For undergraduate medical students, illustrated simple presentation of lipid metabolism with clinical case studies as per MCI 2010 standard.

1. Introduction to Lipid Metabolism
Rakesh Sharma
Professor
NDMC Medical College and Hindurao Hospital,
Delhi

2. Bio-Chemical Nature of Human Body
Hormones
Receptors
Enzymes
Carbohydrates
Amino Acids/Proteins
Lipids
Nucleic Acids Vitamins/Minerals
Exercise
Behavior
Environment Energy
Circulation, Distribution and Molecular Reactions Generate Bio-Energy for Life
Signs, Symptoms and Manifestations
7/7/2020 2
Rakesh Sharma fior 1st MBBS Biochemistry
Students
Fatty Acids
Ketone Bodies
Cholesterol
Sphingolipids
Lipoproteins
Food
Digestion &
Absorption
LIVE HUMAN
BODY
Pathology
Hematology
Cytology
ClinicalChemistry
Molecules
Gases&
Electrolytes
•Atoms (C,H,O,P,N,S,minerals)
Free Radical Diseases
•Molecules
Molecular Diseases
•Super-Assemblies
Structural Diseases
•Cell membrane
Transport Diseases
•Organelles, Skeleton
Cell Diseases
•Tissues
Tissue Diseases
•Organs
Organ Diseases
•Systems Sign,Symptoms
Manifestations
Tests/Diagnosis
ECG
Imaging
HealthyLifeStyle

3. Indications and Intervention Monitoring Treatment and Management
• Hyper/Hypo- condition of atoms, Energy indicators Drugs and Life support
molecules, organelles, size of cells Electrophysiology Supplements
tissues, organs Neurophysiology Environment
• Status of Organ functions Organ function tests Detoxification
• Medical/Surgery Procedures System function tests Body-Mind Purification
• Blood transfusion and Clinical manifestations MY-IDEA approach
Molecules purification Physical sign & symptoms Immunity and Longitivity

4. Objectives
• Fatty acid beta-oxidation makes acetyl-CoA
and ATP
• Ketone bodies formation (Ketogenesis)
• Ketoacidosis
• Gluconeogenesis by fatty acid beta-oxidation
• Fatty acid synthesis
• Cholesterol
• Lipoproteins

5. Lipid Digestion by Lipases
• In mouth: Lipase
• In stomach: Gastric lipase
• In pancreas: Lipase + Co-lipase
• In duodenum: Emulsification
• In intestine: Cholesterol esterase, Phospholipase A2
• Lipases break down Triacylglycerols into Fatty acids
and Glycerol
• Lipid absorption is in form of micelles

6. Link between Carbohydrate & Lipid
Metabolism
• In liver, DHAPGlycerol 3PGlycerol
• In adipose tissue,Glycerol 3PDAGTAG
• Insulin and Glucagon, Epinephrin regulate Lipase
action by cAMPProtein KinaseTAG Lipase
1stFatty Acyl CoA 2ndFatty Acyl CoA

7. Fatty Acid
• Palmitic Acid 16:0
Fatty Acid+CoA.SH  Fatty Acyl-CoA
• Active fatty acid means Fatty Acyl-Coenzyme A
3
-CoA.SH

8. Coenzyme A molecule

9. Fatty Acid Oxidation makes Acetyl-CoA
• Fatty acid oxidation in mitochondria and fatty
acid biosynthesis in the cytosol
• By fatty acid oxidation, fatty acyl-CoA
derivatives, specific enzymes, Oxygen, NAD+ and
FAD coenzymes generate acetyl-CoA  ATP
• Beta oxidation: β carbon on fatty acid is
converted to β-keto acid.
• Alfa- and Omega- Oxidation on α carbon & ω
carbon

10. Two enzymes catalyze Acyl-CoA formation
• Activation of Fatty Acids in cytoplasm
Fatty acyl CoA Synthase(Thiokinase)
Carnitine Acyl Transferase
• 7 times Fatty acid acyl CoA converted to 8
Acetyl CoA (8 acetyl CoA make 80 ATP)
• Each acetyl CoA molecules generate 10 ATP

11. Carnitine in Mitochondria
• Carnitine is a Acyl-CoA transporter made from Lys+Met
• Carnitine activates fatty acid(Fatty Acyl-CoA)
Carnitine-Acyl Transferase-I (Outer membrane)`
Carnitine-Acyl Transferase II(Inner membrane)
Carnitine TRANSLOCASE(Inner membrane)
• Medical Biochemistry explains
-CARNITINE DEFICIENCY and
-TRANSLOCASE DEFICIENCY
β-hydroxy- γ-trimethylammonium butyrate)
(CH3)3N+—CH2—CH(OH)—CH2—COO–

12. β Oxidation in 5 Steps
(Palmitic acid )C18
Acyl CoA Synthase
FAD linked Dehydrogenase
Hydration
NAD dependent Dehydrogenase
Cleavage
Net Outcome of Palmitic acid oxidation:
• 7FAD, 7NAD
• ATP Yield (Energetics) 106
• Regulation: glucagon; insulin ratio, CAT-I

13. Carnitine in β-Oxidation
-2 ATP
+1.5ATP
+2.5ATP
C16C14(step 1)
C148 acetyl-CoA(steps 2-5)
(7 cycles)
10 x 8 ATP=80+7x4
Net 80-2=78 +28=106 ATP
CARNITINE
ACYLTRANSFERASE
CPT-I
7 cycles
TCA
2
3
4
5 R-CH2-CO-CoA
+CH3CO.CoA
CO2 + ATP

15. Fatty Acid Oxidation Reactions
Fatty Acid
16Carbons
-2 C
-2 C
-2C

16. Diseases of Fatty Acid Oxidation
• Medium Chain FA Acyl CoA Dehydrogenase deficiency
• Jamaican Vomiting Syndrome(Hypoglycin)
• Methylmalonyl Aciduria(B12 deficiency)
• Propionic Acidemia
Symptoms: Hypoglycemia, Ketoacidosis, Muscle weakness
• PEROXISOMAL ALPHA OXIDATION DISEASES
 Refsum Disease is Phytanic acid deficiency
Symptoms: Blindness with Cardiomegaly-Neuro-deafness
Treatment: Children need milk, meat and ruminant fat
 Zellweger Syndrome
X-linked Adrenoleukodystrophy
Mechanism: STAR proteinAdrenal HypoplasiaNeuro-
demyelination (Lorenzo oil therapy)
 Rhizomelic Chondroplasia Punctata(RCDP)

17. Carnitine Deficiency
• Poor kidney function, Cardiomyopathy,
Myopathy, hypoglycemia in prematured babies
• Mechanism: impaired β-Oxidation
• CPT-1, CPT-2,Translocase deficiency
• Treatment: Carnitine + Medium-long chain fatty
acids in diet

18. A teenage girl complained tired at gym, weak muscles, fever, No
appetite. Lab test: High TG(long chain FA)+vacuoles in muscle biopsy.
Pathogenesis: Deficiency of carnitine / CPT I and CPT II 
Causes: Less ATP affects
Methyl Malonic Aciduria,
Propionic acidemia, Heart
Isovaleric acidemia Muscle
Diarrhea, Diuresis, Hemodialysis Kidney
Ketosis
Sepsis, Burn, GI Surgery
Zidovudine,Valproate Liver
Poor diet,TPN
Physical Sign/Symptoms: Fatigue,Confusion(hyperammonemia),Cardiac pain,
Cramps of weak muscle(lipid storage), Poor appetite, Viral infections
Mechanism:Fatty acids stay in muscleNo β-oxidation/ATP formed +Lipid dropsCramps
Clinical Manifestations: Cardiomyopathy, Myopathy, Hypoglycemia, Fatty Liver
Primary Carnitine Deficiency:
 Na+ gradient dependent Carnitine Transporter in heart, Muscle,
Kidney mitochondria keeps 20-30 times high Carnitine inside.
 Autosomal Recessive SLC22A5 gene mutation arrests
Acylcarnitine.
Diagnosis:
 Muscle biosy, plasma carnitine 1-2%N(Primary-Liver/Muscle),
 K.B.dicarboxylic FA+ve urine (Heterozygots-kidney)
Treatment: Oral carnitine (cardiomyopathy), EFA, High Carb/Low fat diet
Medium chain Fatty Acids(They donot require Carnitine)
Management: No streneous exercise, No fasting

