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Metabolism of lipids
Dr. Roshan Ali
Assistant professor of Biochemistry
Institute of Basic Medical Sciences
Khyber Medical University
YouTube Education: https://www.youtube.com/user/roshanali5
YouTube General: https://www.youtube.com/channel/UCgBU1AZrLESj0mLoCZDX-5Q
IPMR Biochemistry Fourth Semester
Course Contents
 4 of 7. Metabolism of Lipids
• Digestion & Absorption of Lipids
• Metabolism & Clinical Significance of Lipoproteins
• Fatty acid oxidation biosynthesis and metabolism of Triacylglycerols
• Metabolism & clinical Significance of Cholesterol
• Metabolism of Eicosanoids
 Resources used for the preparation of these
slides
• Wikipedia
• Encyclopaedia Britannica
• Research articles
• Google images
• Slideshare and other PPT providers
 Recommended Material
• Harper’s Biochemistry by Robbert K. Murray, Daryl K. Granner, Peter A. Mayes, Victor W.
Rodwell, Latest Ed.

• Lippincott’s Illustrated Review of Biochemistry by Pamela C. Champe and Richard A.

Harvey, Latest Ed.

• Practical Clinical Biochemistry by Varley.

• Textbook of Biochemistry by Devlin, 5th Ed.

• Textbook of Medical BiochemistryVol-I and II by M.A. Hashmi. Biochemistry by Stryer,

Lubert, Latest Ed
Digestion & Absorption of Lipids
Digestion and
Absorption Of
Lipids
 Lipids
Lipids are heterogeneous group of water insoluble organic molecules
Major source of energy for the body
 Dietary fat Composition
More than 95% are triglycerides,
the other are
Cholesterol,
Cholesteryl esters,
Phospholipids, and
Unesterified fatty acids.
 Dietary sources of Lipids

 Animal Sources
Dairy products- Meat, butter, ghee
Meat and Fish, eggs

 Vegetable Sources
Cooking oils- Sun flower oil, Mustard oil,
Ground nut oil
Fats from other vegetable sources
Digestion
 Digestion in Mouth
Enzyme: Lingual lipase
Function: Hydrolysis of triacylglycerols:
They attack the sn-3 ester bond
forming 1,2-diacylglycerols and free fatty acids

Secretion: By dorsal surface of tongue

Active at (pH 2.0 – 7.5)

Enzymatic action continues in stomach

Short chain fatty acids, released are absorbed directly from the
 Triglyceride degradation

Triglycerides are degraded by lipases to form free fatty acids and glycerol
 Digestion in Stomach
Enzyme: Gastric Lipase
Optimum pH: 7.8
Less effective in stomach due to acidic p H
Metal ion required for activity: Ca++
Effective for: short and medium chain fatty acids
Digestion in small intestine
 Digestion in small intestine
Major site of fat digestion

Pancreatic Juice:
Pancreatic lipase, Phospholipase, Cholesterol esterase
Emulsifying agent:
bile salt
Gastro intestinal hormones:
Secretin
Cholecystokinin
Pancreozymin

Secretion of pancreatic juice is stimulated by-

Passage of acidic gastric contents in to the duodenum
By secretion of the gastro intestinal hormones
 Contents of Pancreatic Juice
Pancreatic Lipase- For the digestion of triglycerides

 Phospholipase A2- for the digestion of Phospholipids

Cholesterol esterase-For the digestion of Cholesteryl esters

 Triacyl glycerol degradation
by pancreatic lipase
 Pancreatic lipase is specific for the hydrolysis of primary ester linkages(Fatty
acids present at position 1 and 3)

It can not hydrolyze the ester linkages of position -2

Digestion of Triglycerides proceeds by removal of a terminal fatty acid to

produce an 1,2 diglyceride.

The other terminal fatty acid is then removed to produce 2 mono glyceride.
Triacyl glycerol degradation by pancreatic
lipase
 What happens to the central
fatty acid
The last fatty acid is linked by secondary ester
group, hence can not be hydrolyzed by pancreatic
lipase.

