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Biochemistry MBBS > Lipids 2 > Flashcards

Lipids 2 Flashcards

1
Q

Hormone sensitive lipase

A

Acts on stored TAG (in adipocytes) and is converted to FA and glycerol.
Located in the adipocytes

Inhibited by insulin (activated during diabetic ketoacidosis).

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2
Q

Ketone body synthesis reactions upto primary ketone body formation

A
  1. Acetoacetyl CoA (from beta oxidation) and Acetyl CoA combine with the help of HMG CoA Synthase (RDS)
  2. The HMG CoA formed is split by HMG CoA Lyase to acetoacetate (and Acetyl CoA)
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3
Q

Ketone body synthesis occurs in

A

Exclusively Liver mitochondria

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4
Q

Secondary ketone body synthesis from primary

A

Acetoacetate is either

a) spontaneously decarboxylated to acetone
b) converted to Beta Hydroxy Butyrate by b-OH Butyrate dehydrogenase utilising NADH

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5
Q

Two organs that cannot utilise ketone bodies are

A

Liver, RBC

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6
Q

Ketone body utilisation from primary ketone body

First step

A

Acetoacetate accepts CoA by Thiophorase (S- CoA Acetoacetate CoA transferase) from succinyl CoA to become acetoacetyl CoA (and succinate but no GTP/ATP is generated)

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7
Q

Ketone body utilisation from primary ketone body

Second step

A

Acetoacetyl CoA is converted to 2 Acetyl CoA as part of beta oxidation by thiolase

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8
Q

Fate of secondary ketone bodies

A
  1. Beta OH butyrate is converted to acetoacetate producing NADH+
  2. Acetone is volatilised and excreted through lungs (fruity smell in ketosis)
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9
Q

Energetics of ketone body utilisation from acetoacetate

A

2 Acetyl CoA are formed
TCA cycle occurs twice but in one cycle thiophorase is used instead of thiokinase
So 20-1= 19 ATP

If it is beta OH butyrate 19+2.5= 21.5 ATP

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10
Q

Most common ketone body in a normal person

A

Beta Hydroxy butyrate = acetoacetate

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11
Q

Most common ketone body during starvation

A

Beta Hydroxy Butyrate: Acetoacetate = 6:1

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12
Q

Neutral ketone body

A

Acetone

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13
Q

Test for ketone body

A
  1. Rothera’s test
    a) Purple ring - acetoacetate and acetone
    b) Beta Hydroxy Butyrate does not answer Rothera’s test
  2. Gerhard’s test answered only by acetoacetate
  3. Ketostix - dipstick test
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14
Q

Organs where FA are synthesised

A

Liver, adipose tissue, brain, kidney, lungs, lactating mammary glands

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15
Q

Steps of FA is elucidated by

A

Feodor lynen

Hence FA synthesis is also called Lynen’s spiral

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16
Q

Steps of FA synthesis

A
  1. Transfer of Acetyl CoA from mitochondria to cytoplasm
  2. Acetyl CoA carboxylase
  3. FA synthase complex reactions requires Mn+2
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17
Q

Transport of Acetyl CoA into cytoplasm for FA synthesis

A
  1. First step of TCA occurs
  2. Citrate exits via Tricarboxylic Acid Transporter
  3. It is split into Acetyl CoA and OAA by ATP Citrate Lyase
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18
Q

Acetyl CoA carboxylase , the second step of FA synthesis

A

Acetyl CoA is carboxylated to Malonyl CoA using:

  1. bicarbonate (HCO3-)
  2. Acetyl CoA carboxylase
  3. ATP
  4. Biotin
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19
Q

FA synthase complex structure

A
  1. Homodimer
  2. Each monomer unit has 6 enzyme activity + 1 Acyl carrier protein (ACP)
  3. ACP has a pantothenic acid as 4 phosphopantotheine.
  4. Multifunction enzyme-single polypeptide has more than 2 enzyme activity.
  5. X shaped (using X-ray crystallography)
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20
Q

Domains of FA synthase

A
  1. Condensing unit
  2. Reduction unit
  3. Releasing unit
  4. Acyl Carrier Protein
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21
Q