19. A New born infant had abnormal ZELLWEGER facies, severe muscle
weakness, Hypotonia, Food/Milk Sucking Refusal, Dull.
Pathogenesis: Deficiency of carnitine / CPT I and CPT II 
Causes: Less ATP affects
Methyl Malonic Aciduria,
Propionic acidemia, Heart
Isovaleric acidemia Muscle
Diarrhea, Diuresis, Hemodialysis Kidney
Ketosis
Sepsis, Burn, GI Surgery
Zidovudine,Valproate Liver
Poor diet,TPN
Lab Test: High Fe, Cu in blood
High VLC Fatty acids in muscle biopsy
Physical Sign/Symptoms: Poor appetite,Large liver, blue face(Fe+Cu), Blurred
vision-Glucoma, Slow growth, Muscle tone loss, Zellweger face looks(high
forehead,fissures, sunken eyes), Jaundice, Low IQ, Seizures
Mechanism: Very long chain Fatty acids stay in muscle peroxisome 
No β-oxidation/ATP formed +Lipid dropsCramps
Clinical Manifestations: Cerebro-Hepato-Renal symptomsPrimary Peroxisomal Defect / Deficiency:
 Leukodystrophy
 Inherited damaging white matter
 Body metabolism defect in blood, organs
Diagnosis:
 Zellweger (facies) or Refsum Disease,
 Neonatal Adrenoleukodystrophy,
 Rhizomelic Chondrodysplasia(RCDP)
Treatment: No treatment because of fetal origin defect
Supportive treatment of EFA, High Carb/Low fat diet
Management: No streneous exercise, No fasting

20. Pathogenesis:
 Accumulation of phytanic acid (C20 branched (3,7,11,15
tertramethylhexadecanoic acid) in plasma, brain, blood, other tissues from
plants/animal origin
 Tissue EFA is replaced by phytanic acid  Ichthyosis
 High plasma pristanic acid
 Very long chain FA
 C27 bile acids
Causes: Less ATP affects
C20 branched (3,7,11,15 tertramethylhexadecanoic acid)
Lab Test: Low cholesterol, Low HDL,LDL(-5-30%)
High phytinic acid in blood (10-50 mg/dL) normal 0.2 mg/dL
CSF proteins 100-600 mg/dL
Phytanic Oxidase present in skin fibroblast culture
Bone change by imaging
A 6 year child with smell and hearing loss(normal at birth), complained
difficulty in finding things at night.
Physical Sign/Symptoms: Dysmorphic features(flat bridge of nose, lowset ears),
Regular pulse, enlarged liver
Mechanism: No Phytanic Acid Alpha-Oxidation in peroxisomes(Phytanic acid accumulates)
Phytanic acid/Phytol Pristanic acidPropionyl CoA
No α-oxidation/ATP formed +Lipid dropsCramps
Clinical Manifestations:
 Cerebro-Cutaneous syndrome (Peripheral polyneuropathy, Cerebellar ataxia,
Retinitis pigmentosa, ichthyosis, Slow growth) within year
 Cerebellar Ataxia(foot drop, loss of balance, Weakness)
 Night blindness(retina damage)
 Concentric visual field constriction
 Cataract
 Smell and sense loss (Anosmia)
 Deafness
 Cardiac arrhythmia
 Short bones in fingers, toes
Primary Defect / Deficiency:
 Leukodystrophy
 Inherited autosomal recessive damaging white matter
 Peroxisomal metabolism defect in blood, organs
Diagnosis:
 Refsum Disease,
 Neonatal Adrenoleukodystrophy,
 Rhizomelic Chondrodysplasia(RCDP)
Treatment: No GLV chlorophyll, No animal fat in diet(Keep 5 mg/ day)
Supportive treatment plasmapheresis
Management: No animal fat, No GLV

21. Unsaturated Fatty Acid Oxidation
• Fatty Acid Oxidation with an Odd Number of
Carbon Atoms Yields Acetyl-CoA + Propionyl-
CoA
• Propionic acid Carboxylase makes
MethylMalonyl CoA
• Propionic acid Recemase makes Succinyl CoA
• Dicarboxylic Aciduria

22. Regulation of Ketogenesis
• At lipolysis level: FFAAcetyl CoAK.B.
In diabetes, starvation: Lyase stimulates
• At Oxidation level: Acetyl CoA Carboxylase
enhanced CPT-1 Acetyl CoAMalonyl CoA
• At Acetyl CoA oxidation level: TCA cycle or K.B.

23. Ketone Bodies
• Acetyl CoA makes Ketone Bodies if
Carbohydrates are high in liver
• LIPIDS BURN IN FLAME OF CARBOHYDRATES
• Ketone Bodies are: Acetoacetate,
Hydroxybutyric Acids and Acetone

24. Organic Aciduria
• Methyl Malonyl Aciduria (B12 deficiency)
• Dicarboxylic Aciduria
(-CH3-COOH by microsomal Cyt P450+NADH)
Mechanism:Lack of alpha-, Beta-, Omega-
Oxidation
Lack of Medium Chain Acyl-CoA
Dehydrogenase.

25. Ketogenesis in Starvation (High carb available)
Mitochondrial
NAD/NADH Ratio
Fatty AcidAcyl CoA
Glucose2Acetyl CoA
2CO2 TCA
LIVER LUNGS
URINE
FFA
Liver
Ketone bodies
Blood
Lungs
Kidney
Muscle
Acetoacetyl CoA
Synthase
HydroxyMethyl CoA
Lyase Acetyl CoA

26. Ketone Bodies Serve as a Fuel (Ketolysis) in
Extrahepatic Tissues
BLOOD
2
Thiophorase
Lung
Kidney

27. Regulation of Ketogenesis
High Glucagon: Insulin Ratio in Blood
• Lipolysis (Lipase)
• CAT-I (Carnitine Acyl Transferase-I)
• Acetyl CoA conversion to Ketone bodies
• High Gluconeogenesis
26 ATP formed (acetoacetate);21 ATP formed(βHBA)
Medical biochemistry explains.. Ketosis: Metabolic
Acidosis; DM-1; Reduced buffers; Acetone smell;
Osmotic diuresis and dehydration; Sodium loss;
Coma due to Dehydration-Acidosis-Hypokalemia