 2- Mono acyl glycerol can be converted to 1-

Mono acyl glycerol by isomerase enzyme and then
hydrolyzed by Pancreatic lipase.
 Gastro Intestinal hormones
Secretin- Increases the secretion of electrolytes and fluid components of pancreatic juice
electrolyte

Pancreozymin: stimulates the secretion of the pancreatic enzymes

Pancreatic enzyme

Cholecystokinin: causes the contraction of the gall bladder and discharges the bile
Contraction Bladder (cyst)

Hepatocrinin- stimulates more bile formation

Liver (bile)
 Emulsification and digestion
 Emulsification: The breaking up of fat globules into much smaller emulsion droplets.

 Lipids are hydrophobic

 thus are poorly soluble in the aqueous environment of the digestive tract.

 The digestive enzyme, lipase, is water soluble

 and can only work at the surface of fat globules.

 Digestion is greatly aided by emulsification

 Bile Salts: They help in emulsification

 Bile Salts
Bile salts are formed from bile acids
cholic acid
chenodeoxycholic acid .

Bile salts are required for the proper functioning of the pancreatic lipase

 Bile salts also help in the emulsification of fats

Bile salts are synthesized in the liver

stored in the gall bladder

They are derivatives of cholesterol
Absorption of lipids
 Before and After Absorption
• Triacylglycerols, phospholipids, and cholesterol
• 1. Emulsification
• 2. Hydrolysis by lipases  FAs + monoacylglycerol + Lysophospholipids + Cholesterol
• 3. Diffusion/facilitated transport into enterocytes
• Diffusion:
• Small molecules (Glycerol + short chain fatty acids)
• Micelle:
• Long chain molecules
• Bile salt anions are hydrophilic on one side and hydrophobic on the other side
• The bile salts surround long-chain fatty acids and monoglycerides, forming tiny spheres called micelles
• micelles are taken up into the epithelial cells

• 4. FFAs to various organelles for further processing and resynthesis (ER etc.)
• Resynthesize
• 1a. Monoacylglycerols + FFAs –(monoacylglycerol acyltransferases) Diacylglycerol
• 1b1. Diacylglycerol + FFAs –(diacylglycerol acyltransferases) Triacylglycerols
• 1b2. Diacylglycerol + choline or ethanolamine –(choline/ethanolaminetransferases) phospholipids
• 2. Cholesterol + FFA –(acyl-CoA:cholesterol acyltransferases) Cholesterol esters
 After Resynthesis
• 5. Secreted with
• chylomicrons and HDL
• Their secretion is dependent on MTP and ABCA1
• majority of phospholipid, cholesterol and vitamin E are absorbed through the chylomicron pathway
• Chylomicron = triglycerides + phospholipids + cholesterol + proteins
• They are transported to the Glogi by vesicles for modification (Glycosylation etc)
• released from Golgi and enter the general circulation at the thoracic duct
• significant amount of these lipids are also absorbed via the HDL pathway
or
• stored as cytoplasmic lipid droplets
• They are hydrolyzed and are secreted later
• They are large spherical particles surrounded by a phospholipid monolayer
• Their surface contains several proteins
• The core consists of neutral lipids (triglycerides, cholesterol esters)
• They are subsequently mobilized and secreted during fasting state in enterocytes
• Mobilization is hydrolysis of triglycerides, entry of FAs to ER and re-synthesis of triglycerides and secretion

• MTP: Microsomal Triglyceride Transfer Protein

• ABCA1: ATP-binding cassette transporter
 Micelles
Micelles are lipid molecules that arrange themselves in a spherical form in aqueous solutions
These contain molecules with amphiphilic structures that have a hydrophobic core and a hydrophilic shell.
It is an aggregate of surfactant molecules dispersed in a liquid, forming a colloidal suspension
Metabolism & Clinical Significance of
Lipoproteins
 Lipoprotein
soluble proteins combined with fat or other
lipids
 lipoproteins

• Assembly of proteins and lipids

They help in transport of fats

The proteins serve to emulsify the lipid
 Lipoproteins- Introduction
Lipids must be transported between various cells and organs for utilization and storage

Lipids are insoluble in water

the problem of transportation in the aqueous plasma is solved by
associating
nonpolar lipids (triacylglycerols and cholesteryl esters) with
amphipathic lipids (phospholipids and cholesterol) and
proteins to make water-miscible lipoproteins
 General Structure of Lipo proteins

