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CV II Exam II > Lipid biochemistry (Choudhury) > Flashcards

Lipid biochemistry (Choudhury) Flashcards

1
Q

chylomicron

apoproteins>
functions?

A

apoB-48
apoC-II
apoE

secreted by intestine
activates LPL
uptake of remnants by the liver

assembled from/tranpsorts dietary triglyceride and cholesterol from intestine to tissue

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2
Q

VLDL

A

transports triglyceride from liver to tissue

secreted by liver
activates LPL
uptake of remnants (IDL) by liver

ApoB100
apoC-II
Apo E

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3
Q

IDL

A

VLDL remnant

apoE
apoB-100

uptake by liver

picks up cholesterol from HDL to become LDL

picked up by liver

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4
Q

LDL

A

Delivers cholesterol into cells

uptake by liver and other tissues via LDL receptor (apoB-100)

apoB100

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5
Q

HDL

A

apoA-1

Picks up cholesterol accumulating in blood vessels

Delivers cholesterol to liver and steroidogenic tissues via scavenger receptor SR-B1

Shuttles ApoC-II and ApoE in blood

activates Lecithin cholesterol acyltransferase to produce cholesterol esters

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6
Q

lipoprotein lipase

A

required for metabolism of chylomicrons and VLDL

induced by insulin and transported to luminal surface of capillary endothelium where it has direct contact with blood

hydrolyzes the fatty acids from triglycerides carried by chylomicrons and VLDL

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7
Q

what receptor does LDL bind to on hepatocytes for its uptake

A

apo B 100 receptor

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8
Q

what does LCAT do

A

lecithin-cholesterol acyltransferase (LCAT)

enzyme in the blood that is activated by apoA-1 on HDL

LCAT adds a fatty acid to cholesterol producing cholesterol esters, which dissolve in the core of HDL allowing HDL to transport cholesterol from periphery to the liver

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9
Q

CETP

A

Cholesterol ester transfer protein

HDL cholesterol esters picked up in the periphery can be distributed to other lipoprotein particles such as VLDL remnants (IDL) converting them to LDL

and CETP facilitates this transfer

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10
Q

Scavenger receptors (SR-B1)

A

this is the receptor through which HDL cholesterol is picked up in the periphery

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11
Q

type I hypertriglyceridemia

A

rare genetic absence of lipoprotein lipase

results in excess triglyceride

chylomicrons are elevated in the blood–> milky trubidity in the serum or plasma

red-orange eruptive xanthomas are seen

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12
Q

type IIa hypercholesterolmia (LDL receptor deficiency)

A

elevated LDL cholesterol and increased risk for atherosclerosis and coronary artery diease

Cholesterol deposits:

  • Xanthomas of the achilles tendon
  • subQ tuberous xanthomas over the elbows
  • Xanthelasma (lipid in the eye)
  • Corneal arcus

homozygotes–> have MI before age 20

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13
Q

abetalipoproteinemia

A

low to absent serum apoB-100 and apo-B48

serum triglycerides may be near zero and cholesterol extremely low

b/c chylomicro levels are low, fat accumulates in intestinal enterocytes and in hepatocytes

essential fatty acids and vitamins A and E are not well absorbed

symptoms include:

  • Steatorrhea
  • Cerebellar ataxia
  • Pigmentary degeneration in the retina
  • Acanthocytes (thorny appering erythrocytes)
  • possible loss of night vision
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14
Q

what does HMG-CoA reductase do?

A

rate limiting enzyme in de novo cholesterol synthesis

its on the smooth endoplasmic reticulum

activated by insulin
inhibited by glucagon

takes HMG-CoA to Mevalonate

competitively inhibited by statins ==> subsequently increases LDL receptor expression

cholesterol represses the expression of HMG-CoA

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15
Q

A teenage girl was brought to the medical center because of her complaints that she used to get too tired when asked to participate in gym classes.
A neurologist found muscle weakness in girl’s arms and legs.
When no obvious diagnosis could be made, biopsies of her muscles were taken for test.

Biochemistry lab results revealed greatly elevated amounts of triglycerides esterified with primary long chain fatty acids.
Pathology reported the presence of significant numbers of lipids vacuoles in the muscle biopsy.

What is the cause for these symptoms?

What is the probable diagnosis?

