Please enable JavaScript.
Coggle requires JavaScript to display documents.
Case 4: Lipoprotein Metabolism (Atherosclerosis and LDL Receptor Pathway) …
Case 4: Lipoprotein Metabolism (Atherosclerosis and LDL Receptor Pathway)
Disorders
List the types of Lipid Disorders
Atherosclerosis
Familial combined Hyperlipidaemia
Familial Hypercholesterolaemia
Dysbetalipoproteinaemia
Pancreatitis
Other Problems: Malabsorption
Describe the characteristics of the types of Lipid Disorders
Atherosclerosis
Atherosclerosis is due to an INCREASE in LDL and IDL and/or a DECREASE in HDL
Atherosclerosis is mostly due to the mild-moderate increase in LDL related to the Lifestyle or Genes
Familial combined Hyperlipidaemia
Familial combined Hyperlipidaemia is due to an increase in LDL and/or VLDL
Familial Hypercholesterolaemia
Familial Hypercholesterolaemia is due an INCREASE in LDL
Dysbetalipoproteinaemia
Dysbetalipoproteinaemia is due to an INCREASE in IDL
Pancreatitis
Pancreatitis is due to a Triglyceride level of more than 10 mmol/L
This signifies accumulation of Chylomicrons, or Chylomicrons plus VLDL
Other Problems include Malabsorption resulting in a low betalipoproteinaemia in plasma
Treatment of Lipid Disorders
List the treatment option in Lipid Disorders
Diet Manipulation
LDLR upregulation
LpB Production
Lipoproteins
Define Lipoproteins
Lipoprotein is a particle of Lipid and (apo)proteins in association, found in the plasma and to lesser extent in the interstitial fluid.
Lipoproteins varies in size, composition, density and function.
Describe the structure of Lipoproteins
Lipoproteins have three distinct structures:
Shell (CAP)
Shell of a Lipoprotein is made from Phospholipids, Cholesterol and Apoproteins
Core
Core of a Lipoprotein Cholesterol ester, Triacylglycerol and Loops of ApoB
Other
List the types of Lipoproteins in the order of Increasing Diameter and Decreasing Density
There is a range of Lipoproteins which differ in Density and Diameter
Lipoproteins with Little density carry the least amount of Protein
Lipoproteins with High density carry the most amount of Proteins
In the order of Increasing Diameter and Decreasing Density, the Lipoproteins are as follows:
HDL3 (High Density Lipoprotein)
HDL2 (High Density Lipoprotein)
LDL (Low Density Lipoprotein)
IDL (Intermediate Density Lipoprotein)
VLDL (Very Low Density Lipoprotein)
Chylomicron (CM)
Chylomicrons and VLDL particles are adequately large to scatter light
And they impart Turbidity or even Lipaemia to plasma Samples
Clinical Practice: Investigations
Outline the Investigations conducted in Lipodology
In clinical practice there are several investigations that can be performed such as:
Basic Lipogram
Basic Lipogram is done for a fasting Triglyceride, Total Cholesterol, HDLC, and LDLC
This is done on an Automated Machine, Spectrophotometric, Calculated or Direct LDL concentration
Extended Lipogram
Extended Lipogram is done for the Apoprotein A (ApoA), Apoprotein B (ApoB) and Lipoprotein(a)
ApoA parallels HDLC
ApoB parallels LDLC
Electrophoresis
Electrophoresis is done to characterize an Apoprotein profile
There are two types of Electrophoresis:
Agarose Gel Electrophoresis
Acrylamide Gel Electrophoresis
Electrophoresis is used in the Fredrickson classification of Hyperlipidaemia
There is also Acrylamide Gel Electrophoresis used in LDL sp, Dysbetalipoproteinaemia, LpX
Genetics
Genetic testing is used in selected cases, and is better used in Counselling for Homozygotes
Lipoprotein Separation by Gradient Gel Electrophoresis
Describe how Lipoproteins are separated by the Acrylamide Gel Gradient Electrophoresis
Gradient Gel Electrophoresis makes use of the Acrylamide Gel
Gradient Gel Electrophoresis was designed to separate all Lipoproteins containing Apoprotein B (ApoB)