Condensing unit- enzymes

A
  1. Acetyl/ Malonyl transacylase
  2. Ketoacyl synthase

ACP

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22
Q

Reduction unit-enzymes

A
  1. Ketoacyl reductase
  2. Dehydratase
  3. Enoyl reductase
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23
Q

Releasing unit-enzyme

A

Thioesterase

This unit takes place only once per FA

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24
Q

Cys-SH group of first monomer unit and Pan-SH group of 2nd monomer unit

A

By Acetyl/Malonyl transacylase
a Acetyl group combines with Cys-SH and
a Malonyl group combines with Pan-SH

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25
Q

Action of ketoacyl synthase, 2nd enzyme of first unit

A

From Malonyl group, a CO2 is removed and then the Acetyl group condenses with it
A keto compound of 4C is formed at pan-SH

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26
Q

Reduction unit

A

Ketoacyl compound is reduced using NADPH to Acyl group (Acetoacetyl initially)

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27
Q

Releasing unit

A

Acyl group combines with CoA and separated from the complex by thioesterase.

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28
Q

Different types of regulation of FA synthesis

A
  1. Short term
    a) allosteric
    b) covalent
    c) compartmentalisation
  2. Long term
    Increased Acyl CoA decreases the expression of enzymes that synthesise FA
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29
Q

Acetyl CoA carboxylase regulation

A

Inactive state- dimeric
Active- polymeric

Activator-citrate (also activates TCA transporter)
Inhibitor-LCFA (also inhibits TCA transporter)

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30
Q

Compartmentalisation of FA acid synthesis

A

Beta oxidation occurs in the mitochondria while FA synthesis occurs in the cytoplasm

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31
Q

Elongation of FA

A
  1. Major
    In SER by microsomal FA elongase system
  2. Minor
    By mitochondrial FA elongase

For myelination of brain

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32
Q

Synthesis of unsaturated FA

A

Involves the enzyme in ER :

  1. Desaturase
  2. Elongase

Humans cannot insert a double bond between C10 and terminal methyl

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33
Q

Cholesterol concepts

A 
Regulated by insulin
Cannot generate energy
Purely animal sterol
27C
50% excreted
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34
Q

Cholesterol is synthesised in

A

all nucleated cells especially in liver, adipose tissue, adrenal cortex, gonads,intestine
It is synthesised in SER and cytoplasm

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35
Q

Stages of synthesis of cholesterol

A
  1. Synthesis of HMG CoA (6C)
  2. Synthesis of Mevalonate (6C)
  3. Synthesis of isoprenoid unit(5C)
  4. Isoprenoid units join to form 30C squalene
  5. Trimmed to Cholesterol
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36
Q

HMG CoA is involved in

A
  1. Synthesis of Cholesterol (cytoplasmic)
  2. Synthesis of Ketone body (mitochondrial)
  3. Leucine metabolism
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37
Q

Synthesis of Mevalonate

A

HMG CoA is converted to Mevalonate by HMG CoA reductase (RDS)
Statins is a competitive inhibitor of this enzymes
Occurs in SER

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38
Q

Synthesis of isoprenoid units

A

Mevalonate is decarboxylated and phosphorylated to isoprenoid unit (5C)

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39
Q

Squalene formation

A

2 Isoprenoid unit = Geranyl PPi 10C
Combines with isoprenoid unit (5C) to form Farnesyl PPi
2 Farnesyl PPi combine to form Squalene (30C)

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40
Q

Trimming to cholesterol

A 
Squalene
Lanosterol (first cyclical compound)
Zymosterol
Desmosterol
Cholesterol

SLZDC

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41
Q

Regulation of cholesterol synthesis

A
  1. Feedback regulation
  2. Feedback inhibition
  3. Hormonal regulation
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42
Q

Long-term feedback regulation of Cholesterol synthesis

A

Dietary cholesterol decreases binding of SREBP at genes which in turn reduces expression of HMG CoA reductase (RDS)

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43
Q

Feedback inhibition of cholesterol synthesis

A

Mevalonate inhibits HMG CoA reductase

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44
Q

Formation of primary bile acids in liver

A 
From cholesterol by 7-alpha Hydroxylase (Cytochrome P7A1 or CYP7A1) using
1. NADPH
2. vitamin C
3. O2
To get 7-Hydroxy cholesterol

