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BIOCHEMISTRY III > LECTURE 6 (Lipid metabolism) > Flashcards

LECTURE 6 (Lipid metabolism) Flashcards

1
Q

What are the properties of Ketone bodies?

A
  • Alternative fuel for some cells
  • During fasting/starvation fatty acids are sent to liver -> converted into ACETYL-COA via B-OXIDATION
  • High levels of acetyl-CoA exceeds capacity of TCA cycle -> ACETYL-COA shunted towards ketone bodies
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2
Q

What causes high levels of Acetyl-CoA?

A
  • Decreased pyruvate dehydrogenase activity
  • B-oxidation of fatty acids
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3
Q

Where does Ketogenesis occur?

A
  • Liver hepatocytes (mostly)
  • Kidney epithelia
  • Astrocytes
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4
Q

Describe the importance of Ketones in the brain

A

Brain utilises ketone bodies during fasting to reduce reliance on glucose -> Brain is entirely dependent on glucose since FATTY ACIDS cannot penetrate through BLOOD-BRAIN BARRIER -> has to use ketone bodies instead of glucose during fasting -> Ketone bodies allow use of fatty acids energy by brain

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5
Q

What is the pathway from fatty acids to the its use in the brain?

A

Fatty acids -> Liver -> Ketone bodies -> Brain -> Acetyl-CoA

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6
Q

Why are Ketone bodies used by other tissues during a state of fasting?

A

To reserve glucose for brain

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7
Q

What are the properties of Acetone?

A
  • Not used as fuel
  • Excreted by lungs
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8
Q

What happens when Fatty acid levels are high during fasting?

A

Increased synthesis of ketone bodies

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9
Q

Can the liver use ketone bodies? (YES/NO)

A

NO

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10
Q

What is Ketolysis?

A

The process by which HYDROXYBUTYRATE and ACETOACETATE are converted into ATP

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11
Q

What happens in Ketoacidosis?

A

Ketone bodies release H+ at plasma pH -> Increase ketones in blood -> Metabolic acidosis

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12
Q

What is the link between diabetes and increased Ketone bodies production?

A
  • Low insulin -> High fatty acid utilisation -> Increased acetyl-CoA levels -> Ketone bodies production
  • OAA (Oxaloacetate) îs depleted (used for glucose production) -> TCA cycle stalls -> Increased Acetyl-CoA levels increase -> Ketone bodies production
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13
Q

How does Alcoholism lead to Ketoacidosis?

A
  • Alcohol metabolism -> excess NADH -> OAA shunted to malate -> TCA cycle stops -> Increased acetyl-CoA -> Ketone production
  • OAA depleted -> not enough for gluconeogenesis -> Hypoglycaemia
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14
Q

What is the clinical correlation of Ketoacidosis caused by Alcoholism?

A

Urinary ketones

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15
Q

In which stage of Cholesterol synthesis are Statins introduced?

A

In the conversion of HMG-COA (6C) to MEVALONATE (6C)

Explanation: It inhibits HMG-CoA reductase

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16
Q

What are the different types of Lipoproteins?

A
  • Chylomicrons
  • Very low-density lipoproteins (VLDL)
  • Intermediate-density lipoproteins (IDL)
  • Low-density lipoproteins (LDL)
  • High-density lipoproteins (HDL)
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17
Q

What are Apolipoproteins?

A
  • Proteins in lipoproteins that bind lipids
  • FUNCTION: surface receptors & co-factors for enzymes
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18
Q

How are Chylomicrons formed?

A
  • Fatty acids -> converted into TRIGLYCERIDES
  • Cholesterol converted into CHOLESTERYL ESTER by ACAT (Cholesterol Acyltransferase)
  • Triglycerides and Cholesteryl esters are packaged into CHYLOMICRONS by intestinal cells -> To lymph -> To bloodstream
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19
Q

What is found in Chylomicrons?

A
  • Triglycerides
  • Cholesteryl esters
  • Vitamins A, D, E & K
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20
Q

What happens once chylomicrons begin to circulate in the bloodstream?

A

They encounter the extracellular enzyme LIPOPROTEIN LIPASE (anchored to capillary walls)

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21
Q

What are the properties of Lipoprotein lipase?