• They have a nonpolar core and a single surface layer of amphipathic lipids
• Core: The nonpolar lipid core consists of mainly
• Triacylglycerol
• cholesteryl ester
• Surface: layer has a single surface layer of
• amphipathic phospholipid
• cholesterol
• These are oriented so that their polar groups face outward to the aqueous medium
• The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein

01/22/2024 Biochemistry for medics 33

General Structure of Lipo proteins

Some apolipoproteins are integral and cannot be removed, whereas others can
be freely transferred to other lipoproteins
Classification of Lipoproteins
 Types of Lipoproteins
Lipoproteins with high lipid content will have low density, larger size and
so float on centrifugation. Those with high protein content sediment 99%

easily, have compact size and have a high density.

92%

Chylomicron
Bad
85%
Good
VLDL
80%

50% IDL
LDL
HDL
 1: Protein
2: Phospholipid
3: Cholesterol
4: Triglyceride

Chylomicron VLDL IDL LDL HDL

 APOC2
Chylomicrons
HDL
Liver
• It carries triglycerides (fats)
APOE
• from
• Intestines Tissues
• to Blood stream
• Adipose tissue
• Cardiac
• Skeletal muscle Mature Chylomicron Remnant Chylomicron
Nascent Chylomicron
• Liver

Intestine Enterocyte Lacteals TGL

Digested lipid from diet Triglyceride + phospholipids + cholesteryl esters + apolipoprotein B-48
 VLDL APOC2
• It carries newly synthesized triglycerides (fats)
• from HDL
• Liver Liver
• to APOE
• Adipose tissue
• Liver Tissues
Blood stream

IDL LDL

Liver TGL

Nascent VLDL Apob100, apoc1, apoe, Triglyceride + cholesterol +cholesteryl esters

 Intermediate-density lipoproteins (IDL)
• It is intermediate between VLDL and LDL.
• In general, IDL, is somewhat similar to LDL,

• It transports a variety of triglyceride fats and cholesterol.

 Low-density lipoproteins (LDL)
• Carry cholesterol
• from the
• liver
• to
• cells of the body.

• LDLs are sometimes referred to as the "bad cholesterol" lipoprotein.

 High-density lipoproteins (HDL)
• Collect cholesterol
• from the
• body's tissues,
• bring it back to the
• liver.

• HDLs are sometimes referred to as the "good cholesterol" lipoprotein

 Role of LDL in atherosclerosis
• Damage to endothelium (hypertension, smoking etc).
• LDLs penetrate vascular wall, deposit in the intima
• LDL oxidation.
• Oxidised LDLs attract the attention of macrophages which ingest the LDL.
• Macrophages become overloaded with lipid and become “foam” cells which die and release pools of lipid in the vessel wall
(plaques).
• A complex processes mediated by cytokines and growth factors causes smooth muscle cells to form a collagenous cap over the lipid
(mature atherosclerotic plaque).
• Cap grows and can constrict the vessel (causing angina for example).
• Macrophages can degrade the cap while T cells can inhibit collagen synthesis – the cap can rupture to expose collagen and lipids
• This leads to aggregation of platelets and blood clot formation.
• If the coronary artery is blocked by a clot – heart attack.
• Blocking of arteries in the brain causes stroke.
• Antioxidants (vitamin E and C) may protect LDL from oxidation and so protect against heart attack and stroke.
Biosynthesis
 Biosynthesis of chylomicrons