28. 22 y diabetic boy complained 2-day history of vomiting and abdominal pain with
drowsy, deep rapid breaths with acetone smell. Diagnose & suggest management.
-Physical Signs and Symptoms:Dehydration,Tachycardia, Ketonic fruity odor, Nausea,
Vomiting, Thirst, Excessive urine, Abdominal pain, Cerebral edema, Headache, Pupil reflex
-Physical Clinical Manifestations:Hyperglycemia,Deep gasping(Kussmaul respiration),Coffee
color vomiting, Stupor, Lethargy, Confusion, Coma
-Mechanism: Low insulin results high blood sugar(DM-1) and Ketones+Organic acids in urine
or DIABETIC ACIDOSIS as a result of Pneumonia, Influenza, Gastroentritis, Pregnancy, Stroke,
Cardiac arrest, High cocaine intake.
-Pathophysiology:
Glucagon,Catecholamines,
Cortisol,Growth Hormones
Low Insulin/Glucagon
Glut-4 Transporter
Enzymes of
Gluconeogenesis(L),
Glycogenolysis (M)
Hyperglycemia
No β-Oxidation
Ketogenesis
Low pHMetabolic lactic+Ketoacidosis
CO2 compensation by HCO3Buffer+
Ventilation(Kussmaul respiration)
Ketones Osmotic Diuresis +
Na/K/Cl/P/Mg/Ca Electrolyte
Loss  Dehydration
FATG+VLDL
DM1+CKD
-Lab diagnosis: Blood glucose 250 mg/dL; Ketonuria, KetoAcidosis(low blood pH); Low GFR(Cr/U); Low
electrolytes; High Amylase + Lipase; CT for fluid accumulation
-Management and Prognosis:
1.Replace fluids+electrolytes; Insulin injection to reduce blood glucose + ketogenesis
2.Monitor heart rate and correct potassium levels(Hypokalemia Heart failure) Insulin given
3.Correct blood acidosis by NaHCO3 solution
4.Correct cerebral edema by iv mannitol+ 3% hypertonic saline
5.Follow up Hypo-glycemia/-Kalemia/-Phosphatemia; Thrombosis,RDS,GI bleeding
6.Monitor insulin resistance in pregnant mothers to save fetal loss
-Prevention: Life style with regular insulin, Drink Water, Checks of FBS, ketones in urine

29. Disorders of Ketogenesis
• CPT-I deficiency: Impaired Fatty Acid Oxidation
Gives Rise to Hypoglycemia, muscle weakness
• Jamaican Vomiting Sickness: Deficiency of acyl-
CoA Dehydrogenase and Dicarboxylic Aciduria
• Refsum disease: Phytanic Acid deposits
• Zellweger’s Cerebro-hepato-renal disease:
Polyenoic acid deposits
• Ketosis develops Ketoacidosis

30. Fatty Acid Synthesis
• Non-Essential Fatty Acid de novo synthesis
(Acetyl CoAPalmitic Acid) using NADPH(from HMP Shunt)
• Chain elongation makes long chain FA
• Pyruvate-Citrate-Malate shuttle pumps Acetyl CoA
in cytosol from mitochondria
• Fatty Acid Synthase enzyme (6 enzyme complex)
has TWO sites of Acyl Carrier Protein

31. Acetyl CoA Carboxylase
Acetyl CoAMalonyl CoA
• It is dimer
• Enzyme Dimer is polymerized by phosphorylation
• Polymer regulates citrate entry from mitochondria to
cytosol by TRICARBOXYLATE TRNSPORTER on inner
membrane
• Lyase enzyme: Citrate  OAA + Acetyl CoA
• Polymer stimulates Palmitoyl CoA formation
• It stops entry of Pyruvate
• Covalent modification
(citrate,insulin,dephosphorylation activate)
(Acyl CoA,Glucagon,Epinephrin,Phosphorylation inhibit)

32. Fatty acid Synthesis
• Acetyl CoA + CO2  Malonyl CoA
Acetyl CoA Carboxylase
CE-SH Transacetylase ATP ADP + Pi Transacetylase ACP-SH
Acetyl-S-CE Malonyl-S ACP
Acetoacetyl ACP
Betahydroxy Butaryl ACP
Enoyl ACP
Butyryl ACP(4C)
Palmitic Acid (16C)
Synthase
Reductase
Dehydratase (x 6 cycles)
Reductase
Thioesterase
CO2
NADPH
NADP
H2O
NADPH
NADP
+ H2O
Fatty Acid Acyl Synthase Complex contains: Ketacyl synthase, A- and M-
Transacetylase, Hydratase, Reductase, ACP, Thioesterase
CO2-Biotin

33. Fatty acid Synthesis
• Acetyl CoA + CO2  Malonyl CoA
Acetyl CoA Carboxylase
CE-SH Transacetylase ATP ADP + Pi Transacetylase ACP-SH
Acetyl-S-CE + Malonyl-S ACP
Acetoacetyl ACP
Betahydroxy Butaryl ACP
Enoyl ACP
Butyryl ACP(4C)
Palmitic Acid (16C)
Ketocyl Synthase
Ketoacyl Reductase
Dehydratase (x 6 cycles)
Enoyl Reductase
Thioesterase
+CoA + Free ACP-SH
CO2
NADPH
NADP
H2O
NADPH
NADP
+ H2O
Fatty Acid Acyl Synthase Complex contains: Ketacyl synthase, A- and M-
Transacetylase, deHydratase, Reductase, ACP, Thioesterase (TSRDRT)
-COCH3
-CO-CH2COOH
S.COCH2CO.CH3
S.COCH2CHOHCH3
S.CO.CH=CHCH3
S.CO.CH2CH2CH3
HOOC-CO.CH2CH2CH3
Shiftofacylchain
toACPsite2

34. Fatty Acyl Synthase Complex
TAKEH MAK

35. Arachidonic Acid Makes Prostaglandins
and Leukotrienes
Arachidonic Acid
Cyclooxygenase Lipooxygenase
Prostaglandins 5HPETE
(with 2 double bonds)
Prostaglandins Thromboxanes LTA4
LTB4
LTC4
LTD4
LTE4

36. Diseases of Fatty Acid Biosynthesis
• Linolenic acid Arachidonic Acid
• Omega 3, Omega 6 PUFA
• Low essential fatty acids cause:
Cystic fibrosis,
Crohn disease,
Cirrhosis,
Reye’s syndrome,
Zellweger’s Syndrome

37. FATTY LIVER
(Non-Alcoholic Fatty Liver Disease)
• NO LIPOPROTEIN SYNTHESIS or Metabolic Block
• No lipotropic factors(Vit E,Se,Choline, Betaine, Met,
Linoleic acid,Pyridoxin,Pentothenate)
• Starvation,High fat feeding,Uncontrolled DM, Twin
LambDisease, Cattle ketosis
• Orotic Acid
Symptoms: NADH/NADTG, LactateGout
(Alcoholic FD:Alcohol DH,Aldehyde DHLipogenesis)

38. Bio-Chemical Nature of Human Body
Hormones
Receptors
Enzymes
Carbohydrates
Amino Acids/Proteins
Lipids
Nucleic Acids Vitamins/Minerals
Exercise
Behavior
Environment Molecules
Circulation, Distribution & Molecular Reactions of cholesterol Generate Molecules for Life
7/7/2020 38Steroids, Sex Hormones, Bile Salts,
VitaminD3, Prostanoids, Lipoproteins
Fatty Acids
Ketone Bodies
Cholesterol in ER
Sphingolipids
Lipoproteins
Food
Digestion &
Absorption
LIVE HUMAN
BODY
HealthyLifeStyle
Pathology
Hematology
Cytology
ClinicalChemistry
Molecules
Gases&
Electrolytes
•Atoms (C,H,O,P,N,S,minerals)
Free Radical Diseases
Cancers
•Molecules Stroke
Molecular Diseases
Genetic/Inborn errors
•Super-Assemblies MI
Structural Diseases ATH
Organopathy
•Cell membrane Hypercholesterolemia
Transport Diseases
Genetic defects
•Organelles, Skeleton Gallstone
Cell Diseases
hematic/cell disorder
•Tissues
Tissue Diseases
Tissue metabolic disease
•Organs
Organ Diseases
•Systems Sign,Symptoms
Manifestations
Tests/Diagnosis
ECG
Imaging
INVESTIGATIONS & DISEASES

39. Steroid Lipids
Objectives:
Steroids? (next to Fatty acids, Ketone Bodies)
Why cholesterol is gateway to Vitamin D3, Bile
salts, Adrenal, Cortex, Sex-Ovary, Testes, Follicle
hormones, Prostaglandins and Lipoproteins?
Diseases of cholesterol deposits: Gall stone, ATH,
Stroke, MI
Differential Diagnosis: Types of C/LP diseases