These include: Chylomicrons, VLDL, LDL, IDL, Lp(a) and LDL
HDL does not contain ApoB and therefore migrates further than LDL in GGE and Agarose Electrophoresis
In the GGE a small sample of plasma is stained with Sudan Black in order to track movements of the Lipoprotein in the Gel
The Gel is arranged such that at the end of the investigation the LDL is at the bottom and Chylomicrons are at the top
Order: LDL, IDL, VLDL2, VLDL3 and CM
Ideal Fasted Lipid Profile
List the findings of an Ideal fasted Lipid Profile
VLDL has the highest concentration of Triacylglycerol
LDL has the Highest Cholesterol concentration
Total Cholesterol is Less then 5.0 mmol/L
Total Triacylglycerol is less than 1.5 mmol/L
Friedewald Calculation of LDLC
Outline the calculation of LDLC using the Friedewald Calculation
LDLC is calculated using the Friedewald Calculation
The Principle is as Follows:
TC = CMC + VLDLC + IDLC + LDLC + HDLC + Lp(a)
LDLC = TC - CMC - VLDLC - IDLC - HDLC - Lp(a)
In most fasted Samples the
CMC = 0
IDLC = 0
Lp(a) = 0
LDLC = TC - VLDLC - HDLC
Therefore, under normal circumstances with Low Triglyceride Concentrations and the absence of Dysbetalipoproteinaemia
The Composition of VLDL is standard
Where VLDL = TG/2.8
LDLC = TC - (TG/2.18) - HDLC
Generalisation in the Approach to Lipid Disorders
Outline the Generalisations in the Approach to Lipid Disorders
Concentration of analyte depends on rates of input and output. The Time to reach Equilibrium varies
TG-rich Lipoproteins have a turnover of less than 1 hour, after which TG rebound if they have been removed.
Whereas, LDL has a turnover of 2 days
There is Redundancy in some systems, meaning that a metabolic defect may not be critical in some stage of patient development BUT may decompensate the patient at a later stage.
Each cell can make Cholesterol, BUT importation of LDL is more efficient.
If the normal development of Homozygous LDLR is deficient at a young age it may not cause a problem but Atherosclerosis from exposure to LDL may kill a patient later on
Primary and Secondary causes result in overproduction and/or under-clearance
Under-clearance raises concentration more than overproduction
Underproduction lowers than concentration more than over-clearance (LDL in Abetalipoproteinaemia vs LOFPCSK9)
Type 2 Diabetes mellitus increased VLDL production and decreased clearance by LPL activity
Pathology varies with critical nature of error and time
Energy supply from carbohydrates and Lipids in the baby, fasting exposes baby to Beta-Oxidation errors
Individual with Homozygous FH may have Atherosclerosis at 15 years
Individual with Heterozygous FH may have Atherosclerosis at 45 years
Pathology varies with critical nature of sites in the body
Abetalipoproteinaemia develops Steatosis in the enterocyte and hepatocyte
High LDL and IDL causes Atheroma
Most Genetic Disorders are due to a Loss Of Function (LOF) of a Protein and a few disorders are due to a Gain of Function (GOF) of a Protein
LOF of LDLR causes high LDL concentration
PCSK9 errors can be a LOF or a GOF
ApoB may have a LOF by binding to LDLR or LOF to assemble CM and VLDL due to being Truncated
Some reactions need several molecules or components (Cofactors and Activators)
Lipolysis of Chylomicrons and VLDL requires LPL (Lipoprotein Lipase)
Some errors may manifest under metabolic stress
Diabetes increases NEFA supply and increases VLDL secretion
Terminology of Dyslipidaemias
List the types of Dyslipidaemias and the characteristics of each
Disorders of Lipidaemia are characterised by their Triglyceride (TG) Level and their Total Cholesterol (TC) Level measured in mmol/L
Disorders of Lipoproteinaemia are characterized by their LDLC, HDLC and Lp(a) Levels
Normolipidaemia
TG less than 1.7 mmol/L
TC of less than 5.0 mmol/L
Hypercholesterolaemia