This after multiple steps forms primary bile acids cholic acid and chenodeoxycholic acids requiring NADPH and producing propionyl CoA

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45
Q

Formation of secondary bile acids

A

After deconjugation and dehydroxylation of primary bile acids:

  1. cholic acid to deoxycholic acid
  2. chenodeoxycholic acid to lithocholic acid

98-99% of secondary bile acids undergo enterohepatic circulation

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46
Q

Least enterohepatic circulation is for

A

Lithicolic acid

47
Q

Regulation of bile acid synthesis

A

Farnesoid X receptor (FXR)
RDE is 7-alpha hydroxylase (CYP7A1)
Increased bile acid (Chenodeoxycholic acid) will decrease the binding of this receptor to the gene
Thus decreasing expression of this enzyme

48
Q

Layers in lipoprotein

A
  1. Hydrophobic lipids (TAG,cholesterol ester)
  2. Amphipathic lipids (cholesterol, phospholipids)
  3. Proteins (integral, peripheral)
49
Q

Maximum lipid content (TAG) and least protein content is in

A

Chylomicron

50
Q

Apolipoproteins in chylomicron and remnant chylomicron

A

Unique :
app B 48

Major :
Apo C2
Apo E

51
Q

VLDL is assembles in

A

Liver

and carries endogenous TAG from liver to peripheral organs

52
Q

VLDL contains the apo lipoproteins

A

Apo B100

From HDL:
Apo C2
Apo E

53
Q

Lipoprotein cascade pathway

A

VLDL to IDL to LDL

54
Q

Maximum cholesterol and cholesterol ester content is present in

A

LDL or beta lipoprotein

55
Q

Apolipoprotein present in LDL

A

Apo B100 only

56
Q

Maximum apoprotein and phospholipid content is in

A

HDL
Formed from liver and intestine
Participates in reverse cholesterol transport

57
Q

Repository for apo E and Apo C2

A

HDL or alpha lipoprotein

58
Q

Lipoprotein of HDL

Enzyme activity of HDL

A

Apo A1

Enzyme activity:

  1. LCAT (Lecithin Cholesterol Acyl Transferase) activated by apo A1
  2. Cholesterol ester transfer protein (CETP)
59
Q

LCAT

A

Lecithin + Cholesterol

cholesterol ester + Lysolecithin

60
Q

CETP

A
  1. Transfers cholesterol ester from HDL to other lipoproteins like LDL,…
  2. in turn transfers TAG from other lipoproteins to HDL

Inhibited by apo C1

61
Q

LP(a)

A

Lipoprotein that contains apo(a) and apo B100 linked by a disulphide bond
apo(a) is a structural analog of plasminogen and hence inhibits clot lysis

62
Q

Lipoprotein X

A

Lipoprotein produced during cholestasis from unexcreted cholesterol and phospholipids

Indicator of cholestasis

63
Q

Pre beta lipoprotein

A

VLDL

64
Q

Broad beta lipoprotein

A

IDL

65
Q

Order of lipoproteins from cathode to anode

A 
Chylomicron
LDL
VLDL
IDL/remnant VLDL
HDL

Protein content~ electrophoretic mobility

66
Q

Nascent chylomicron contains the lipoproteins

A

B48

Helps in the assembly of chylomicron in intestine

67
Q

LPL HP(Lipoprotein Lipase)

A

Anchored to the capillaries surrounding the peripheral organs

Hydrolyses the TAG
Activated by apo C2

Involved in both chylomicron and VLDL metabolism

68
Q

Function of apo E

A

Ligand for hepatic receptors for internalisation of remnant chylomicron and IDL
Receptor mediated endocytosis

69
Q

Apo proteins of nascent VLDL

A

B100
Helps in the assembly of CLDL
Ligand for LDL

70
Q

Fates of IDL

A
  1. Receptor mediated Endocytosis into the liver via ligand apo E
  2. Loses some TAG (via endothelial and hepatic lipase)
    Apo E and Apo C2 are removed and then converted into cholesterol ester rich LDL (having only Apo B100)