A

Carnitine deficiency or CPT I/II deficiency

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16
Q

in the glucagon world what is going on with lipid catabolism

A

TGL inside adipose tissue is broken down to glycerol and fatty acids

fatty acids are transferred to the liver and undergo beta oxidation and are made into Acetyl-CoA –> energy

this is lipolysis of triglycerides in response to stress and hypoglycemia

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17
Q

what is beta oxidation

A

oxidation is the process by which fatty acid molecules are broken down in the mitochondria to generate acetyl-coA, which enters the citric acid cycle, and NADH and FADH2, which are used by the electron transport chain to generate ATP

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18
Q

how do short chain, long chain and very long chain FA’s get into the mitochondria

A

Short chain FAs (2-4 C) and Medium chain FAs (6-12 C) diffuse freely into mitochondria to be oxidized

Long chain FAs (14-20 C) activated first then transported into mitochondria by a Carnitine shuttle to be oxidized

Very long chain FAs ( >20C) enter peroxisomes via unknown mechanism for oxidation

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19
Q

long chain FA are activated on the outer mitochondrial membrane and transported across the outer membrane. Then what occurs?

A

FA + CoA by fatty acyl-CoA synthetase

FaCoA turns into FA-carnitine b/c of CPT1 (on the outer membrane)

Fa-carnitine is shuttled inside inner mitochondrial membrane by carnitine transporter

once inside Fa-carnitine is changed back into Fa-CoA by CPT II

Fa-Acyl CoA then undergoes Beta oxidation and forms acetyl coA

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20
Q

what occurs with carnitine deficiency ?

A
  • leads to impaired carnitine shuttle activity
  • decreased LCFA metabolism
  • accumulation of LCFAs in tissues and wasting of acyl-carnitine in urine produces
    cardiomyopathy, skeletal muscle myopathy, encephalopathy and impaired liver function

due to inherited CTP-I or CPT-II deficiency (rare disorders - autosomal recessive inheritance)
impaired carnitine synthesis due to liver disease
disorders of b-oxidation

muscle weakness during prolonged exercise - important characteristic of CPT deficiency b/c muscle relies on FA’s as long term source of energy

medium chain FA’s do not require carnitine to enter mitochdondria and are oxidized normally in these patients

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21
Q

CPT-I deficiency

A

deficiency produces fasting hypoglycemia, inability to use LCFAs as fuel by liver

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22
Q

CPT - II deficiency

A

common, muscle weakness upon exercise, hyperammonemia, death

23
Q

how are CPT-I and CPT II treated?

A

avoiding fasting, dietary restrictions of LCFAs, carnitine supplement

Pharmacological doses of oral carnitine is highly effective in correcting the cardiomyopathy, muscle weakness, and impairment in fasting ketogenesis

Patient must avoid fasting and strenuous exercise

Some patients require supplementation with medium-chain triglycerides and essential fatty acids (e.g., Linoleic acid, Linolenic acid)

Patients with a fatty acid oxidation disorder require a high-carbohydrate, low fat diet

24
Q

clinical manifestations of carnitine and/or CPT I and CPT II deficiency

how do you make the diagnosis?

A 
muscle necrosis
Myoglobinuria
Rhabdomyolysis
Hypoglycemia
fatty liver
muscle aches
Fatigue
cardiomyopathy (age 2-4 yrs, energy deprived muscle cells are damaged)

DIagnosis
Patients have extremely reduced plasma and muscle carnitine
levels (1-2% of normal)
Fasting ketogenesis is normal if carnitine transport is normal.
Fasting ketogenesis is impaired when dietary carnitine intake is interrupted.
Hypoglycemia is a common finding.
Hypoglycemia is precipitated by fasting and strenuous exercise.
Muscle biopsy reveals significant lipid vacuoles.

25
Q

A 24 y/o man complains of “brown urine” and pain in the muscle of his arms and
legs experienced while playing soccer. The pain usually resolved overnight. Physical
examination reveals a well-fed male of normal stature. A muscle biopsy is taken and
sent for specialized testing. The patient is sent home with a recommendation to
take a dietary carnitine supplement.
Which of the following is the most likely diagnosis?

  A. Carnitine deficiency
         B. CPT-I deficiency
         C. CPT-II deficiency
         D. Marfan syndrome
         E. MCAD deficiency
A

Most likely diagnosis is CTP-II deficiency, although this is apparently a mild case.
The patient’s muscle weakness and brown urine are characteristics of this disorder.

CPT-I deficiency would most likely manifest as liver dysfunction.

MCAD usually manifests within the first 3-5 years of life.

The patient’s normal stature is inconsistent with Marfan syndrome, which is characterized by tall stature and very long bones in the extremities.

26
Q

systemic primary carnitine deficiency
symptoms
first suspicion based on?
treatment?