40. What is Cholesterol?
What is Lipid Profile?

41. Cholesterol and Lipoproteins
• Cholesterol is steroid only in human & animals
• Plasma Lipids are LIPOPROTEINS
• Lipid Profile:Triglycerides; Lipoproteins; Cholesterol
• Lipoproteins:
VLDL
LDL and LDL-receptors
HDL

42. Cholesterol
• Liver, Adrenal cortex, Testes, Ovary, Intestine synthesize it
• Cholesterol makes Prostenoids, Sterols, Bile Acids, Vitamin D
• Complex molecules consisting of four fused carbon rings
Cyclo-pentano-perhydro-
phenanthrene ring (CPP)
Cholesterol: 3-hydroxy-5,6-cholestene CPP

43. How Cholesterol is synthesized in ER?

44. Cholesterol BiosynthesisCondensation of 2 Acetyl-CoA
HMG CoA formation
Mevalonate Formation
Isopentanyl Pyrophosphate
Geranyl Pyrophosphate
Farnesyl Pyrophosphate
Squalene
Lanosterol
Zymosterol
Desmosterol
Cholesterol
HMG CoA Synthase
HMG CoA Reductase
Kinase, Decarboxylase
Transferase
Transferase
Squalene Synthetase
Epoxidase
Cyclase
2 CH3-CO-S.CoACH3-CO-CH2-CO-S.CoA
CH3
HOOC-CH2-C-CH2-CO-S.CoA
OH
CH3
HOOC-CH2-C-CH2-CH2-OHCH3.C=CHCH2
OH CH3
Thiolase
CoA-SH Acetoacetyl CoA
HMG-CoA Synthase
|
HMG-CoA
| 2NADPH +2H+
HMG CoA Reductase
2NADP+ + CoA-SH
Decarboxylase
| Hydroxylase
| |
Mevalonate Isoprene
x 5 Squalene
Statin drug inhibits
In endoplasmic reticulum,

45. Cholesterol BiosynthesisCondensation of 2 Acetyl-CoA
HMG CoA formation
Mevalonate Formation
Isopentanyl Pyrophosphate
Geranyl Pyrophosphate
Farnesyl Pyrophosphate
Squalene
Lanosterol
Zymosterol
Desmosterol
Cholesterol
Synthase
HMG CoA Reductase
Kinase, Decarboxylase
Transferase
Transferase
Squalene Synthetase
Epoxidase
Cyclase
Acetyl CoA Mevalonate Isoprene
It is regulatory step
X 2 I Geranyl P
GerP+1I Farnesyl P
2 Farnesyl PSQ
CHOLESTEROL

46. Cholesterol BiosynthesisCondensation of 2 Acetyl-CoA
HMG CoA formation
Mevalonate Formation
Isopentanyl Pyrophosphate
Geranyl Pyrophosphate
Farnesyl Pyrophosphate
Squalene
Lanosterol
Zymosterol
Desmosterol
Cholesterol
Synthase
HMG CoA Reductase
Kinase, Decarboxylase
Transferase
Transferase
Squalene Synthetase
Epoxidase
Cyclase
Carboxylase
Reductase
In Endoplastic Reticulum, acetyl
CoA makes Cholesterol via
mevalonate, squalene inside
adrenal cortex, intestine, ovary,
testes.
Cholesterol reaches in liver/gall
bladder, arteries, skin, glands

47. How cholesterol biosynthesis is regulated?

48. Regulation of Cholesterol Synthesis
• HMG CoA-Reductase:Mevalonate,Cholesterol inhibit
Gene transcription by Steroid Regulatory Element-BP
Covalent modification by cAMPPKHMG.CoA
MCholesterol
• Diet Makkhan 100 mg cut will
reduce 0.13 mmol/L serum cholesterol
• 700 mg C synthesis in ER (L & I), rest 1 g from diet
• Fate of CholesterolBile, Coprostenol, vit D, Sex
hormones, Corticosteroids. It means CHOLESTEROL
CANNOT MAKE ATP
Phosphatase+HMGCoAR
Insulin,Thyroxine(+)
Glucagon,GlucoCorticoid(-)

49. How cholesterol breakdown happens
and makes different molecules?

50. Cholesterol Breakdown
• Cholesterol cannot make ATP but molecules
HMG CoAMevalonateC
Cholesterol  HydroxyCholesterol
Cholesterol 7α Hydroxylase
HMG CoA Reductase
Cholesterol Pregnanolone Progesterone
17α Hydroxyprogesterone Corticosterone
Cortisol Androstenedione Aldosterone
Testosterone
17 βEstradiol
Estriol
Cholesterol
Cholestane 3,7,12Triol Cholestane 3,7 diol
Cholic Acid Chenodeoxycholic
Acid
Cholyl CoA ChenodeoxycholylCoA
Glycine Taurine
Glycocholic Acid Tauro CDCA
Deoxycholic Acid Lithocholic Acid
Cholesterol7dehydrocholesterolProD3
25 OH-CholecalciferolVitamin D3
1,24,25 Tri OH-D3
(1)HMG CoA Red/Chol.7α Hyd
(Arteries)
(2) Cholestane (Liver) (3) Pregnanolone(Gonads)
7αHydroxylase Farnesoid XR
(4) Vitamin D(Skin, Bones)

51. Several diseases occur by Cholesterol
Synthesis and Breakdown disorder

52. Cholesterol Diseases
• Hypertension: High BP(>140/>90 mm Hg) cause
endothelial dysfunction
• Atherosclerosis Fatty deposits in arteries cause
lumen narrowing, Plaques
• Stroke Cholesterol deposits in cerebral artery
• Coronary Heart Disease
• Metabolic Syndrome (insulin resistance, diabetes
type II) and X-Syndrome(uric acid), CKD
• Gall Stone and Cholelithiasis Cholesterol/PL+BS
in gall bladder

53. Cholesterol Diseases
• Hypertension: High BP(>140/>90 mm Hg) cause
endothelial dysfunction
• Atherosclerosis Fatty deposits in arteries cause
lumen narrowing, Plaques
• Stroke Cholesterol deposits in cerebral artery
• Coronary Heart Disease
• Metabolic Syndrome (insulin resistance, diabetes
type II) and X-Syndrome(uric acid), CKD
• Gall Stone and Cholelithiasis Cholesterol/PL+BS
in gall bladder

54. Case studies of Gallstone disease, Stroke,
Atherosclerosis, Coronary Heart Disease

55. Hypercholesterolemia and Gall Stones
Physical Symptoms:
Pain in upper right quadrant
Mechanism:
 High ratio >3 of HMG CoA Reductase/Cholesterol 7α
Hydroxylase causes more cholesterol synthesis
 In bile(bile salt+cholesterol+phospholipids), High
cholesterol synthesis inhibits bile salt formation and
precipitation makes GALLSTONES
 CDCAFarnesoid X Receptor7αHydroxylase high
•Clinical Lab Test:
Plasma CHOL: >250 mg%, TG >160 mg%, PL < 50 mg%
Diagnosis: Cholelithiasis
Intervention:
•Diet low in cholesterol, Fibrate drugs, synthetic Bile
salts CDCA
Surgery:
•Laproscopic cholecystectomy (Gall Bladder removal)

