Theme 3: Lecture 15 - Lipid metabolism and pathways Flashcards
What are the biological functions of lipids
- Essential components of cell membranes e.g. phospholipids, glycolipids, cholesterol
- Inter- and intra-cellular signalling events e.g. precursor of steroid hormones
- Energy generation and fuel storage i.e. triglycerides
- Metabolism e.g. bile acids
Describe triacylglycerols
- Constitute c. 90% of dietary lipids
- Major form of metabolic energy storage in humans
- Hydrophobic
What are the 2 major metabolic pathways for TG metabolism
- Synthesis of fatty acids from acetyl-CoA (joined to a glycerol molecule for storage)
- TGs broken into free fatty acids and glycerol. Oxidation of fatty acids in the mitochondria to release energy in the form of ATP
What are the 3 stages to achieve complete oxidation of fatty acids to CO2 and H2O
- Removal of glycerol and oxidation of long chain fatty acids to 2-carbon fragments in the form of acetyl-CoA: THIS IS β-OXIDATION
- Oxidation of acetyl-CoA to CO2 in the citric acid cycle
- Transfer of electrons from reduced electron carriers to mitochondrial respiratory chain
What are the 3 steps of beta oxidation
1st step: fatty acids activated by attachment to Coenzyme A (CYTOSOL)
2nd step: transfer of acyl-groups across mitochondrial membrane
3rd step: progressive oxidation of fatty acids by removal of 2-carbon units at a time to form acetyl-CoA which enters the citric acid cycle
What is the rate limiting step of beta oxidation
Step 2 - transfer of acyl groups across mitochondrial membrane
What is formed through each cycle of beta oxidation which shortens the fatty acid chain by 2C
- 1 acetyl-CoA
- 1 FADH2
- 1NADH
How are acyl groups transferred across the mitochondrial membrane
- The acyl group dissociates from CoA on the cytosol side of the mitochondrial membrane
- Carnitine palmitoyl transferase I catalyses binding of the acyl group to Carnitine
- Carnitine carrier protein transfers the acyl group bound to carnitine across the membrane
- The acyl group dissociates from carnitine and recombines with another CoA on the mitochondrial side of the membrane catalysed by carnitine palmitoyl transferase II
Where does fatty acid synthesis occur
Mainly in the liver and adipocytes
Where does fatty acid synthesis occur
in the cytosol
How does acetyl CoA get out of the mitochondria to be used in fatty acid synthesis
Due to the citrate malate cycle
What is the rate limiting step of fatty acid synthesis
Formation of malonyl CoA from acetyl CoA, catalysed by acetyl CoA carboxylase
Describe fatty acid synthesis
-Citrate is converted into Acetyl CoA which is converted into Malonyl CoA
The conversion of acetyl CoA to Malonyl CoA is catalysed by acetyl CoA carboxylase
-Malonyl CoA and acetyl CoA both bind to fatty acid synthase
-A series of condensation reactions involving malonyl CoA adds further C2 units
Describe the citrate malate cycle
- Acetyl CoA combines with oxaloacetate in the mitochondria to make citrate
- This is catalysed by citrate synthase
- Citrate is transported out of the mitochondria into the cytosol via the tricarboxylate transporter
- Citrate is converted back into oxaloacetate and acetyl CoA
- This is catalysed by citrate lyase
- Oxaloacetate is converted into malate
- Malate is converted into pyruvate
- Pyruvate is transported back into the mitochondria via the pyruvate transporter where it can reform oxaloacetate and acetyl CoA
What is cholesterol’s relationship with water
it is amphipathic
What is cholesterol synthesised from
Acetyl CoA
What is cholesterol eliminated as
Bile salts
Which enzymes catalyse formation of cholesterol esters
Cholesterol acyltransferases
What are the roles of cholesterol
- Important lipid component of biological membranes
- Precursor of steroid hormones
- Source of bile acids
What are bile acids
Bile acids are polar derivatives of cholesterol
What are the roles of bile acids
- lipid digestion
- lipid absorption
- cholesterol excretion
Describe cholesterol synthesis
- Acetyl CoA is converted into HMG-CoA
- HMG-CoA is converted into mevalonate which is catalysed by HMG-CoA reductase
- Mevalonate is converted into squalene
- Squalene is converted into cholesterol
What is the target site for statins
HMG-CoA reductase
What is the rate determining step of cholesterol biosynthesis
Conversion of HMG-CoA into mevalonate
What are feedback inhibitors for conversion of HMG-CoA to mevalonate
cholesterol and mevalonate
Why do lipids need to be transported around the body
- Bring dietary lipids to cells for energy production or storage
- Move lipids from storage in adipose tissue for use in energy production
- Provide lipids from the diet to cells for synthesizing cell membranes
- Carry cholesterol from peripheral tissues to the liver for excretion
How are short chain fatty acids transported in the blood
bound to blood proteins like albumin
How are the bulk of neural lipids which are insoluble in water transported in the blood
Via lipoproteins
Describe the structure of lipoproteins
- Lipoproteins are composed of hydrophobic, hydrophilic and amphipathic molecules
- Lipids are carried in the central core
- The outer layer of amphipathic phospholipids contains cholesterol and apolipoproteins
All classes of lipoproteins contain apolipoprotein E apart from
LDL
What apolipoprotein does LDL contain
B-100
Which lipoprotein carries the greatest amount of protein
LDL
Where do chylomicrons transport lipids
deliver dietary TGs to muscle and adipose tissue + dietary cholesterol to the liver
Where does VLDL transport lipids
transport endogenous TGs and cholesterol
Where does LDL transports lipids
Transport cholesterol from liver to tissues
Where does HDL transport lipids
Transport cholesterol from tissues to liver i.e. remove cholesterol from tissues (reverse cholesterol transport)
What are the major steps in digestion of dietary TGs
- TGs need to be first emulsified by bile acids
- TGs are then hydrolysed by the enzyme pancreatic triacylglycerol lipase
What enzyme allows release of TG at tissues
Lipoprotein lipase
Chylomicrons and VLDL particles give up lipid (TG) to tissues by the action of what
tissue bound lipases
How does the liver recognise remnants of chylomicron and VLDL particles
By their apolipoprotein E content
What does the liver do to remnants of chylomicron and VLDL particles
Takes them up for recycling
How are LDL particles that contain apolipoprotein B-100 recognised by cells
By cell surface LDL receptors (LDLRs)
Describe how LDL receptors are regulated
-Expression of LDL receptors increased
by SREBPs in response to low cholesterol. SREBPs are transcription factors
-The LDL receptor is then recycled back into the membrane
-PCSK9 binds to LDL receptor and results in it’s degradation so the LDL receptor is not recycled back into the membrane
-This reduces the amount of cholesterol taken into the cell meaning that there in more in the blood
-PCSK9 = proprotein convertase subtilisin/kexin type 9
What does uptake of cholesterol into the cell result in
Decrease in cholesterol and LDL receptor synthesis