Moderate Hypercholesterolaemia
TG is less than 1.7 mmol/L
TC is between 5.0-7.5 mmol/L
Severe
TG is less than 1.7 mmol/L
TC is between 7.5-15 mmol/L
Extreme
TG is less than 1.7 mmol/L
TC is greater than 15 mmol/L
Hypertriglyceridaemia
Severe Hypertriglyceridaemia
TG is greater than 5 mmol/L
Extreme
TG is greater than 15 mmol/L
Betalipoproteinaemia
Hypobetalipoproteinaemia
LDL is less than 1.0 mmol/L
Abetalipoproteinaemia
LDLC is less than 0.1 mmol/L
Alphalipoproteinaemia
Hypoalphalipoproteinaemia
HDLC is less than 0.8 mmol/L
Hyperalphalipoproteinemia
HDLC is greater than 2.0 mmol/L
Severe Hyperlipoproteinemia
Lp(a) is less than 0.050 g/L
Most Important Lipid Disorders
List the most important Lipid Disorders
Mixed Hyperlipidaemias
Lipoprotein overproduction (FCH)
Dysbetalipoproteinaemia
Hypertriglyceridaemias
Lipoprotein Lipase Deficiency
apoCii Deficiency
Hypobetalipoproteinaemias (LDLC is less than 1 mmol/L)
Truncations of apoB
MTP Deficiency
Hyperbetalipoproteinaemias
LDL Receptor mutations
Binding defective apoB100
PCSK9 GOF mutations
Hypoalphalipoproteinaemias (HDLC is less than 0.8 mmol/L)
ApoAi mutations/deletions
Hyperalphaproteinaemias (HDLC is greater than 2.0 mmol/L)
CETP deficiency
EL Deficiency
apoCII
Exogenous Lipid Pathways: Chylomicrons Errors
Exogenous Lipid Pathway involves transporting Dietary Lipids to the body and recycling whats left to the Liver
Outline Disorders of Exogenous Lipid Pathway: Chylomicrons
Disorders of Exogenous Lipid Pathway: Chylomicrons are as follows:
Abetalipoproteinaemia
Abetalipoproteinaemia is due to an MTP (microsomal Triglyceride Transfer protein) deficiency
Recessive disorder
BOTH parents of a child with this disorder will a have normal Lipid Profile
Truncated ApoB (ApoB is too short to have a Lipid loaded onto it by MTB therefore, the Chylomicron and VLDL can not be assembled)
Dominant disorder
Each parent of such a child will have a Low Cholesterol
Chylomicronaemia
Chylomicronaemia is the inability to clear the Chylomicrons that have been released from the intestines into the circulations
Chylomicronaemia is due to the following Recessive Disorders:
Complete LPL (Lipoprotein Lipase) Deficiency
Complete apoCii or -Av Deficiency
Deficient maturation and transport
Remnant Disease
Chylomicron remnants are cleared by way of the ApoE binding to LDLR in the liver
Remnant Disease is due to ApoE mutations
Recessive disorder and metabolic Stress
Some Dominant forms also have a delayed onset to adulthood
Generalised Lipodystrophy
In Generalised Lipodystrophy there is NO adipose tissue thus nowhere for NEFA (Non-esterified Fatty Acid) to go except to the Liver and return to Plasma as Triglyceride: VLDL compete for Chylomicron clearance
Abetalipoproteinaemia has the same effect on the liver as ApoB-lipoprotein production also affects the endogenous syste
Sequelae (Consequences) of Disorders in Exogenous Lipid pathway
Describe the Sequelae (Consequences) of Disorders in Exogenous Lipid pathway
No Lipoprotein Assembly
Mechanisms:
No Digestive enzymes and/or Bile
No ApoB for assembly
No MTP (Microsomal Triglyceride transfer Protein) to transfer Triglyceride to ApoB
Lipid Profile:
Triglyceride is Low
Total Cholesterol is Low
Effects:
Steatorrhea
Failure to thrive
Prone to Colic
Short height due to lack of energy intake
Low Triglyceride and no rise after a meal
Neuromuscular degeneration
No Chylomicron Lipolysis
Mechanisms:
No Lipoprotein Lipase or activator such as ApoCii or Av
No maturation or retention of Lipoprotein Lipase
Lipase maturation factor 1, apoAV, GPIHBP1
Lipid Profile:
Triglyceride is extreme
Total Cholesterol is High
Effects:
Pancreatitis
Lipaemia due to high triglyceride
Eruptive Xanthoma
Endogenous Triglyceride Pathway: VLDL, IDL and LDL
Describe the Disorders of Endogenous Triglyceride Pathway: VLDL, IDL and LDL
