LECTURE 6 (Lipid metabolism) Flashcards
What are the properties of Ketone bodies?
- 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
What causes high levels of Acetyl-CoA?
- Decreased pyruvate dehydrogenase activity
- B-oxidation of fatty acids
Where does Ketogenesis occur?
- Liver hepatocytes (mostly)
- Kidney epithelia
- Astrocytes
Describe the importance of Ketones in the brain
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
What is the pathway from fatty acids to the its use in the brain?
Fatty acids -> Liver -> Ketone bodies -> Brain -> Acetyl-CoA
Why are Ketone bodies used by other tissues during a state of fasting?
To reserve glucose for brain
What are the properties of Acetone?
- Not used as fuel
- Excreted by lungs
What happens when Fatty acid levels are high during fasting?
Increased synthesis of ketone bodies
Can the liver use ketone bodies? (YES/NO)
NO
What is Ketolysis?
The process by which HYDROXYBUTYRATE and ACETOACETATE are converted into ATP
What happens in Ketoacidosis?
Ketone bodies release H+ at plasma pH -> Increase ketones in blood -> Metabolic acidosis
What is the link between diabetes and increased Ketone bodies production?
- 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
How does Alcoholism lead to Ketoacidosis?
- Alcohol metabolism -> excess NADH -> OAA shunted to malate -> TCA cycle stops -> Increased acetyl-CoA -> Ketone production
- OAA depleted -> not enough for gluconeogenesis -> Hypoglycaemia
What is the clinical correlation of Ketoacidosis caused by Alcoholism?
Urinary ketones
In which stage of Cholesterol synthesis are Statins introduced?
In the conversion of HMG-COA (6C) to MEVALONATE (6C)
Explanation: It inhibits HMG-CoA reductase
What are the different types of Lipoproteins?
- Chylomicrons
- Very low-density lipoproteins (VLDL)
- Intermediate-density lipoproteins (IDL)
- Low-density lipoproteins (LDL)
- High-density lipoproteins (HDL)
What are Apolipoproteins?
- Proteins in lipoproteins that bind lipids
- FUNCTION: surface receptors & co-factors for enzymes
How are Chylomicrons formed?
- 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
What is found in Chylomicrons?
- Triglycerides
- Cholesteryl esters
- Vitamins A, D, E & K
What happens once chylomicrons begin to circulate in the bloodstream?
They encounter the extracellular enzyme LIPOPROTEIN LIPASE (anchored to capillary walls)
What are the properties of Lipoprotein lipase?
- 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)
Describe Lipid transport
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]
What are Lipoproteins composed of?
- Cholesterol
- Triglycerides
- Phospholipids
- LDL & HDL (carry the most cholesterol)
What is the function of Chylomicrons?
- Delivers dietary triglycerides to peripheral tissues
- Delivers cholesterol to liver in the form of chylomicron remnants
SYNTHESIS: Secreted by intestinal epithelial cells
What is the function of cholesterol?
- Maintains cell membrane integrity
- Synthesises bile acids, steroid and vitamin D
What is the function of VLDL?
Delivers hepatic triglycerides to peripheral
SYNTHESIS: secreted by liver
What is the function of IDL?
Delivers triglycerides and cholesterol to liver
SYNTHESIS: formed from degradation of VLDL
What is the function of LDL?
- 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
What is the function of HDL?
- Mediates reverse cholesterol transport from peripheral tissues to liver
- Acts as a repository for apolipoproteins C and E
What is Atherosclerosis?
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
What are the properties of Hyperlipidemia?
- Elevated total cholesterol, LDL or triglycerides
- Risk factor for coronary disease and stroke
- A modifiable risk factor (related to lifestyle factors)
What are the signs of Hyperlipidemia?
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
What are the properties of Pancreatitis?
- Occurs when triglycerides are elevated
- Exact mechanism is unclear
- May involve increase chylomicrons in plasma
What is the mechanism behind Pancreatitis?
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
Describe Type I Familial Hypercholesterolemia Hyperchylomicronemia
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
Describe Type II Familial Hypercholesterolemia Familial Dyslipidemia
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
Describe Type III Familial Hypercholesterolemia Familial Dysbetalipoproteinemia
Autosomal recessive
CAUSES:
- Defective ApoE
[Mediates remnant uptake]
= accumulation of chylomicron remnants and VLDL
SYMPTOMS:
- Premature atherosclerosis
- Tuberoeruptive and palmar xanthomas
What is the difference between the ApoE2 and ApoE4 allele subtype?
ApoE2 allele = decreased risk of Alzheimer’s
ApoE4 allele = increased risk of Alzheimer’s
Describe Type IV Familial Hypercholesterolemia Familial Hypertriglyceridemia
Autosomal dominant
CAUSES:
- Hepatic overproduction of VLDL or impaired catabolism
= increased VLDL and triglycerides
SYMPTOMS:
- Hypertriglyceridemia -> can cause acute pancreatitis
- Related to insulin resistance
Describe Abetalipoproteinemia
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
What is the difference between Apo B48, Apo C-II & Apo E?
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
What are the properties of Chylomicron remnants?
- Have Apo-E receptors on liver -> take up remnants via receptor-mediated endocytosis
- Usually only present after meals
- Give plasma milky appearance
Summarise the function of Chylomicrons
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)
What are the 2 main lipoproteins secreted by the liver to deliver cholesterol & triglycerides to tissues?
VLDL & HDL
What are the properties of HDL?
- 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
What are the properties of VLDL?
- 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
What are the properties of IDL?
- 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
What are the properties of Hepatic Lipase?
- Found in liver capillaries
- Release fatty acids
- Very important for IDL to LDL conversion
What are the properties of LDL?
- 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
What are Foam cells?
- Macrophages filled with cholesterol
- Found in atherosclerotic plaques in patients with vascular disease
- Contain LDL receptors and can consume LDL particles
