cell metabolism 2 Flashcards
What are the 5 classes of lipids?
Free fatty acids
Triglycerides
Phospholipids
Glycolipids
Steroids
Where are fatty acids stored?
Cytoplasm
Often as triglycerides
What are triglycerides?
Molecules made up of 3 fatty acids attached to a glycerol molecule
Attached via ester linkages
What do ester linkages do?
Help neutralise carboxylic acid groups
What are fats broken down into?
Fatty acids and glycerol
What is Acetyl CoA produced from?
Both types of major food molecules within mitochondria (fats and sugars + polysaccharides).
Mitochondria is where most of cellular oxidation reactions occur and where majority of cellular ATP is made
Where is fat derived from?
Diet
De novo biosynthesis (liver)
Storage deposits in adipose
Where are bile salts made and stored?
Made in liver
Stored in gall bladder
During digestion they pass from bile duct into intestine
Whats the role of bile salts?
Emulsify fats in intestine aiding their digestion and absorption
What are the fat soluble vitamins?
A, D, E, K
What does a lack of bile salts lead to?
Undigested and unabsorbed fats and steatorrhea (fatty stool)
What is Olistat?
Tetrahydrolipstatin
A potent inhibitor of gastric and pancreatic lipases
Chemically synthesised derivative of lipostatin (a product of streptomycin toxytrini)
Orlistat reduces fat absorption by 30% which is almost complexity excreted in faeces
Trials show it can treat obesity for up to 2 years
What are the main side effects of olistat?
Abdominal pain, urgency to defecate, increased flatus, steatorrhea
Where are lipids transferred to and how?
Transferred to the plasma by lipoproteins
What are the 5 types of lipoproteins and what are their sources?
- Chylomicrons (CM): intestines
- Very low density lipoproteins (VLDL): liver
- Intermediate density lipoproteins (IDL): VLDL
- Low density lipoproteins (LDL): IDL
- High density lipoproteins (HDL): Liver
What the role of the different lipoproteins?
CM: Dietary fat transporters
VLDL: Endogenous fat transport
IDL: LDL precursor
LDL: Cholesterol transport
HDL: Reverse cholesterol transport
How are chylomicrons made?
Digested dietary products are absorbed by enterocytes that line the brush border of small intestine
Triglycerides are resynthesised and are incorporated into chylomicrons
How are chylomicrons transported?
Transported via lymphatics and into bloodstream
They acquired apoproteins from HDL following release into bloodstream
How do chylomicrons enter the bloodstream?
They travel from lacteals of intestine to the thoracic duct to the left subclavian vein where they enter blood stream
Where is lipoprotein lipase located?
Capillary endothelial cells lining variety of tissues including adipose, heart and skeletal muscle
What reaction do fatty acids undergo?
B oxidation
Glycerol is returned to liver to be used in gluconeogenesis
What is the role of apoprotein?
Chylomicrons pick up apoproteins from HDL
These can be recognised by lipoprotein lipases on the surface of adipose and skeletal muscle
What do lipoprotein lipases do?
Breakdown triglycerides into fatty acids and glycerol Chylomicron remnants can pick up more apoproteins from HDL- allows them to be recognised by the liver
What is so important about lipoproteins?
Transport hydrophobic molecules in an aqueous environment
How is a lipoprotein structured?
Has a monolayer containing cholesterol and apoproteins
This surrounds a core of cholesterol esters and triglycerides
What are cholesterol esters?
Synthesised in plasma from cholesterol and acyl chain of phosphatidylcholine (lecithin) via a reaction catalysed by lecithin:cholesterol acyltransferase (LCAT)
What happens when apoprotein transfers onto HDL?
Formation of intermediate density lipoprotein
How is LDL formed?
HDL can transfer cholesterol esters to IDL to make LDL
What are LDLs taken up by?
Tissues with receptors for it
Macrophages
Liver
What are HDLs?
Often called ‘good cholesterol’
Take cholesterol from peripheral tissues back to liver for use or disposal
Help lower total cholesterol
What are LDLs?