Synthesis of Apolipoprotein B: in RER

Incorporation into lipoproteins: in SER

Carbohydrate addition in golgi bodies

Release from the cell by reverse pinocytosis

Chylomicrons pass into the lymphatic system

45
 Catabolism of Chylomicrons

• Enzyme: Lipoprotein lipase

• Chlmcrnremains (cholesterol+cholesteryl esters) + triacylglycerol+apo C

To liver by endocytosis to HDL

Hepatic lipase
Further Metabolism Products to VLDL
46
 Synthesis of VLDL

• Chylomicrons are synthesized by intestinal cells

• VLDL is synthesized by hepatic parenchymal cells

• The process is almost identical

47
 Catabolism of VLDL

Catabolism of VLDL is similar to chylomicrons

48
 Catabolism of LDL

30% of LDL is degraded in extra-hepatic tissues

70% in the liver
The LDL is taken into a cell via the LDL receptor via endocytosis
Where the contents are either
stored
used for cell membrane structure
converted into other products such as
 steroid hormones
 bile acids
There is a receptor-independent catabolism pathway as well
49
Metabolism of HDL
 Composition of HDL
• HDL is composed of
• cholesterol
• triglycerides
• various apolipoproteins
• Apo-AI, Apo-AII, Apo-AIV, Apo-AV, Apo-C1, Apo-CII, Apo-CIII, and Apo-E
 enterocytes and hepatocytes
Metabolism of HDL peripheral tissues, chylomicrons, VLDL

Apo A1 is synthesized + (cholesterol + phospholipids)  pre-beta HDL

Pre-beta HDL travels in circulation + (free cholesterol + phospholipids)
HDL is synthesized and secreted from both liver and intestine

Apo C and Apo E are synthesized in the liver + Liver HDL

Liver HDL transfers Apo C and E to intestinal HDL

52
 Metabolism of HDL
• Lecithin Cholesterol Acyl Transferase (LCAT)
• LCAT and the LCAT activator apo A-I—bind to HDL

• Surface Lecithin and free cholesterol  cholesteryl esters and lysolecithin

• cholesteryl esters move into the hydrophobic interior of HDL

• lysolecithin is transferred to plasma albumin

53
 Metabolism of HDL

• The class B scavenger receptor B1 (SR-B1) an HDL receptor

• In the tissues, SR-B1 mediates the acceptance of cholesterol from the cells by HDL
• In the liver it binds HDL via apo A-I
• cholesteryl ester is injected into the cells,

• excretion via the bile (either as cholesterol or after conversion to bile acids)

54
 Clinical Significance of lipoprotein metabolism

Fatty Liver
• Abnormal accumulation of certain fats (triglycerides) inside liver cells.
• Impaired VLDL formation or secretion leads to nonmobilization of
lipid components from the liver, results in fatty liver

55
 Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
Inherited defects in lipoprotein metabolism lead to
hypolipoproteinemia
hyperlipoproteinemia
 In addition, secondary abnormal lipoprotein patterns can cause
diabetes mellitus
hypothyroidism
atherosclerosis

56
 Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
Name Defect Characteristics

Hypolipoproteinemias

Abetalipoproteinemia No formation of Rare;

chylomicrons blood acylglycerols low;
VLDL intestine and liver accumulate
LDL acylglycerols.
Intestinal malabsorption.

Familial alpha-lipoprotein deficiency All have low or near absence of Hypertriacylglycerolemia due to
HDL absence of apo C-II,
Low LDL levels.
Tangier disease Atherosclerosis in the elderly.

Fish-eye disease

Apo-A-I deficiencies
57
 Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
Name Defect Characteristics
Hyperlipoproteinemia
Familial lipoprotein lipase deficiency Hypertriacylglycerolemia due to Slow clearance of
(type I) deficiency of LPL, Chylomicrons
abnormal LPL VLDL.
apo C-II deficiency Low levels of LDL and HDL.
causing inactive LPL. No increased risk of coronary disease

Familial hypercholesterolemia Defective Elevated

(type II a) LDL receptors LDL levels and hypercholesterolemia
mutation in ligand region of apo B-100 It results in atherosclerosis and
coronary disease.

58
 Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)- contd.
Name Defect Characteristics

Familial type III hyperlipoproteinemia Deficiency in remnant clearance by the Increase in chylomicron and VLDL
broad beta disease, liver is due to abnormality in apo E. remnants , Causes
remnant removal disease, hypercholesterolemia, xanthomas, and
familial dysbetalipoproteinemia atherosclerosis.

Familial Hypertriacylglycerolemia Overproduction of VLDL often associated High cholesterol, VLDL, Subnormal LDL
(type IV) with glucose intolerance and and HDL. Associated with Alcoholism,
hyperinsulinemia. diabetes mellitus and obesity.