A

also known ascarnitine uptake defect,carnitine transporter deficiency(CTD) orsystemic carnitine deficiencyis an inborn error of fatty acid transport.
Symptoms such as chronic muscle weakness,cardiomyopathy,hypoglycemia and liver dysfunction.
The first suspicion of SPCD in a patient with a non-specific presentation is an extremely low plasma carnitine level
Treatment for SPCD involves high dosecarnitine supplementation, which must be continued for life

27
Q

CPT-I (CAT-1) deficiency

A

is a raremetabolic disorder that prevents the body from converting certain fats called long-chainfatty acids into energy, particularly during periods without food.

Symptoms include low levels ofketones and low blood sugar (hypoglycemia).

People with this disorder typically also have an enlargedliver (hepatomegaly), muscle weakness, and elevated levels of carnitine in the blood.

28
Q

CAT-2 or CPT II deficiency

A

is a metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into themitochondria for utilization as an energy source.

It is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults

brown urine
muscle weakness

Treatment:High-carbohydrate (70%) and low-fat (<20%) diet to provide fuel for glycolysis; use of carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines

29
Q

Two sisters, aged 17 and 19 years, were referred to the dermatologist because they had large number of yellowish spots on the exposed parts of the body.

On thorough examination and after conducting a series of laboratory investigations they were advised to increase physical activity and reduce
the intake of fats.

What is the cause of yellow spots?

How are the medical advices going to help these patients?

A

yellow spots due to hyperlipoproteinemia

30
Q

xanthomas with hyperlipidemia?

A

Xanthomas are lesions characterized by accumulation of lipid-laden macrophages
Xanthomas develops in altered systemic lipid metabolism or as a result of local cell dysfunction
Most of the disorders of hyper-lipidemia (hyper-lipoproteinemia)

31
Q

type I hyperlipidemia

A

familial lipoprotein lipase deficiency

Primary disorder
Deficiency of lipoprotein lipase in tissue leads to hyperlipidemia

Massive accumulation of chylomicrons in plasma

Severe elevation of plasma triglyceride levels

Plasma cholesterol levels are NOT elevated

Manifest in early childhood, with acute pancreatitis

Eruptive xanthomas - characteristic skin manifestation of this disorder

32
Q

type II a hyperlipidemia

A

Accumulation of LDL
Familial LDL receptor deficiency and familial defective apo-B100

Plasma cholesterol levels are elevated

Plasma triglyceride levels are normal

Manifest severe atherosclerosis 
May present with:
      - tendinous xanthomas, or
              - tuberous xanthomas, as well as,
              - xanthelasmas
33
Q

type II b hyperlipidemia

A

Accumulation of both LDL and VLDL
Defective apo-B100 protein
Variable elevations of both triglyceride and cholesterol levels
May present with:
- tendinous xanthomas, or
- tuberous xanthomas, as well as,
- xanthelasmas

34
Q

type III hyperlipidemia

A

Type III hyperlipidemia (familial dysbeta-lipoproteinemia)

Accumulation of IDL
Increase in both triglyceride and cholesterol levels

Various mutations of apo-protein E impairs its ability to bind to IDL receptor

Presents with

- premature atherosclerosis and    - xanthomas (plane xanthomas)
35
Q

type IV hyperlipidemia

A

(familial hypertriglyceridemia)
Over production of VLDL, resulting in extreme elevations of plasma triglyceride levels.**
Plasma cholesterol levels are normal**

May present with
- eruptive xanthomas

  • associated with coronary hear disease, type II diabetes mellitus, obesity, and alcoholism.
36
Q

type V hyperlipidemia

A

(genetic defects of the apo-lipoprotein C–II gene)
Accumulation of chylomicrons and VLDL

Severe elevations of triglyceride levels in plasma

May present in early childhood (similar to type I) with

         - acute pancreatitis
         - eruptive xanthomas
37
Q

decreased synthesis of HDL

A

decreased formation of apo-protein A-I and apo-protein C-III
decreased reversed cholesterol transport

Increased LDL levels
Presents with
- premature coronary artery disease
- plane xanthomas

38
Q

hepatic lipase deficiency

A

Leads to accumulation of large triacylglycerol-rich HDL and VLDL
Presents with
- coronary heart disease
- xanthomas

