction of dihydroxy acetone phosphate (DHAP).

102. Adipose tissue metabolism
• The adipose tissue serves as a storage site for excess calories ingested.
• The triglycerides stored in the adipose tissue are not inert.
• They undergo a daily turnover with new triacylglycerol molecules
being synthesized and a definite fraction being broken down

103. Changes in adipose tissue
Well-fed state During fasting
Lipogenesis increased Lipogenesis inhibited
Lipolysis inhibited Lipolysis increased
Insulin inhibits HS-lipase Glucagon activates HS-lipase
Lipoprotein lipase active FFA in blood increased

104. Role of adipose tissue in diabetes mellitus
• In diabetes, lipolysis is enhanced and high FFA level in plasma is
noticed.
• Insulin acts through receptors on the cell surface of adipocytes.
• These receptors are decreased, leading to insulin insensitivity in
diabetes.

105. Adipose tissue and Obesity
• The fat content of the adipose tissue can increase to unlimited
amounts, depending on the amount of excess calories taken in. This
leads to obesity.
• A high level of plasma insulin level is noticed.
• But the insulin receptors are decreased; and there is peripheral
resistance against insulin action.
• When fat droplets are overloaded, the nucleus of adipose tissue cell is
degraded, cell is destroyed, and TAG becomes extracellular.
• Such TAG cannot be metabolically reutilized and forms the dead bulk
in obese individuals.

106. • Adipokines :- are adipose tissue derived hormones.
• The important adipokines are leptin, adiponectin, resistin, TNF-alpha
(tumor necrosis factor) and IL-6 (interleukin-6).
• Leptin :-is a small peptide, produced by adipocytes.
• Leptin receptors are present in specific regions of the brain.
• The feeding behaviour is regulated by leptin.
• A defect in leptin or its receptor, can lead to obesity.
• Decreased level of leptin increases the chances of obesity.
• Adiponectin:- is another polypeptide, which increases the insulin
sensitivity of muscle and liver.
• Low levels of adiponectin will accelerate atherosclerosis.
• Low levels are also observed in patients with metabolic syndrome.

107. Action of leptin

112. Fatty liver
• deposition of excess triglycerides in the liver cells.
• The balance between the factors causing :-
A. Causes of fat deposition in liver
1. Mobilization of fatty acids (FFA or NEFA) from adipose tissue.
2. More synthesis of fatty acid from glucose.
B. Reduced removal of fat from liver
3. Toxic injury to liver. Secretion of VLDL needs synthesis of Apo
B-100 and Apo C.
4. Decreased oxidation of fat by hepatic cells.

114. Causes of fatty liver

115. Fatty liver due to poison

116. Fatty liver due to alcoholism

117. What are lipoproteins & Its clinical
importance

129. Clinical manifestation
• Enlarged liver, vision disturbances ,mental retardation , seziures
• Lack of muscle tone , jaundice
• Laboratory diagnosis :-
• Very long chain fatty acid high
• Prognosis ;- FOR INFANT VERY POOR

130. ketogenesis
• Ketone bodies are three types :-
• Acetone & beta hydroxy butyrate secondary ketone bodies.
• Acetoacetate primary ketone body
• Synthesized by the liver mitochondria
• The acetyl-CoA formed from fatty acids can enter and get oxidized in
TCA cycle only when carbohydrates are available.
• During starvation and diabetes mellitus, acetyl-CoA takes the
alternate route of formation of ketone bodies.

134. • Blood level of ketone bodies is less than 1 mg/dL.
• Ketone bodies are not detected in urine.
• But when the rate of synthesis exceeds the ability of extrahepatic
tissues to utilize them, there will be accumulation of ketone bodies in
blood.
• This leads to ketonemia, excretion in urine (ketonuria) and smell of
acetone in breath.
• All these three together constitute the condition known as ketosis.

135. • Causes :-
• Diabetes mellitus:
• Untreated diabetes mellitus is the most common cause for ketosis.
• The deficiency of insulin causes accelerated lipolysis.
• More fatty acids are released into circulation.
• Oxidation of these fatty acids increases the acetyl-CoA pool.
• Oxidation of acetyl-CoA by TCA cycle is reduced, since availability of oxaloacetate
is less.
• Starvation:
• In starvation, the dietary supply of glucose is decreased.
• Available oxaloacetate is channelled to gluconeogenesis.
• The excess acetyl-CoA is converted to ketone bodies.
• The high glucagon favors ketogenesis.
• The brain derives 75% of energy from ketone bodies under conditions of fasting.
• Hyperemesis (vomiting) in early pregnancy may also lead to starvation-like
condition and may lead to ketosis.

137. Features of ketosis
1. Metabolic acidosis. Acetoacetate and beta-hydroxy butyrate are acids. When
they accumulate, metabolic acidosis results.
2. Reduced buffers. The plasma bicarbonate is used up for buffering of these
acids.
3. Kussmaul's respiration. Patients will have typical acidotic breathing due to
compensatory hyperventilation.
4. Smell of acetone in patient's breath.
5. Osmotic diuresis induced by ketonuria may lead to dehydration.
6. Sodium loss. The ketone bodies are excreted in urine as their sodium salt,
leading to loss of cations from the body.
7. Dehydration. The sodium loss further aggravates the dehydration.
8. Coma. Dehydration and acidosis are contributing for the lethal effect of
ketosis

138. Management of ketosis
i. Treatment is to give insulin and glucose. When glucose and insulin
are given intravenously, potassium is trapped within the cells. Hence,
the clinician should always monitor the electrolytes.
ii. Administration of bicarbonate, and maintenance of electrolyte and
fluid balance are very important aspects

144. Definition :-
- Hardening of arteries , due to formation of plaque, results in the
endothelial damage and narrowing of the lumen .
- Due to dysregulation of cholesterol metabolism.
- As cholesterol cannot be catabolized by animal cells.
- Excess cholesterol can only be removed by excretion or conversation
to bile salts .

145. • MCQ :-
• Age :- as age increase elasticity
of vessels wall decrease
• Sex : more prone Male because
male sex hormone is atherogenic
, female sex hormones are
protective
• Genetic factor:- derangement of
lipoprotein metabolism leads to
high cholesterol .

146. Modifiable risk factors
• Hyperlipidemia
• Lipoprotein a
• Level of HDL
• Hypertension
• Cigarette smoking
• Diabetes mellitus
• Obesity
• High hs CRP

147. Pathophysiology , Stages :-
• Stage I : Formation of foam
cells: The LDL cholesterol,
especially oxidised LDL
particles are deposited in the
walls of arteries.
• Stage II: Progression of
atherosclerosis: Lipid
droplets are seen in the
lesion.

148. • Stage III. Fibrous proliferation:
• Thus there is a definite component of inflammation in
atherosclerosis. This chronic infection leads to increased hs-
CRP.
• Stage IV: This leads to narrowing of vessel wall when
proliferative changes occur. The blood flow through the
narrow lumen is more turbulent and there is tendency for clot
formation.

153. Role of LDL in plaque formation