Hepatic lipase deficiency Deficiency of the enzyme leads to Patients have xanthomas and coronary
accumulation of large triacylglycerol-rich heart disease.
HDL and VLDL remnants
59
Thank You
Biosynthesis and Degradation of Triglycerides
Fatty Acid Oxidation
Metabolism of Cholesterol
Metabolism of Eicosanides
Biosynthesis of triacylglycerol
Breakdown of Triacylglycerol
Types of fatty acid oxidation
 TYPES OF FATTY ACID OXIDATION

Fatty acids can be oxidized by-

1) Beta oxidation- Major mechanism, occurs in the mitochondria matrix.

2-C units are released as acetyl CoA per cycle.

2) Alpha oxidation- Predominantly takes place in brain and liver,

one carbon is lost in the form of CO2 per cycle.

3) Omega oxidation- Minor mechanism, becomes important in conditions of impaired beta oxidation

4) Peroxisomal oxidation- Mainly for the trimming of very long chain fatty acids.

65
Fatty acid oxidation
Beta Oxidation
of
fatty acids
Energy production
 BETA OXIDATION- ENERGY YIELD
16 Carbon Fatty Acid
Total Cycles required: (16/2)-1 = 7
ATPs consumed in first cycle only: 2 (1ATP to 1AMP means 2ATP to 2ADP) X 1 = 2

NADH produced per cycle: 1 X 7 = 7

FADH produced per cycle: 1 X 7 = 7
Acetyl CoA produced per cycle (6 cycles): 1 X 6 = 6
Acetyle CoA produced in last cycle: 2 X 1 = 2
Total Acetyl CoA produced: 2 + 6 = 8

NADH to ATPs: 7 X 2.5 = 17.5

FADH to ATPs: 7 X 1.5 = 10.5
Acetyl CoA to ATPs: 8 X 10 = 80
Total = 108 ATPs
Net Energy output- 108-2 = 106 ATP 69
 BETA OXIDATION OF UNSATURATED FATTY ACIDS

Most of the reactions are the same

Only two additional enzymes an isomerase and a reductase are needed
Energy yield is less since they are less reduced
Per double bonds 2 ATP are less formed
since the first step of dehydrogenation to introduce double bond is not required
as the double already exists

70
 BETA OXIDATION OF
UNSATURATED FATTY ACIDS
 Palmitoleoyl Co A undergoes three cycles of degradation
carried out by the same enzymes
cis- Δ 3-enoyl CoA is formed in the third round
It is not a substrate for acyl CoA dehydrogenase
isomerase converts double bond into a trans- Δ 2 double bond
The subsequent reactions are again the same

71
Metabolism & clinical Significance of
Cholesterol
 Cholesterol Functions

• Membrane component
• Precurser to
• Bile acids
• Vitamin D
• Steroid hormones
Steroid hormones from Cholesterol
Five major classes of steroid hormones derived from cholesterol
cholesterol
(C27)

pregnenolone
(C21)

progestagens
(C21)

glucocorticoids mineralocorticoids androgens

(C21) (C21) (C19)

estrogens
(C18) 75
Cholesterol synthesis
 Biosynthesis of Cholesterol

• Primary site: liver (~1g/d)

• Secondary sites: adrenal cortex, ovaries, testes
https://www.google.com.pk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=
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April 17, 2016
Metabolism of Eicosanoids
 Eicosanoids
• Signalling molecules

• Made by oxidation of 20-carbon fatty acids

• They exert complex control over many bodily systems

• mainly in inflammation or immunity
• as messengers in the central nervous system

• There are multiple subfamilies of eicosanoids

• Such as.
• Prostaglandin
• Prostacyclins
• Thromboxanes
• Lipoxins
• Leukotrienes.
 Steps before eicosanoid pathway

• 1. A cell is activated by
• mechanical trauma, cytokines, growth factors or other stimuli
• This triggers the release of a phospholipase at the cell membrane
• 2. The phospholipase travels to the nuclear membrane
• 3. Phospholipase catalyzes ester hydrolysis
• of phospholipid (by phospholipase A2) or
• Of diacylglycerol (by phospholipase C).
• 4. This frees a 20-carbon fatty acid
• 5. Fatty acid is oxygenated along any of several pathways
• The eicosanoid pathways
Prostanoid pathways
Leukotriene pathways
Thank You