56. 44 y female complained midepigastric discomfort, nausea/vomiting with severe
pain soon after oily meals and later relapsed. Lab tests showed high
S.cholesterol, US showed gall stones in normal gall bladder wall.
Physical Signs and Symptoms:Abd. upper quard. pain, Sudden wt loss or
High carb diets, Obesity or no physical activity, Crohn diseaseintestine
Clinical Manifestations: Colic pain in gall bladder & lower abd, Pancreatitis
Cholangitis(fever, chills, jaundice), Peritonitis, DM, Cirrhosis, Hepatitis
Mechanism: Cholelithiasis(Gall Stones) High ratio
Pathophysiology: 1.HMGCoA-R(CyP7A1) poor control over bile acid synthesis
2.Saturated Bile(Cholesterol+PL+Bile salts)C Crystals
3.Low Acyl CoA:Cholesterol AcylTransferase(ACAT)C
4.Deoxycholate BS inhibits HMG-CoA-Reductase
.
Diagnosis:Elevated cholesterol, bilirubin, ALT/AST in serum, Cholesterol
Gall stones by US/CT/ERCP
Treatment: Low fat diet, BS,Gall bladder Laparoscopic cholecystectomy
Prognosis: Low carb-high MUFA/PUFA-high fiber diet, physical activity,
caffinated coffee
HMGCoA Reductase
--------------------------------------------
Cholesterol 7α Hydroxylase

57. Atherosclerosis
• Atherosclerosis: Cholesterol deposits in arteries
cause lumen narrowing, Plaques
• Smooth Muscle Cells in artery
make foam cells and deposit
lipids, cholesterol
• Endothelial layer dysfunction
in carotid and coronary arteries
• Very less blood reaching in heart
and brain cause death

58. 51 y male complained chest pain since a year spreading from chest
to left side with nausea and sweats. On examination,ECG showed
high ST-QRS changes. Lab tests showed high cholesterol,LDL-C.
Discharged with Lovastatin + Telmasartan & low fat diet.
Physical Signs/Symptoms:Chest pain with sweats,High BP
Mechanism: AcetylCoAHMGCoA Mevalonate;
MevalonateIsoprene; 6 IsoprenesGPFPSqualene;
CyclizationLanosterolCholesterol LDL-C/HDL-Cholesterol
Lovastatin arrests cAMP-HMGCoA Reductase Dephosphorylation
Thyroid Hormones+Insulin enhance Sterol Regulatory Element BP
Diet Risk: Butter,Beef, Palm Oil, Starch/Sucrose/Fructose
Physical Examination: Pale, diaphoretic, HT,
Hypotension(ventricle dysfunction,Ischemia,RVI), Acute valve
dysfunction, Mitral regurgitation, Neck vein distension, Heart S4
sound, Dysarrhythmia, Fever, Peripheral pulses, ST segment > 1
mm and new Q waves (MI), depressed ST-T wave, inverted T
wave(immediate MI)
Lab Tests: CPK, CK-MB, Troponin, Myoglobin, LDH, CBC, C-reactive
protein, Lipid profile, Creatinine, K+, Mg++ levels, ESR, plasma
homocyteine levels
Imaging tests: Chest radiography, Echo, 99mTc scan, Thallium scan,
CT scan, MRI, Coronary artery calcium
Pathophysiology: Cholesterol+EstersVLDL+LDL deposits cause
atherosclerois with DM, Nephrosis, Hypothyroidism Ischemic HDCHD
Narrowed arteries, Atherosclerosis plaques, coronary thrombosis,
platelet aggregation, coagulation, endothelial injury, myocardial
necrosis, STEMI; Occluded/Thrombus in AD branch(ALV, IVseptum MI),
LCA branch(AL or PL MI), Right coronary branch(PInf LV or RV MI) with
AV block or sinus node block.
Causes of Atherosclerosis: Thrombus formation due to age, male,
menopause, pre CAD/CHD; Smoking, Alcohol, HT, DM, Obesity,
Dyslipidemia, High homocysteine, baldness, slow life, stress; Vasculitis,
Coronary emboli, trauma, spasm, high oxygen needs, exersion
Clinical Manifestations: Chest pain, Left arm pain, Dyspnea, Nausea,
Vomiting, Infarction, Anxiety, Syncope, Diaphoresis, Fatigue, Dementia
Treatment: General care by oxygen supply, pulse oximetry, iv aspirin,
Nitroglycerin spray, Telemetry and ECG
Perfusion restoration (myocardium salvage) by PCI or CABG
Medical therapy: Antithrombotics(aspirin, heparin), Vasodilators-
Nitrates, Beta-adrenergic blockers, Thrombolytic agents (Alteplase,
Tenecteplase, Anistreplase, Streptokinase, Reteplase),
Platelet aggregation inhibitors (Clopidogrel, Eptifibatide, Tirofiban,
Abciximab), Analgesics(Morphine), ACE inhibitors(Captopril),
Angiotensin receptor blocker(Telmasertan), Calcium channel blockers
(Diltiazem, Varapamil)
Surgery: Percutaneous coronary intervention, CABG

59. 45 y male complained chest pain for 15 minutes with nausea and
sweats. On examination,ECG showed QRS changes but normal
lungs and heart function. Lab tests showed high cholesterol,LDL-C.
Discharged with Lovastatin and low fat diet.
Physical Signs/Symptoms:Chest pain with sweats,High BP
Mechanism: AcetylCoAHMGCoA Mevalonate;
MevalonateIsoprene; 6 IsoprenesGPFPSqualene;
CyclizationLanosterolCholesterol LDL-C/HDL-Cholesterol
Pathophysiology: Cholesterol+EstersVLDL+LDL deposits cause
atherosclerois with DM, Nephrosis, Hypothyroidism Ischemic HDCHD
Lovastatin arrests cAMP-HMGCoA Reductase Dephosphorylation
Thyroid Hormones+Insulin enhance Sterol Regulatory Element BP
Diet Risk: Butter,Beef, Palm Oil, Starch/Sucrose/Fructose
Treatment: Niacin, Clofibrate, Omega-3 FA reduce LDL-C+C
Ezetimibe inhibit cholesterol absorption in intestine
Cholestyramine,Colestipol Resin reduce LDL-C+ more BS
Management:
1.Weight management-Exercise+No Smoking/Alcohol/Drugs;Low fat diet;
Fibrates+Nicotinic Acid+Statins; Canola oil, Fish oil
2.Monitor DM2,Gaucher Disease,Malnutrition,low LCAT(Tangier Dis.)

60. Acute Coronary Syndrome
• Major complications of acute
myocardial infarction
 Ventricular dysrhythmias
 Atrial dysrhythmias
 Heart block (incomplete or complete)
Bradycardia
 Extensive right ventricular infarction
 Acute ventricular septal defect
 Valvular rupture
 Heart failure
 Ventricular rupture
 Systemic emboli from mural thrombus
 Left ventricular aneurysm
 Real-Time changes in metabolites,
enzymes, proteins
Cardiac artery ascending and Descending
branches blocked by Acute Myocardial
Infarction and Atheromatous(cholesterol+
hemorrhage mass) narrowing of coronary
arteries

61. Hypercholesterolemia
• Hypercholesterolemia (treatment)
 HMG CoA Reductase inhibitors(statin)
 Cholesterol absorption NPC1L1 inhibitors(Eztimibe)
 Resins as Bile acid sesquetrants
(Cholestyramine,Cholestipol,Colesevelam) divert
cholesterol to bile acid synthesis(Bile acid pool)
 LDL Apheresis: In column LDL removed (LDL clearance)
 MTP inhibitor-Lomitapide
 Apo B inhibitor-Mipomerson