39
Q

what causes secondary hyper-cholesterolemia

A
  • pregnancy
    - hypothyroidism
    - cholestasis
    - acute intermittent porphyria
40
Q

what causes secondary hyper-triglyceridemia

A
  • diabetes mellitus
    - pancreatitis
    - gout
    - type I glycogen storage disease
    - alcoholism–> because liver cirrhosis can’t metabolize fats in the same way
    - oral contraceptive use
41
Q

combined hyper-cholesterolemia and hyper-triglyceridemia found in …

A

nephrotic syndrome
chronic renal failure
steroid immunosuppressive therapy

42
Q
  • is the most common xanthomas
    - lesions are soft, velvety, yellow, flat,
    around the eyelids
    - associated with hyperlipidemia
    - secondary to cholestasis
A

xanthelasma palpebrarum

43
Q
  • firm, painless, red-yellow nodules
    usually develops in pressure areas,
    extensor surfaces of knees, elbows
    - associated with hypercholesterolemia
    and increased levels of LDL
    - secondary to nephrotic syndrome,
    hypothyroidism
A

tuberous xanthomas

44
Q
  • associated with severe hypercholesterolemia
    and elevated LDL levels.
    • lesions often related to trauma
    • nodules related to tendons or ligaments
    • secondary to cholestasis
A

tendinous xanthomas

45
Q
  • associated with hyper-triglyceridemia
    • erupt as crops of small, red-yellow
      papules, may spontaneously resolve
      over weeks
  • secondary to diabetes
A

eruptive xanthomas

46
Q

associated with dysbetalipoproteinamia

  • can occur in any site
  • covers large areas of face, neck, thorax
  • secondary to cholestasis
A

plane xanthomas

47
Q

A 45 y/o male presented to the ER with chest pain. The chest pain lasted for approx 15 minutes then subsided on its own. He also noticed that he was nauseated and was sweating during the pain episode. He had no medical problems and had not been to a physician for several years.

On examination, he was in no acute distress with normal vital signs. His lungs were clear to auscultation bilaterally, and his heart had a regular rate and rhythm with no murmurs. An electrocardiogram (ECG) revealed slight ischemic changes. The blood biochemistry revealed raised serum total cholesterol and LDL cholesterol levels. He was placed on a low-fat diet and Lovastatin therapy.

He was without complaints and was feeling well on his subsequent follow-up visit. On repeat serum cholesterol screening, a decrease in the cholesterol level was noted.

What is the mechanism of action of this drug?

What are the alternative options to treat this patient?

A

The patient had an episode of IHD (Ischemic heart disease) and had hyperlipidemia
Hyperlipidemia:
- treatable risk factors of coronary heart disease
- when fasting LDL is found elevated, life style modification, diet, exercise,
weight loss
- if LDL level is still elevated, pharmacological therapy is initiated

About half the cholesterol of the body arises by synthesis (~700 mg/dL), rest by diet.
All nucleated cells are capable of cholesterol synthesis, which occurs in ER and cytosol.
HDL is a transporter of cholesterol from peripheral tissues to liver for degradation
HDL-C acts as a scavenger to lower serum cholesterol (good cholesterol)
LDL-C is a transporter of cholesterol from liver to peripheral tissues
Excess LDL is responsible for artherosclerosis and is a risk factor for IHD (bad cholesterol)

48
Q

prlonged elevated levels of VLDL, IDL, or LDL in plasma result in….

A
  • Artherosclerosis – deposition of cholesterol and cholesterol ester from plasma lipoproteins into artery wall
    • Diabetes mellitus, lipid necrosis, hypothyroidism – often accompanied by severe atherosclerosis
49
Q

what do statins do?

A
  • a family of drugs proved efficacious in lowering plasma cholesterol
    - act as competitive inhibitors of the enzyme HMG-CoA reductase
    - these molecules mimic the structure of the normal substrate of the
    enzyme (HMG-CoA) and act as transition state analogues
    - while statins are bound to the enzyme, HMG-CoA cannot be converted
    to mevalonate, thus, inhibiting the whole cholesterol biosynthesis process
50
Q

what does niacin do?

A
  • vit B3 (Niacin or Nicotinic acid) deficiency causes Pellagra
    - vitamin used in high doses to treat hypercholesterolemia
    - inhibits the release of free fatty acids from adipose tissue which leads to
    decrease of free fatty acids entering the liver and decreased VLDL synthesis
    - inhibits VLDL secretion, which in turn decreases LDL production
    - increases HDL plasma levels by unknown mechanism
51
Q

fibrates?

A
  • lowers plasma triacylglycerols by decreasing the secretion of triacylglycerol
    and VLDL by liver
52
Q

Ezetimibe

A
  • reduces blood cholesterol levels by inhibiting the absorption of cholesterol
    by the intestine
    • new class of drugs, belongs to azetidinone class of cholesterol absorption
      inhibitors
53
Q

bile acid sequestrants ?

A

they bind to bile acids in intestine and promote their excretion in stool
- to maintain bile acid pool size, liver diverts cholesterol to bile acid synthesis
- decreased hepatic intracellular cholesterol content results in up regulation
of LDL receptor and enhanced LDL clearance from the plasma.

CV II Exam II (5 decks)

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