A
  • Located mostly in adipose tissue, muscle and heart
    [not liver - liver has hepatic lipase]
  • Converts triglycerides into fatty acids & glycerol -> fatty acids are used for storage or fuel
  • Required APO C-II for activation (carried on chylomicrons)
22
Q

Describe Lipid transport

A

1) Chylomicron enters lymphatics
2) HDL transfers APO CII and APO E and Chylomicron APO CII activated LIPOPROTEIN LIPASE
[Impaired in type I familia dyslipidemia]
3) Liver releases VLDL
[overproduction in type IV familial dyslipidemia]
4) VLDL APO CII activated LIPOPROTEIN LIPASE
5) IDL delivers TaGs and cholesterol to liver via APO E
6) Endocytosis of LDL
[impaired in type II familial dyslipidemia]

23
Q

What are Lipoproteins composed of?

A
  • Cholesterol
  • Triglycerides
  • Phospholipids
  • LDL & HDL (carry the most cholesterol)
24
Q

What is the function of Chylomicrons?

A
  • Delivers dietary triglycerides to peripheral tissues
  • Delivers cholesterol to liver in the form of chylomicron remnants

SYNTHESIS: Secreted by intestinal epithelial cells

25
Q

What is the function of cholesterol?

A
  • Maintains cell membrane integrity
  • Synthesises bile acids, steroid and vitamin D
26
Q

What is the function of VLDL?

A

Delivers hepatic triglycerides to peripheral

SYNTHESIS: secreted by liver

27
Q

What is the function of IDL?

A

Delivers triglycerides and cholesterol to liver

SYNTHESIS: formed from degradation of VLDL

28
Q

What is the function of LDL?

A
  • Delivers hepatic cholesterol to peripheral tissues
  • Formed by hepatic lipase modification of IDL in liver and peripheral tissue
  • Taken up by target cells via receptor-mediated endocytosis
29
Q

What is the function of HDL?

A
  • Mediates reverse cholesterol transport from peripheral tissues to liver
  • Acts as a repository for apolipoproteins C and E
30
Q

What is Atherosclerosis?

A

A form of arteriosclerosis caused by buildup of cholesterol plaques in intima

LOCATION:
- abdominal aorta
- coronary artery
- popliteal artery
- carotid artery
- circle of willis

RISK FACTORS:
- hypertension
- smoking
- dyslipidemia
- diabetes
- age
- being male
- postmenopausal status
- family history

PROGRESSION:
Endothelial cell dysfunction -> macrophage and LDL accumulation -> foam cell formation -> fatty streaks -> fibrous plaque -> calcification

31
Q

What are the properties of Hyperlipidemia?

A
  • Elevated total cholesterol, LDL or triglycerides
  • Risk factor for coronary disease and stroke
  • A modifiable risk factor (related to lifestyle factors)
32
Q

What are the signs of Hyperlipidemia?

A

Most patients have no signs/symptoms

However, those with severe hyperlipidemia have:
- XANTHOMAS = plaques of lipid-laden macrophages. Appear as skin bumps or on eyelids.
- TENDINOUS XANTHOMA = lipid deposits on tendons (common in Achilles)
- CORNEAL ARCUS = lipid deposit in cornea

33
Q

What are the properties of Pancreatitis?

A
  • Occurs when triglycerides are elevated
  • Exact mechanism is unclear
  • May involve increase chylomicrons in plasma
34
Q

What is the mechanism behind Pancreatitis?

A

When triglycerides are too high, they may obstruct capillaries -> ischemia -> vessel damage can expose triglycerides to pancreatic lipases -> triglycerides breakdown and release free fatty acids -> acid leads to tissue injury and pancreatitis

35
Q

Describe Type I Familial Hypercholesterolemia Hyperchylomicronemia

A

Autosomal recessive

CAUSES:
- Lipoprotein lipase deficiency
[degrades triglycerides in circulating microns]
- ApoC-II deficiency
[Cofactor of LPL}
= increased levels of chylomicrons and triglycerides

SYMPTOMS:
- Recurrent pancreatitis
- Hepatosplenomegaly
- Eruptive/pruritic xanthomas
- Creamy layer in supernatant

TREATMENT:
- very low-fat diet

36
Q

Describe Type II Familial Hypercholesterolemia Familial Dyslipidemia

A

Autosomal dominant

CAUSES:
- Absent or defective LDL receptors
[LDL delivers hepatic cholesterol to peripheral tissues]
- Defective ApoB-100
[B-100 binds LDL receptor]
= Very high LDL

SYMPTOMS:
- Accelerated atherosclerosis (may have MI before 20)
- Tendon (Achilles) xanthomas
- Corneal arcus

37
Q

Describe Type III Familial Hypercholesterolemia Familial Dysbetalipoproteinemia

A

Autosomal recessive

CAUSES:
- Defective ApoE
[Mediates remnant uptake]
= accumulation of chylomicron remnants and VLDL

SYMPTOMS:
- Premature atherosclerosis
- Tuberoeruptive and palmar xanthomas

38
Q

What is the difference between the ApoE2 and ApoE4 allele subtype?