62. A 48 y male complained heart congestion with history of cardiac arrest
of father and brother on cholesterol lowering drugs. Lab test showed
cholesterol 350 mg/dL, LDL-C 165 mg/dL,ECG high ST, Stress TMTest.
Physical Sign & Symptoms: Stress on climbing stairs, Lifestyle: No
exercise, High Fat diet, Heavy weight, High C+LDL-C in family(Familial
Hypercholesterolemia) with Congestioncoronary artery
,
Clinical Manifestations: Homozygous FHC-Ischemic Heart Disease, Peripheral
Vascular Disease, Aortic stenosis, Tendonitis, Tuberous/Planar/Tendon Xanthoma, Corneal
arcusHigh LDL-C Heterozygous FHC-No CHD/IHD/No corneal arcus but in F or M, high
LDL-C+C
Lab Tests: Cholesterol 600 mg/dL, LDL-C 250/350 mg/dL, LpA >30
suggest No DM/Hypothyroidism/Liver diseaseMechanism:FH1: LDL-R absent; FH2: LDL-R Mutation(No LDL+R; FH3: C Mutation
(No LDL-R endocytosis)  Defective LDL-C  High Cholesterol
Synthesis
-Uptake of LDL-Cholesterol: LDL-R mediated Endocytosis
-LDL-- Apo-B100+Apo-E LDL-R make CLATHRIN pits for endosome-lysosome(CEC+FA )
-LDL-R gene on chromosome 19 short arm, if mutation it stops ACAT HMG-CoAR
-Acetyl CoACholesterol +Cholesterol Esters(LDL) puts C+CE in tissues(Gall bladder, Heart/Artery)
-HDL takes out to liverBile salts
-Diet Chol/Cholesterol FA estersIntestine AbsorptionLiver chylomicron(LDL-R+VLDL)IDL
-Free Cholesterol inhibits HMG-CoAR + LDL-RTreatment: Homozygous FHC-Liver Transplantation, ileal bypass surgery, LDL ApoB apheresis Low LDL-C
+ LpA+TG
Probucol/Gene Therapy,Life style(Healthy diet,Regular exercise,Wt

63. Medical Biochemistry Explains Diseases of
Lipid Transport and Turnover
 Fatty Acid:
 Carnitine Deficiency
 Methylmalonic aciduria
 Ketoacidosis with Diabetes
 Phospholipids, Sphingolipids
 Respiratory Distress Syndrome
 Niemann Pick Disease
 Sphingolipidoses(Gaucher’s disease,Fabry disease, Tay-Sach disease,Sandoff disease),
 Gangliosidoses
 Cholesterol, Lipoproteins
 Hypercholesterolemia
 Hyperlipoproteinemia
 Cholelithiasis
 Atherosclerosis and Dyslipidemia
 Adrenal Hyperplasia
 Non-alcoholic Fatty Acid Disease
 Adipose Tissue and Obesity

64. Triglycerides
• Triose Phosphate makes TRIACYL GLYCEROL
• Stores in Obesity, Diabetes mellitus
• Acyl CoA Synthetase binds:
Glycerol3P+2Acyl CoADiacyl Glycerol-PTAG
Glycerol Cardiolipin Phosphatidylcholine
• hS-Lipase enzyme breaks TG to FA + Glycerol
• Glucagon,Catecholamine, ACTH,TSH,Glucocorticoids,
GH,MSH,Vasopressin activate hS-Lipase by cAMP
• Insulin, Nicotinic acid, Prostaglandin E1 inhibit
Acyl CoA
CDP CDP-CholineGlycerol Kinase

65. Obesity
Physical Symptoms:
Pear shape or Apple shaped Belly
Fat ladden hanging bags
Mechanism:
Abnormal LEPTIN
Insulin Resistance
Hyperlipidemia High FFA, High LDL,VLDL
Metabolic Syndrome or Syndrome X
Diagnosis: BMI > 40 morbid obesity, Hypothyroidism, Depression
Clinical Lab Test: TG >600 mg%, CHOL >250 mg%, VLDL >160 mg%, FBS: >100 mg%
Intervention: Weight, Diet restriction, Bariatic Surgery

66. Phospholipids
• Glycerol 3P + 2 Acyl CoA 1,2 Diacyl Glycerol-P
(called Phosphatidate)
• 1,2 Diacyl Glycerol + CTP  CDP-DAG
Serine Ethanolamine Inositol Glycerol
Lecithin Cephalin Phosphoinositol Cardiolipin
Lysolecithin secondary messenger heart

67. Phospholipase
• Phospholipases: A, B, C and D
lipases break at different points – A1-B (on 1st), A2-
B(on 2nd), C-D(on 3rd) carbons

68. Glycolipids or Glycosphingolipids
• Important in nervous tissue and cell membranes
(outer leaflet).
• Cerebrosides: (no phosphate)
– Glucocerebroside: Ceramide + glucose: extraneural
– Galactocerbroside: Ceramide + galactose: myelin
• Globoside: Ceramide oligosaccharides
– 2 or more hexoses or hexosamines + ceramide
– Lactosyl ceramide: Ceramide + glucose + galactose
(found in RBC membrane)

69. Cerebrosides and Gangliosides
• Glycosphingolipids (cerebrosides and
gangliosides)
• Glycolipids (glycosphingolipids) have a
fatty acid, sphingosine, and
carbohydrate
• Cerebrosides have a single sugar linked
to ceramide
• Gangliosides (sphingolipids) have
oligosaccharides polar head groups +
one N-Acetyl-Galactosamine(NAG) +
residues of N-acetylneuraminic acid
(NeuAc) or sialic acid
Ganglioside
(A sphingolipid)

70. Gangliosidosis Harper p218
Ganglioside Storage Disease:
Gangliosidosis(GM1) (Cer-Glu-Gal-
GalNAc-Neu5Ac-Gal deposits)
Tay-Sachs Disease(GM2) (Cer-Glu-Gal-
Neu5Ac-Gal N Ac deposits)
(GM3) (Cer-Glu-Gal-Neu5-Ac deposits)
Gaucher’s Disease (Cer-Glu deposits)
Sandhoff’s Disease (Cer-Glu-Gal-Gal-N-
Ac deposits)
Fabry Disease (Cer-Glu-Gal-Gal
deposits)

71. Sphingolipids
• In endoplasmic reticulum,
Ser+FA acyl CoACeramideSphingomyelin
Gangliosides Cerebroside Stored
• Genetic defects show enzyme
deficiency:(Lipid Storage)
Treatment: Enzyme Replacement Therapy,
Bone Marrow Transplantation,
Chaperone Therapy,
Gene Therapy
Phosphatidylcholine
UDP-Gal/N-AcetylGaln/UDP-UDP-Glu/UDP-NeuAc UDP-Gal
Cer-Glu.Gal.N-AcGal.Gal
GM2 Neu.Ac GM1
CH3-(CH2)12HC=CH.CHOH.CH.CH2OH
NH.CO.R
Hexosaminidase,
Galactosidase,
Arylsulfatase,
Galactosidase,
Glucosidase,
Sphingomyelinase,
Ceramidase

72. Lipid Storage Disease

73. Sphingolipidoses
• Symptoms:
• Mechanism: (Activator Protein+Lysosomal lipid acid hydrolase) missing
leads to sphingolipid accumulation  Neurological degradation
• Diagnosis:
 Autosomal recessive Niemann Pick Type A and Type B
 Febry, Tay-Sachs, Gaucher Disease

74. Gaucher Disease
• Type 1: in 5-16 years
 Lab: Pancytopenia, bleeding, Gaucher Cells
 Symptoms:Bone pain,Bone cries
• Type 2:Hepatosplenomegaly
 Symptoms:Neurodegeneration,
Visceral damage,Death
• Type 3:Bone Cries, Neurodegeneration
• Diagnosis: in X-Ray, flask shape femur,
β-Glucosidase deficiency
Treatment: β-Glucosidase ERT(Imiglucerase),Velaglucerase,Taliglucerase
Miglustat

75. Niemann Pick Disease
• Autosomal recessive
• Symptom: Hepatosplenomegaly, Neurodegeneration
• Mechanism: Sphingomyelinase deficiency on Chr 11
• Lab: High Sphingomyelin in Monocyte-
Macrophase
• Treatment:
 Transplantation of Liver, Bone Marrow,
Amniotic cells
 Miglustat, ERT

76. Respiratory Distress Syndrome(RDS)
• Dipalmitoyl Phosphatidylcholine keeps lung
alveoli intact at low surface tension or low
breathing effort in new born babies
• Deficiency of DPL causes INFANT RDS
• Treatment: Aerosol, Asthalin, Nebulizer,