Abetalipoproteinaemia
Abetalipoproteinaemia is due to the MTP (Microsomal Triglyceride Transfer Protein) deficiency
Abetalipoproteinaemia is due to a truncated ApoB
Hypobetalipoproteinaemia
Hypobetalipoproteinaemia is due to the Loss of function of the PCSK9 Gene
Results in increased LDLR activity and low concentration of LDL
Overproduction
Overproduction is due to Familial combined Hyperlipidaemia
Overproduction is due to Diabetes
Impaired Lipolysis
Impaired lipolysis is due to the accumulation of VLDL
Impaired lipolysis is susceptible to Chylomicron accumulation
Remnants Disease
Remnants Disease is due to the mutation of ApoE resulting in increased LDLR activity
Also affects Chylomicron receptor
Impaired LDL Clearance
Impaired LDL Clearance is due to the following:
LDLR defects
ApoB Ligand defective
Gain of Function of PCSK9 Gene
Therefore the impaired clearance of LDL results in in severe LDL Hypercholesterolaemia
This is known as Familial Hypercholesterolaemia (FH)
Describe the Sequelae (Consequences) of Disorders in the Endogenous Lipid pathway
No LpB or Low LpB
ApoB truncations, MTP mutations, LOF PCSK9 gene
VLDL increase
Over-production which results in FCH (Familial combined Hyperlipidaemia)
Under-clearance which results in LPL partial defect
Remnants Increase
ApoE defective
LDL Increase (Familial Hypercholesterolaemia)
LDLR defect
ApoB Ligand defective
GOF of the PCSK9 Gene
Clinical Diagnosis: LDLC of less than 5 mmol/L
Tendon Xanthoma, Myocardial infarct in and individual less than 55 years
Rapid Clearance of LP
LOF of PCSK9 Gene
LDL is low and all LP Low
Familial Hypercholesterolaemia (FH) Phenotypes in Clinical Practice
There are 2 Clinical Phenotypes of Familial Hypercholesterolaemia
Heterozygous FH
Tendon Xanthoma
Coronary disease occurs in individuals older than 25 years
LDLC increases from 5 to 12 mmol/L
Homozygous FH
Xanthoma occurs in Tendons and the Skin
Coronary disease can occur in individuals younger than 25 years
LDLC is greater than 12 mmol/L
Disorders of the Reverse Cholesterol Transport: HDL
Describe the Disorders of the Reverse Cholesterol Transport: HDL
ABCA1 Transport absent
Cells cannot export Cholesterol to HDL, enlarged tonsils, Liver and Spleen
ApoAi abnormal
Little or no HDL
Usually atherogenic
LCAT Absent
Little or no HDL
Usually atherogenic or renal disease
CETP Deficient
HDL not cleared well, resulting in an HDL increases
Uncertain if beneficial
ScRB1 Deficient
HDL increases
Uncertain if beneficial
ApoCiii Deficient
Lipolysis of CM and VLDL not limited
All HDL Increases
Beneficial
Lipoprotein
Describe the characteristics of Lipoproteins
There are two types of Lipoproteins
Lipoprotein(a)
Lp(a) is a Lipoprotein in which the LDL particle is linked to apo(a) by a disulfide bridge -S-S-
Apo(a) binds to Fibrin, may limit fibrinolysis
Apo(a) has kringles of plasminogen
Lp(a) may improve wound healing but promotes atherothrombosis immunoassay
Lipoprotein X
Lipoprotein X is a Lp found in Cholestatic jaundice
LpX raises the cholesterol levels significantly
LpX can cause cutaneous xanthomata (feet)
The Pathogenesis of Atherosclerosis
Outline the pathogenesis of Atherosclerosis
Atherosclerosis occurs when the wall of the artery may be injured over many years
Finally, the plaque may rupture and close the vessel by a thrombus
Dyslipidaemias that enhance the process are mild
And typically in Obese and Insulin-resistant individuals may involve mild Hypertriglyceridaemia, LDLC, small dense LDL
However, in monogenic disorders such as Familial Hypercholesterolaemia there is extremely High LDL that is atherogenic, IDL in Dysbetalipoproteinaemia that can cause FH without risk factors
Atherogenic refers to the tendency to promote the formation of fatty deposits in the arteries.