Often called ‘bad cholesterols’
Prolonged elevation of LDL levels leads to atherosclerosis L
DLs transport cholesterol from liver to peripheral tissues (more than 40% of their weight is cholesterol esters)
Whats the importance of fatty acid metabolism?
More than half of the body’s energy comes from fatty acid oxidation
This process is known as beta oxidation and results on formation of acetyl CoA
What happens in the beta oxidation of fatty acids?
Fatty acid + ATP + HS-CoA (coenzyme A) -> Acetyl CoA + AMP + PPi Enzyme: Acetyl CoA synthase
What is the carnitine shuttle?
Generation of acyl CoA species occurs in outer mitochondrial membrane
To transport the species into the matrix its coupled to the molecule carnitine to from acyl carnitine. acyl carnitine and carnitine are moved to and from the matrix by translocase
What is primary carnitine deficiency?
Autosomal recessive Symptoms occur during infancy or early childhood
Symptoms include encephalopathies (cardiomyopathies, muscle weakness and hypoglycaemia)
Mutation in SLC22A5 which encodes a carnitine transporter results in reduced ability of cells to take up carnitine needed for beta oxidation of fatty acids
What happens to acyl CoA in the beta oxidation cycle?
Undergoes oxidation, hydration, oxidation and thiolysis reactions
This results in production of 1 molecule of acetyl CoA and an acyl CoA species which is 2 carbons shorter than original (fatty acyl CoA)
What occurs during the cycles of beta oxidation?
2 carbon units are consecutively removed from acyl CoA making acetyl CoA
On the final cycle, 2 acetyl CoA molecules are made In 7 cycles, 8 molecules of acetyl CoA are made
This acetyl CoA is made from a 16 carbon palmitoyl CoA molecule (B-oxidation of palmitoyl CoA)
How are ketone bodies made?
Acetyl CoA made from beta oxidation enters TCA cycle only if B-oxidation and carbohydrate metabolism are balanced since oxaloacetate is needed for entry
When fat breakdown predominates, acetyl CoA forms acetoacetate, D-3-hydroxybutyrate and acetone. This is collectively known as ketone bodies
What enzymes does fatty acid biosynthesis include?
Acetyl CoA carboxylase
Fatty acid synthase
How are fatty acids formed?
Formed by decarboxylative condensation reactions involving acetyl- CoA and malonyl CoA
After each round of elongation, the fatty acid undergoes reduction and dehydration by action of ketoreductase, dehydratase and enol reductase activity
Growing fatty acid is linked to acetyl carrier protein (ACP)
What does fatty acid synthesis involve? (carrier, reducing power, location)
Carrier: ACP
Reducing power: NADPH
Location: cytoplasm
What does fatty acid degradation involve? (carrier, reducing power, location)
Carrier: CoA
Reducing power: FAD/NAD+
Location: mitochondrial matrix
What is the overall reaction for lipogenesis?
What happens when a fatty acid longer than 16 carbons is made?
Elongation of acyl group to make fatty acids longer than 16 carbons occurs seperately from palmitate syntheisis in the mitochondria and ER
What does desaturation of fatty acids require?
Fatty acyl- CoA desaturases
What enzyme makes oleic acid and palmitoleic acid from stearate and palmitate and what does it do?
delta- 9 desaturase
Generates a double bond nine carbons from the terminal carboxyl group
Where does de novo FA biosynthesis occur in adults?
Liver, adipose tissue and lactating breast
How does de novo biosynthesis differ in cancer?
Can happen in cancer cells where it shouldn’t
Can we target FA synthetase in cancer?
Inhibition of FASN by cerulenin (antifungal antibiotic) can reduce tumour growth of ovarian cancer cells
What catalyses the initial step in each cycle of fatty acid B-oxidation?
A family of different acyl- CoA- dehydrogenases
Each one can bind too fatty acid chain of varying length:
What is medium chain acyl-coenzyme A dehydrogenase deficiency (MCADD)?
Autosomal recessive
Can be fatal if undiagnosed
If diagnosed pateints should never go without food for longer than 10-12 hours- should have a high carbon diet
Patints suffering illness or appetite loss or sever vomiting may need i.v. glucose
