Chylomicrons, LDL, HDL → Lipid transport and disorders😊😍

When total cholesterol is 300 mg/dL, HDL is 25 mg/dL, and triglycerides are 150 mg/dL, what is the value of LDL?

1. 55

2. 95

3. 125

4. 245
ANS
Total cholesterol = HDL + LDL + TG/5
Therefore LDL=Total cholesterol-HDL-TG/5
LDL=300-25-30
LDL=245mg/dl

Lipids

• HDL → 1 (A1 - not transferrable), 2 (C2), 3 (E)

• VLDL/LDL → 100 (B100) + HDL

• Chylomicrons → 48 (B48) + HDL

Friedweld formula

• Total cholesterol = HDL + LDL + TG/5

Fatty Acid Transport

• Fatty acids need a carrier, Carnitine, for transport
• to cross the inner mitochondrial membrane for oxidation

Rate Limiting Enzymes of Lipid Metabolism Pathways

Note:

Hyperlipoproteinemias (Friedrickson's Classification)

• There are six types.

• They are classified into three categories by lipid elevation:
• Hypercholesterolemia.
• Hypertriglyceridemia.
• Both.

Clinical Features of Hyperlipoproteinemias

• Hypercholesterolemia presents with:
• Tendon Xanthomas.



• Small eruptive lesions along tendon attachments.
• Pronounced on knuckles or ankles.
• Accelerated Atherosclerosis.

• Hypertriglyceridemia presents with:
• Eruptive xanthomas.
• Tinier than tendon xanthomas.
• Present on extensive surfaces of limbs, especially elbows.
• Recurrent pancreatitis.
• Lipemia retinalis.

• Isolated elevated Hypercholesterolemia:
• Type 2a
• Chola → DolA → 2a

• Isolated elevated Triglycerides:
• Type 1, Type 4, Type 5.
• TriG → 3 → 1, 4, 5

• Elevated both Cholesterol and Triglycerides:
• Type 2b, Type 3.
• Dola + Tri → 2b + 3

• Autosomal dominant
• Type 2a, Type 4 and Type 5

• Mnemonic:
• Type 1 → 1st → from intestine → ↑ TGA and chylomicrons
• Type 2a → 2nd → from liver → ↑ Cholesterol
• Type 2b & 3 → both ↑ TGA and cholesterol

Type IIa Hyperlipoproteinemia (Familial Hypercholesterolemia)

• It is an autosomal dominant

• Only elevated Cholesterol.

• Defect of the LDL receptor or Apo B100
• prevents LDL clearance
• LDL accumulation
• Hypercholesterolemia.

Type I Hyperlipoproteinemia (Familial Chylomicronemia syndrome)

• Autosomal recessive

• Caused by a defect of Apo CII or Lipoprotein lipase (LPL).

• Chylomicrons:
• Transport dietary TGA from the intestine to extrahepatic tissues.
• Are drained by lymphatics, enter the thoracic duct, then systemic circulation.
• Contain apoproteins:
• Apo CII,
• Apo E,
• Apo B48.

Metabolism:

• Apo CII → activates LPL, which is held to vessel walls by Heparan sulphate.

• LPL cleaves chylomicron triacylglycerol into glycerol and fatty acids.

• Fatty acids enter extrahepatic tissues.

• Glycerol is used by the liver.

• Chylomicrons become remnants after losing triacylglycerol.

• Remnants are accepted by liver LDL or remnant receptors.
• LDL receptor → accepts Apo E or Apo B100
• Remnant receptor → accepts Apo E

Defects in Apo CII or LPL

• prevent chylomicron metabolism.

• This leads to chylomicron accumulation.

• Causes Familial Chylomicronemia syndrome.

Features:

• Massive hypertriglyceridemia.
• Recurrent pancreatitis.
• Eruptive xanthoma.
• Lipemia retinalis.

Diagnosis:

• Check lipoprotein lipase enzyme activity.

• Inject Heparin to detach LPL into the blood.
• ↓↓ post-heparinised LPL activity confirms the diagnosis.

Type III Hyperlipoproteinemia /
Familial Dysbetalipoproteinemia (D - E)

• Homozygous E2 mutation.
• Normal: Homozygous E3 allel
• → Apo E defect.
• Mnemonic:
• Three → Eee (Apo E)
• Dys beta → bad → beat in palm (Palmaris striae, palmaris xanthoma) with a tube → erupted (Tubero eruptive) → 2 times (E2) Cried EEEee (Apo E) → grapes (bunch of grapes)
• Results in elevation of both cholesterol and triglycerides.

• Cerebral amyloid disease?

Also called:

• Remnant disease
• as remnant lipoproteins are not cleared.

• Broad Beta disease.
• Lipoprotein Electrophoresis:
• Broad Beta Band (Pathognomic)

• Familial Dysbetalipoproteinemia.

Dermatological pathognomic feature:

• Palmar eruptive xanthomas.