77. Multiple Sclerosis
• Symptom: Memory loss
• Mechanism: In white matter, loss of Sphingomyelin,
Cephalin and plasmalogens cause DEMYELINATION
• high Cephalin in CSF

78. Separation of Lipoproteins
Centrifuge separates Lipoproteins at different
densities:
• Chylomicrons (Apo B-48) in intestine
• Very Low density (Apo B-100) in liver
• Intermediate density
• Low density (Apo B-100)
• High density (Apo-A)

79. Lipid Transport and Metabolism
• VLDL
• LDL Lipoproteins: Receptors
• HDL: HDL1, HDL2, HDL3 in TAG and Cholesterol
metabolism
• Liver plays central role(digestion and absorption of
lipids, bile, fatty acids, ketogenesis, lipoproteins)
• Cholesterol + FA Cholesterol Esters
• HMG-CoA Reductase, PPTase-I, Cholesterol
hydroxylase, ACAT, LCAT, AMP Kinase
• CETP, SRE-BP(Steroid Regulatory Element BP)
• Apo B-48, Apo B100, Apo CII, Apo E2, Apo D

80. Lipoproteins
• Electrophoresis separates lipoproteins
(apoproteins) by net Amino Acid charge
• Chylomicron: Formed in intestine; Carry TG to liver
• VLDL:Formed in liver, TG to liver
• LDL: Carry C+CE to liver, extrahepatic tissues
• Lp(A): in Liver,binds with Apo B100;
PlasmalogensPlasmin (Thrombosis) or Fibrin
• HDL: Formed in liver, intestine, catch C from
peripheral tissues to liver(reverse transport)
• LpX:Cholesterol+PL=LpX α Cholelithiasis in bile(bile salts)

81. Lipoprotein Electrophoresis
TG
CE
C
Chylomicron
VLDL
LDL,
IDL
HDL
ApoB100
CE
C
PL
Apo A1,C+D+E
TG
CE
C
Apo-B48
• Electrophoresis separates
lipoproteins (apoproteins) by
net Amino Acid charge
Chylomicron
VLDL (pre-β lipoprotein)
LDL(β-lipoprotein)
IDL(broad β-lipoprotein)
HDL(α-lipoprotein)
Apo B-48
TG + C

82. Lipid Profile(in mg/dL)
• Serum cholesterol(fasting) = VLDL+LDL+HDL
• Serum VLDL = Triglycerides / 5
• Serum LDL = Total Cholesterol – HDL – TG/5

83. Apoproteins
• Apo A-I: Activates Lecithin Cholesterol Acyl Transferase(LCAT)
• Apo A-II: Inhibits Lipase
• Apo A-V: Promotes Lipase (TAG lipolysis)
• Apo B-100: VLDL in Liver, part of LDL-R,LRP-1 for LDL uptake
• Apo B-48: Assembles chylomicron in intestine
• Apo C-I: Inhibits Chol. Ester Transport Protein(CETP)
• Apo C-II: Activates Lipoprotein lipase
• Apo C-III: Inhibits Lipoprotein lipase
• Apo D: in brain
• Apo E: (Arg rich)Part of LDL-R for (Chylomicron+VLDL)remnant
 Apo E polymorphic gene expresses E2, E3, E4 isoforms
 Apo E2 two alleles characterize Type III Hyperlipoproteinemia (Familial
Dyslipoproteinemia), poor LDL-R binding
 Apo E4 two alleles characterize Alzheimer Disease

84. Chylomicron
TAGFA; Apo-C+Apo-E from HDL
CEC+FA
Type I-Hyperlipoproteinemia)
Or Low plasma fatty acids
Endocytosis;
Lysosomal
breakdown
Type II Hyperlipoproteinemia
Step 1
Step 2
Step 3
Type IV and Type V
F.Hypertriglyceridemia

85. VLDL
TAG rich; Transport TAG from liver to tissues; Apo CII TAG exchange from HDL to VLDL
B-100 favors endocytosis
CETP
Endocytosis
Step 1
Step 2
Step 3
Type III
F.Dysbetalipoproteinemia
Type IIa
F.Hypercholesterolemia
Type IIa Familial Autosomal
Dominant Hypercholesterolemia

86. LDL Receptor
• Glycoprotein
• Apo B100, Apo E ligand with LDL Receptor
• Present in liver and Extrahepatic tissues on
Clathrin (inner membrane surface pits)
• High Cholesterol stops LDL-R by SRE-BP path
• LDL uptake by receptor endocytosis
• PUFA/MUFA upregulate LDL-R or LDL-C lysis

87. HDL
Nascent HDL3
L+CLL+CE
CETPCholesterol is
Pumped out
(scavenging)
Sitosterolemia
ABCG5 & ABCH8
Transports C in reverse from tissues
CE
TG
VLDL,LDL
Hormones CCE
Hydrolase
ACAT
CCE

88. Cholesterol Reverse Transport
• Lecithin Cholesterol Ester Acyl Transferase
• Cholesterol Ester Transfer Protein
• Scavenger Receptor B1 (Class B Receptor)
• ATP Binding Cassette Transporter

89. Cholesterol Transport
Big size
Oversize
Medium size
Oversize small size
-Apo-A1,Apo-B100,Apo-CII,Apo-E2,Apo-D
-TAGCE exchange in VLDL, HDL by CETP
-ACAT, LCAT, Enzymes
-CETP, SREBP
TG
CE
C
PL
Apo-B48
Chylomicron
VLDL, LDL, IDL
HDL
Apo A1, C+E
ApoB100
+ Fatty acid
Type IIa
F.Hypercholestrolemia
ADH II
ADH III LDL-RAP
Autosomal Recessive Hypercholesterolemia

90. Cholesterol Transport
• Cholesterol Transport between tissues:
Dietary Cholesterol as Chylomicron remnant go in Liver
From liver, it goes in VLDLIDLLDL
LDL-C goes to liver and extrahepatic tissues
• Cholesterol balance in tissues:
A. Increased cholesterol synthesis
 Increased cholesterol ester hydrolysis by Cholesterol Ester Hydrolase
 Receptor high uptake of lipoproteins
B.Cholesterol go membrane to HDL by ABC-A1,ABC-G1,SR-B1
 Cholesterol esterification by ACAT(Acyl-CoA:Cholesterol
Acyltransferase)
 Cholesterol  Sex hormones, Bile salts, Vit D3 in liver

91. Treatment of Lipid Disorder
• Hypertriglyceridemia:
Fibrates():Gemfibrozil,Fenofibrate
FPA+DHAFibric acid derivatives
 Niacin in adipocyte GPR109A, hepatic lipid lowering
• Hypercholesterolemia
 HMG CoA Reductase inhibitors(statin)
 Cholesterol absorption NPC1L1 inhibitors(Eztimibe)
 Resins as Bile acid sesquetrants(Cholestyramine,Cholestipol,Colesevelam)
divert cholesterol to bile acid synthesis(Bile acid pool)
 LDL Apheresis: In column LDL removed (LDL clearance)
 MTP inhibitor-Lomitapide
 Apo B inhibitor-Mipomerson

92. ATP III Guidelines for Lipoproteins
Biochemical Parameters Conc mg/dL Risk level
LDL-C <100 Optimum
Free Cholesterol 100-129
130-159
160-189
>190
More than Optimum
Borderline high
High
Very High
Total Cholesterol <200
200-239
>240
Desirable
Borderline high
High
HDL-Cholesterol <40
>60
Low
High
Prediction of Coronary Artery Disease:
• hsCRP
• Total Cholesterol/HDL Ratio
• Apo B/Apo A Ratio
• LDL
• Non HDL Cholesterol
• HDL Cholesterol