Low LDL is an unusually cause of Atheroscleorsis
Diagnostic Evaluation of Lipidology
Outline the factors involved in the Diagnostic Evaluation of Lipidology
Symptoms
Lifestyle
Diet
Smoking
Alcohol
Drugs
Medication
Medication can alter the Lipid profile
Retinoids increase Triglycerides
Signs: Xanthoma
Cutaneous Xanthomata which occurs when there is repetitive skin creasing
Due to Triglyceride rich Lipoproteins
Tendinous Xanthoma which occurs when there is repetitive tendon injury
Due to Sterol rich Lipoproteins
Tendon and Skin Xanthoma is due to mixed Hyperlipidaemia or extreme sterol
Xanthelasma (Eye)
Corneal arcus
Xanthomata (Feet and Achilles Heels)
Physical signs of Dyslipidaemias have variable presence
Urine
Glycosuria
Proteinuria
Dietary Intervention
Severe Hypertriglyceridaemia
Limit dietary fats
Eat cereals, vegetables, fruits and fish
No oils, nuts, and spreads
sever Hypercholesterolaemia
Eat cereals, vegetables, fruits, fish and poultry
Treatments of Dyslipoproteinaemia
Describe the Treatments of Dyslipoproteinaemia
Diet
Low TG intake if individuals is HyperTG
Less Saturated fatty acids will lower LDL
Low Cholesterol intake if Hypercholesterolaemia
Low Cholesterol uptake
For a low cholesterol uptake:
Eat Dietary Fibre
Eat plant sterols
Cholesterol synthesis
To inhibit the synthesis of cholesterol:
Take Statins to limit LDL in the plasma through the process of LDLR upregulation
Statins limit HMGCoAR
HSL Inhibitors
Niacin results in less TG and less VLDL
Lp assembly
Lipoprotein assembly is inhibited by MTP inhibitor
Anti-PCSK9 Gene
Take monoclonal antibodies to prevent PCSK9 from binding to LDLR for Cholesterol and LDL synthesis
This results in Degradation
Secondary Dyslipidaemias
Raised LDLC (Low-Density Lipoprotein Cholesterol)
Raised LDLC is due to Diabetes, Hypothyroidism, Pregnancy, Liver and Renal Disease
Mixed Dyslipidaemias
Weight gain and obesity
Diabetes mellitus
Medications: Retinoids
Raised Triglyceride
Diabetes mellitus
Weight gain and obesity
Pregnancy
Alcohol excess
Sterol Biosynthetic Errors
Outline the Sterol Biosynthetic Errors
Sterol Biosynthetic Errors are Rare and mostly recessively inherited
It uncommon for metabolic errors to result in Congenital Abnormalities
Cholesterol is involved in tissue differentiation in the embryo and foetus
Some fatal intra-uterine
Most common disorder is the Smith Lemli Opitz Syndrome (SLOS)
Similar phenotype for SLOS is Lathosterolosis and Desmosterolosis
Infant will develop the following:
Infant is dysmorphic
Microcephaly
Low ears
Cleft palate
Abnormal esophageal and bowel function
Very poor feeding
Neurological development delay
Syndactyly of the toes
Cholesterol may be low but not reliable for diagnosis
Fatty Acid metabolic Errors
Rare, mostly recessively inherited but adrenoleukodystrophy is X-linked
Defects in FA Beta-Oxidation
Failure of transport through carnitine at mitochondria membrane
Failure to oxidise long, medium or short chain fatty acids
Resulting in Hypoglycaemia whiteout Ketosis
Presentation may be when weaning and carbohydrates deplete
Cannot make ketones and cannot oxidise fatty acids for energy: Hypoglycaemia
Unusual fatty acids