Thus is the lipoprotein cascade pathway

71
Q

Fates of LDL

A
  1. 70% of LDL is taken by the liver via LDL receptors
  2. 30% LDL is taken by extra-hepatic tissues via LDL receptors
    Ligand for LDL receptors is Apo B100 (receptor mediated endocytosis)

Oxidation may occur which is ingested by macrophages leading to atheroma

72
Q

Transporters present in HDL

A

ABCA1
ABCG1
SRB1 (Scavenger Receptor B1)

ATP Binding Casette
Transports cholesterol and its esters from peripheral organs to HDL3 (spherical)

73
Q

Why newly formed HDL is disc shaped

A

Cholesterol and phospholipid which it contains are both amphipathic compounds (which exists in a structure similar to cell membrane)

74
Q

Change of shape from discoidal to spherical HDL3

A

Due to the formation of hydrophobic cholesterol ester by LCAT from cholesterol

75
Q

Formation of spherical HDL2 and the conversion back to HDL3

A

After receiving cholesterol from peripheral cells, spherical HDL3 is converted to spherical HDL2

which later donates the cholesterol to liver to mostly form HDL3 again

76
Q

Pre beta HDL

A

While HDL2 is donating cholesterol, certain lipase liberate apo A1.
Apo A1 accepts cholesterol, phospholipid,… to form poorly lipidated HDL, i.e, pre beta HDL

The most potent HDL

77
Q

Function of apo C3

Function of apo A2

A

Inhibits lipoprotein lipase

78
Q

Function of apo A5

A

Facilitates the binding of chylomicron and VLDL to lipoprotein lipase

79
Q

Apo D

A

Associated with human neurodegenerative diseases like Parkinson’s disease

80
Q

Special features of apo E

A

Arginine rich

Apo E4 is associated with late onset of Alzheimer’s disease

81
Q

Classification of hyperlipoproteinemia is done by

A

Fredrickson and Levy

82
Q

Primary hyperlipoproteinemia are classified into (according to Harrison’s)

A
  1. Primary hyperlipoproteinemia with hypertriglyceridemia
  2. with hypercholesterolemia
  3. with both hypertriglyceridemia and hypercholesterolemia
83
Q

Primary hyperlipoproteinemia with hypertriglyceridemia (Fredrickson’s classification)

A

Type 1 :
Familial chylomicronemia syndrome

Type 4 :
Familial hypertriglyceridemia apo A-V defect

Type 5 :
Familial hypertriglyceridemia apo A-V defect and GPIHBP-1 defect

84
Q

Primary hyperlipoproteinemia with hypercholesterolemia (Fredrickson’s classification)

A

Type 2

85
Q

Primary hyperlipoproteinemia with both hypertriglyceridemia and hypercholesterolemia

A

Type 3 or Familial Dysbetalipoproteinemia (FDBL)

86
Q

Type 1 hypercholesterolemia

Familial chylomicronemia syndrome

A
  1. Apo C2
  2. Lipoprotein lipase

Chylomicron and VLDL increased
TAG accumulates

87
Q

Clinical features of type 1 hyperlipoproteinemia

A
  1. Milky white plasma
  2. Eruptive xanthoma
  3. On fundoscopy, lipemia retinalis
  4. TAG>1000gm leads to pancreatitis and then abdominal pain
88
Q

Treatment of familial chylomicronemia syndrome

A

Gene therapy:
A lipogene -Tiparvovec

Adeno associated viral vector expressing LpL variant leading to myocyte expression of LpL

89
Q

Type 4 hyperlipoproteinemia

A

Apo A5 defect which facilitate the association of chylomicron,VLDL with LpL

Familial hypertriglyceridemia

90
Q

Type 5

A
  1. Apo A5 defective or
  2. Defect in glycosylated phosphatidyl inositol HDL binding protein-1 (GPIHBP-1) which helps in the export of lipoprotein lipase to vascular endothelium

Increased TAG

91
Q

Familial hypercholesterolemia/

ADH type 1

A

Fredrickson’s type 2a
Most common
Defective LDL receptor
Therefore Cholesterol and cholesterol ester is elevated

92
Q

Clinical features of familial hypercholesterolemia

A
  1. Corneal arcus
  2. Tendon xanthoma
  3. Clear plasma
  4. Increased risk of CAD and PVD