• Palmaris Xanthoma striae
• yellowish discoloration of palmar creases

Abetalipoproteinemia (A - B)

• Mnemonic: A beta () → Beta illa (Failure to thrive) → Beta ye Akkan (Acanthocytes) MTP (MTP gene) cheyth
• Body rash (Petechial rash) ulla akkan
• Fat (Lipid laden enterocytes on biopsy)
• Last → Akkanu bleeding (Vitamin K↓↓↓) vann, kazcha poi (Retinitis pigmentosa)
• Vitamin E tratment

• Autosomal recessive (AR)

• Mutation in
• MTP gene in intestine
• (Microsomal Triglyceride Transfer Protein)
• → ↓↓ synthesis of apo B48 and B100 lipoproteins
• → absence of chylomicrons, LDL, VLDL

• Lipoproteins ↓:
• Chylomicrons, VLDL, LDL

Clinical features:

• Infancy:
• Fat malabsorption,
• steatorrhea,
• failure to thrive

Later:

• Retinitis pigmentosa

• Spinocerebellar ataxia

• Bleeding manifestations
• due to ↓ fat-soluble vitamins like K and E

Diagnosis:

• Lipid-laden enterocytes on biopsy

Treatment:

• Restrict long-chain fatty acids;

• high-dose vitamin E

Retinitis Pigmentosa

Triad:

• Arteriolar attenuation

• Waxy pale Optic disk

• Bony spicules

 

Mnemonic:

• Bony spicules

• Pigmentary epithelium

• Donut scotoma/tunnel vision

• Night → Nyctalopia

• Moon → Lawrence moon biedl syndrome
• Moon has law in bed

 

Features

• Rod-cone dystrophy (Rods > cones affected).

• M/c inheritance: Autosomal recessive (M/c hereditary fundus dystrophy)

• Cause: ↓↓ Docosahexanoic acid

• Clinical Features:
• Nyctalopia.
• Ring/donut scotoma/tunnel vision (rods affected).
• Bony spicule pigmentation.
• Arteriolar attenuation
• Waxy, pale optic disc.

• Systemic association:
• Lawrence-Moon-Biedl syndrome.

• Usher Sx → RP + SNHL

• Treatment:
• Genetic counselling (no specific treatment).

Tangier's Disease:

• Characterised by orange-coloured tonsils.

• Cholesterol esters accumulate in extrahepatic tissues, causing:
• Greyish-orange tonsils.
• Hepatosplenomegaly.
• Mononeuritis multiplex.

• ABC students drink Tang → don't get A1 → cant multiply

• Caused by a mutation in ABC1 (ATP Binding Cassette transporter 1).

• Key Characteristic:
• Significantly reduced levels of apo A1→ very low HDL levels.

Profile Component	Level
HDL	↓↓
LDL	↓
TAG	↑
Total Cholesterol	Normal/Low
Apo A1	↓↓

Fish Eye Disease → LpX

• Partial LCAT deficiency / Hypo alpha lipoproteinemia (↓ LDL)

• LCAT
• discoidal HDL → spheroidal HDL
• Deficiency → ↑↑ Discoidal HDL
• Discoidal HDL → lamellar structure → cannot move

• Electrophoresis
• Appears as band at application point = Lipoprotein X (LpX)

• Features
• No anemia (unlike full LCAT deficiency)
• Chronic Kidney Disease
• LpX accumulates in mesangium
• Corneal opacity (fish eye disease)
• Cholesterol ester accumulation

• NOTE
• Norum’s disease
• Complete LCAT deficiency
• Nooru (100) → complete

HDL

• Highest Apoprotein concentration

• Site: Liver & Intestine

• Steps
1. Apo AI activates LCAT
2. Formation of Cholesterol Esters
3. Discoidal HDL → Mature/Spherical HDL3 → Delivers cholesterol to liver
4. Reverts to HDL3
5. Function: Facilitates reverse cholesterol transport

Lipoprotein electrophoresis

Q. Lipoprotein electrophoresis of a patient presenting with chronic kidney disease, corneal opacity, low HDL is provided here. The band identified as A and the disorder is?

• (Image showing Lipoprotein electrophoresis with bands and band A at application point).
• A. M band and Multiple Myeloma.
• B. Chylomicron and Type I Hyperlipoproteinemia.
• C. LDL and Type II Hyperlipoproteinemia.
• D. LpX and complete LCAT deficiency.

• Done on a glass slide

• Support medium: Agarose

• Serum lipoprotein applied at one end

• Glass slide connected to electrical supply

• Negative electrode:
• near application point

• Positive electrode:
• opposite point

• On current supply → lipoproteins move toward oppositely charged electrode

Migration depends on

• Number of negative charges
• More charges → more rapid movement

• Size
• Larger particles move poorly

VLDL

• Endogenous TAG

LDL

• Max Cholesterol

Alpha band / HDL

• Moves farthest

• Min TAG

• Max PL

• Max protein

• Has more negative charges

Chylomicron band

• Moves closest (due to huge size)

• Maximum TAG

• Fasting sample required

• Normally absent

• It is a product of dietary triacylglycerol

• Presence indicates:
• Patient not fasting
• Or chylomicron elevated → Familial Chylomicronemia Syndrome

Obstructive jaundice

• Bile salt concentration in circulation ↑

• Forms lamellar structure

• Appears as band at application point

Other normal bands

• Beta band → LDL

• Pre-Beta band → VLDL

Remnant concentration

• Normally too low to detect

• If present → after beta band

• Type III hyperlipoproteinemia / remnant disease
• Remnant band significant
• Appears as broad beta band