93. Lipoprotein Metabolic Disorders
Phenotype I IIa IIb III IV V
High
lipoprotein
Chylomicron,
VLDL
LDL LDL, VLDL Chylomicron,
VLDL remnants
VLDL Chylomicron,
VLDL
Triglycerides Normal
Total
Cholesterol
Normal/
LDL
Cholesterol
HDL-
Cholesterol
Normal/ Normal
Plasma
appearance
Lactescent Clear Clear Turbid Turbid Lactescent
Xanthomas Eruptive,
Hepato-
splenomegaly
Tuberous None Palmer
Eruptive
None Eruptive
Pancreatitis +++ 0 0 0 0 +++
CVD 0 +++ +++ +++ +/- +/-
Atherosclerosis 0 + + ++ +/- +/-

94. Lipoprotein Transport Diseases
Tuberoeryptive Xanthoma:Knee,Buttock, Elbow
Palmar Xanthoma:Palm, Wrist
Chylomicron+VLDL remain
Alzheimer Disease due to ApoE4
MTP gene mutationNo
Chylomicron,VLDL,LDL
HYPOLIPOPROTEINEMIA:
-Absent Chy,ApoB-100
-Absent αLP:Tangier, Fish Eye disorder
HYPERLIPOPROTEINEMIA:
-Absent LPL Lipase or Apo CII(Type I)
-Hypercholesterolemia(No LDL-R)
(Type IIa)
-No Apo E (Type III)
-HyperTAG or High VLDL (Type IV)
-High HDL or Hyper αLP and LP-a
-Low lipase, LCAT
-High LpA

95. Hyperlipoproteinemia
• Type I hyperlipoproteinemia(Familial Chylomicronemia):TG>1000 mg/dL
 in childhood, abdominal pain, retinal bloody vessels, Lactescent plasma
 Low TG lipolysis activity in LPL and Apo CII deficiency(add plasma  normal LPL)
 Treatment by Gene therapy-Alipogene tiparvovec viral vector injection
• Type III Hyperlipoproteinemia(Familial Broad Beta Disease)
• Type IV and V hyperlipoproteinemia(hypertriglyceridemia):
Apo A-V mutation, elevated VLDL,Chylomicron; Glycosylated Phosphatidyl Inositol
HDL Binding Protein-I (GPIHDLBP-I) mutation stops LPL to endothelium
• Autosomal Dominant Hypercholesterolemia Type I: LDL-C > 400-1000
mg/dL, LDL-R gene mutation, homozygous or heterozygous; LDL+Cholesterol
accumulation
 Treatment: Lomitapide, Mipomerson oligonucleotide to Apo B
• Autosomal Dominant Hypercholesterlemia Type III: Mutation in PCSK-9
protein; LDL-R degradation high
• Autosomal Recessive Hypercholesterolemia (ARH)
• Sitosterolemia: ATP-binding cassette protein G5/G8 mutation

96. Secondary Hyperlipoproteinemia
• Increased VLDL production: by high Carbs,Alcohol,
Obesity,Insulin resistance,Nephrotic Syndrome,
Cushing Syndrome
• Decreased hepatic uptake of lipoproteins:
Hypothyroidism, Chronic Kidney Disease
• Liver Disorders Hepatitis, Cholelithiasis(PL+CLpX),
Estrogen

97. Hypolipoproteinemia
• Abetalipoproteinemia
• Tangier Disease
• LCAT Deficiency(Norum Disease)
• Partial LCAT Deficiency(Fish Eye Disease)

98. 1st Y MBBS girl and 17 y sister at skin OPD complained
yellow spots on exposed body parts and DM. Advise.
Physical sign & Symptoms:On skin,Xanthoma(lipid filled macrophages) Skin
cell Lipid dysfunction(Yellow Hyperlipoproteinemia)
Clinical Manifestations: Cutaneous Xanthoma: 5 types
-Xanthelasma Palpebrarum:Soft,yellow,flat,polygonal eye papules
-Tuberous Xanthoma: Red-yellow painless nodules(High C+LDL,Dys
βLP,FHC with Hypothyroidism,Nephrotic Syndrome)
-Tendon Xanthoma:Ligament nodules,Trauma,High C+LDL (IIa) with
Cholestasis
-Eruptive Xanthoma:Red-yellow erythromatous papules,High
VLDL+CM(I,IV,V) with diabetes mellitus
-Plane Xanthoma:Palm crease, Face-neck and thorax, High TG+Dysβ-
LP(III) with cholestasis
Diagnosis: Secondary Hyperlipoproteinemia
Type I( ),IIa( ),IIb( ),III( ),IV( ),V( ),Lipase Deficiency
C: Hypothyroidism,Cholestasis,Acute Inter Porphyria
TG:DM,pancreatitis, Gout, Sepsis, Alcoholism, GSD I
C+TG:Nephrotic syn, Chronic renal failure,Steroid therapy
Lab Test:Lipoprotein Electrophoresis Patterns
Treatment:Diet+Lipid lowering statis+Fibrates+Bile acid-resins+
Probucol+Nicotinic acid to lower cardiac risk & Xanthoma spread

99. Diseases of Lipid Metabolism
• Carnitine deficiency
• Carnitine Transport Defects (CPT
I,CPTII, Translocase deficiency) cause
musculopathy and hypoglycemia,
improved by short chain FA in diet.
• FAcyl CoA DH deficiency
• Jamaican Vomiting Syndrome
• Methyl malonic Aciduria
• Organic Aciduria(Methyl Malonic,
Propionic, FA CoA DH deficiency)
• Refsum Disease
• Zellweger Syndrome
• X-linked Adrenoleukodystrophy
• Diabetic Ketoacidosis (Hyperglycemic
Hyperosmolar state
• Diabetic foot
• PUFA required in diet
• Prostaglandins as COX-1 inhibitors
• Prostaglandins in abortion
• Prostaglandins as H2 blockers in
Gastric ulcers
• Obesity (adiponectin, leptin, resistin
enhance TAG) improved by Orlistat
• Fatty Liver( defective VLDL synthesis,
poor Apo-B/Apo-C/Apo-E synthesis
due to puromycin, ethionine, CCl4
drugs)
• Alcoholic Cirrhosis (Alcohol DH +
Aldehyde DH for alcohol acetate +
NADH) cause liver failure, improved
by Lipotropic factors
(Choline,Met,Ser+Essential FA+vit E-
Se)
• Atherosclerosis, Hypertension (HDL
and bad cholesterol)
• Hypercholesterolemia(hypothyroidism,
DM,Jaundice,Nephrotic syndrome)
improved by statins
• Respiratory Distress Syndrome
(Dipalmitoyl Lecithin surfactant deficiency) in
infants, improved by Steroids.
• Leukodydtrophy(sulfatase deficiency)
• SPHINGOLIPIDOSES (ganglioma,TaySach,
Febry,Gaucher,Niemann Pick,Metachromatic
Leucodystrophy)

100. Summary
• Cholesterol (synthesis and degradation)
 HMG CoA Red. and SREBP-2
 AMP Kinase and PPTase1
• Cholesterol  Sterols, Bile Salts, Vit D, Prostaglandins, Sex
hormone
 Cholesterol 7α Hydroxylase and cholelithiasis
• Plasma Lipoproteins (CM,VLDL,LDL,HDL,C)
 Receptors, TAG,CE,PL,Apo-P (B-48,B-100,CII,E)
 Lipoprotein Lipase and Hyper-/Hypolipoproteinemia
 TAGCE exchange in VLDL, HDL by CETP
 LDL receptors (HyperLipoProteinemia) and ACAT
 Apo-A1 induced LCAT
• Phospholipids, Phospholipase and Diacylglycerol-Inositol
triphosphate
• PIP2-DAG-PKC cascade
• Sphingomylin = ceramide(sphingosine +FA)+Phosphocholine
(Niemann Pick Dis)
 Gangliosidoses, Cerebrosidoses