No abdominal pain

93
Q

Treating of familial homozygous hypercholesterolemia

A
  1. Lomitapide-inhibits Microsomal Triglyceride Transfer Protein (decreases VLDL leading to decreased LDL)
  2. Mipomersin-antisense oligonucleotide to apo B
94
Q

Sitosterolemia biochemical defect

A

Type 2a
Primary hyperlipoproteinemia with hypercholesterolemia

Defective ABCG5 and ABCG8 (which usually actively excrete plant sterols from liver and intestinal cells)

95
Q

Clinical features of sitosterolemia

A

Decreased plant sterols in the cells leads to decreased transcription of LDL receptors
This leads to increased LDL in blood which leads to increased cholesterol in blood

96
Q

ADH type 2

A

Familial defective apo B(FDB)
Apo B100 defective
Autosomal dominant

97
Q

ADH type 3

A

PCSK9-secreted protein that accelerate lysosomal degradation of LDL receptors
Gain of function mutation occurs in PCSK9 (increased activity)
Decreased LDL receptor

98
Q

Autosomal recessive hypercholesterolemia

A

Defect in LDL receptor adaptor protein (LRAP)

Decreased LDL uptake

99
Q

Type 3 Hyperlipoproteinemia/ Familial dysbetalipoproteinemia (FDBL)
Clinical features

A
  1. Tuberoeruptive xanthoma (like a bunch of grapes)
  2. Palmar xanthoma /Lipid deposition in palmar creases
  3. Slight risk of CAD
  4. Plasma is clear
100
Q

Type 3 Hyperlipoproteinemia/ Familial dysbetalipoproteinemia (FDBL)
Biochemical defect

A

Apo E mutation (which acted as a ligand for the uptake of chylomicron remnant and IDL/VLDL remnant)
Hence these accumulate leading to accumulation of both TAG and cholesterol

So called as Remnant removal disease or broad beta disease

101
Q

Hypolipoproteinemia

A
  1. Abetalipoproteinemia
  2. Tangier’s disease
  3. LCAT deficiency
102
Q

Abetalipoproteinemia biochemical defect

A

Defective Microsomal Triglyceride Transfer Protein (transport of lipid to the apo protein)

So decreased lipoproteins except HDL

103
Q

Clinical features of abetalipoproteinemia

A
  1. Acanthocytes
  2. Pigmentary retinitis
  3. Bleeding manifestations due to decreased fat soluble vitamins
104
Q

Tangier’s disease

Biochemical defect

A

Defective ABCA1 (transport cholesterol from peripheral organs to HDL)
Decreased spherical HDL
Other lipoproteins are normal

105
Q

Clinical features of Tangier’s disease

A
  1. Orange/yellow tonsils (cholesterol accumulation)
  2. Hepatosplenomegaly
  3. Mononeuritis multiplex
106
Q

Norum’s disease

A

Complete LCAT deficiency
Increased lecithin and cholesterol
Decreased lysolecithin and cholesterol ester

Progresses to end stage renal disease (ESRD)

107
Q

Fish eye disease

A

Partial LCAT deficiency
Benign
Do not progress to end stage renal disease (ESRD)

108
Q

Steps in the action of hormone sensitive lipase

A

TAG➡️2,3-diacyl glycerol ➡️ 2-Mono Acyl glycerol

Then esterases act on the product to form glycerol and FA

109
Q

Activators of hormone sensitive lipase

A

Glucagon
Catecholamines
ACTH,TSH
Glucocorticoids, thyroid hormones

110
Q

Inhibitors of hormone sensitive lipase

A

Insulin
Nicotinic acid
PG E1

111
Q

Lipoprotein lipase is anchored to the capillaries of the organs:

A

Heart, adipose tissue,spleen,renal medulla,aorta, diaphragm, lactating mammary glands

112
Q

Heparin and lipoprotein lipase

A

If we inject heparin the lipoprotein lipase is dislodged and is free to be calculated

113
Q

Hepatic lipase function

A

Act on chylomicron remnant

Convert HDL2 to HDL3

114
Q

Endothelial lipase action

A

Acts on HDL3 to convert it into HDL2 and pre-beta HDL (most potent)

Biochemistry MBBS (10 decks)

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