A

ApoE2 allele = decreased risk of Alzheimer’s

ApoE4 allele = increased risk of Alzheimer’s

39
Q

Describe Type IV Familial Hypercholesterolemia Familial Hypertriglyceridemia

A

Autosomal dominant

CAUSES:
- Hepatic overproduction of VLDL or impaired catabolism
= increased VLDL and triglycerides

SYMPTOMS:
- Hypertriglyceridemia -> can cause acute pancreatitis
- Related to insulin resistance

40
Q

Describe Abetalipoproteinemia

A

Autosomal recessive

CAUSES:
Mutation in a gene that encodes MICROSOMAL TRANSFER PROTEIN (MTP). MTO forms/secretes lipoproteins with ApoB (chylomicrons from intestine (ApoB-48) & VLDL from liver (B-100) -> Chylomicrons, VLDL and LDL present -> Very low triglycerides and total cholesterol levels

DEFICIENCY:
- ApoB-48
- ApoB-100

SYMPTOMS IN INFANTS:
- Severe fat malabsorption
- Steatorrhea
- Failure to thrive

LATER SYMPTOMS:
- Retinis pigmentosa (Vitamin A deficient)
- Spinocerebellar degeneration due to Vitamin E deficiency
- Progressive Ataxia
- Acanthocytosis (Abnormal RBC membrane lipids)

DIAGNOSIS:
- Intestinal biopsy: lipid-laden enterocytes

TREATMENT:
- Restriction of long-chain fatty acids
- Large doses of oral vitamin E

41
Q

What is the difference between Apo B48, Apo C-II & Apo E?

A

Apo B48
- contains 48% of apo-B protein
- required for secretion from enterocytes

Apo C-II
- cofactor for lipoprotein lipase
- carried by chylomicrons, VLDL/IDL

Apo E
- binds to liver receptors
- required for uptake of remnants after chylomicrons have done their job

42
Q

What are the properties of Chylomicron remnants?

A
  • Have Apo-E receptors on liver -> take up remnants via receptor-mediated endocytosis
  • Usually only present after meals
  • Give plasma milky appearance
43
Q

Summarise the function of Chylomicrons

A

1) Secreted from enterocytes with Apo B48
2) Pick up Apo C-II & Apo E from HDL
3) Carry triglycerides & Cholesteryl esters
4) Deliver triglycerides to cells and LIPOPROTEIN LIPASE (w/ co-factor Apo C-II) stimulates breakdown
5) Returns to liver as Chylomicron remnants (Apo E receptor on liver)

44
Q

What are the 2 main lipoproteins secreted by the liver to deliver cholesterol & triglycerides to tissues?

A

VLDL & HDL

45
Q

What are the properties of HDL?

A
  • Bring cholesterol from periphery to liver
  • High HDL -> associated with decreased risk of cardiovascular events
  • KEY APOLIPOPROTEINS = A-I, C-II & APO E
  • Carries LECITHIN-CHOLESTEROL ACYL TRANSFERASE (LCAT) which esterifies esters + packs esters densely in core (activated by A-I)
  • Carries CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) which takes triglycerides from VLDL and gives it more densely packed esters in return
46
Q

What are the properties of VLDL?

A
  • Carries triglycerides & cholesterol to tissues
  • Secreted by liver as nascent VLDL (only B-100) -> pick up C-II & Apo E from HDL -> LPL removes triglycerides + CETP in HDL removes triglycerides from VLDL -> VLDL is now IDL
47
Q

What are the properties of IDL?

A
  • Formed from VLDL
  • HEPATIC LIPASE removes triglycerides
  • HDL removes C-II and Apo E -> End result: LDL with only B-100 -> Less triglyceride content & greater cholesterol
48
Q

What are the properties of Hepatic Lipase?

A
  • Found in liver capillaries
  • Release fatty acids
  • Very important for IDL to LDL conversion
49
Q

What are the properties of LDL?

A
  • Contains small amount of triglycerides & high concentration of cholesterol/cholesteryl esters
  • Transfers cholesterol to cells with LDL receptor -> receptor-mediated endocytosis
  • LDL receptors recognise B100
  • High LDL -> increased risk of cardiovascular disease
50
Q

What are Foam cells?

A
  • Macrophages filled with cholesterol
  • Found in atherosclerotic plaques in patients with vascular disease
  • Contain LDL receptors and can consume LDL particles
51
Q
A

BIOCHEMISTRY III (12 decks)

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