Lipid disorders and metabolism Flashcards
What are the dietary lipids
Triglycerides
Cholesterol
Phospholipids
Describe the sturcture of triglicerides
3 FA chains attached to a glycerol backbone by an ester bond
What are the sources for maintaining plasma TAG/FFA
> FA synthesis
Dietary lipids
TAG in adipose tissue
What processes do plasma TAG/FFA contribute to?
> Production of ketone bodies
beta-oxidation (ATP production)
Phospholipid synthesis for membranes
Stored as TAG in adipose tissue
Where are lipids digested?
Lipid digestion occurs in the small intestine
What enzymes are required for lipid digestion?
Pancreatic lipase and colipase
What is the clinical importance of enzymes used in lipid digestion?
Lipase is a target for orlistat
Orlistat acts as a lipase inhibitor, preventing fat absorption and limits calorie intake
What is the emulsifying agent required in lipid digestion?
Bile salts
Where are bile salts secreted?
Through the bile duct by the liver
What are bile salts synthesised from?
Cholesterol
What is the function of bile salts?
To emulsify fats into micelles
Increase surface area for the enzymes to work on, increasing efficiency of digestion
What are bile acids conjugated form?
Taurine/glycine
How are lipids absorbed?
As chylomicrons transported to liver, adipose tissue removed the lipid component (FA stored as TAG) leaving cholesterol-rich chylomicron remnant
When will there be more chylomicrons?
post-prandial period for absorption of dietary lipids
When will there be fewer chylomicrons
During fasting state
How is TAG transported?
In lipoproteins
How is FFA transported?
Albumin-bound
What is the purpose of lipoproteins?
To transport lipids safely
- prevents loose fatty acids acting as detergents in the circulation
What is NEFA?
Nonesterified fatty acids
Why are NEFA transported in chylomicrons?
Need to be transported in chylomicrons as they are dangerous - could break down cell walls
What is beta oxidation?
The generation of energy from fatty acids
Where does beta oxidation occur?
Within the mitochondrion
What is the function of CoA in fatty acyl-CoA
Addition of CoA to form fatty acyl-CoA
- Traps FFA within the cell (same principle as G6P)
CoA makes FFA soluble and removes the danger of detergent action
How does fatty acyl-CoA cross the inner mitochondrial membrane?
Requires carrier molecule carnitine, as mitochondrion unable to transport fatty acyl-CoA
Where can you find a high carnitine content?
In the muscle
How does carnitine transport fatty acyl-CoA across the inner mitochondrial membrane?
Carnitine palmitoyl transferase (CPT) as catalysts
Carnitine swaps with CoA to form FA carnitine + CoA via CPT 1
This is swapped back via CPT 2
What happens to fatty acyl-CoA in beta-oxidation?
Fatty acyl-CoA are degraded by oxidation at the b-carbon
Process occurs in rounds reducing chain by 2 carbons each time
2 carbons removed and used to make acetyl CoA
What are the products of beta oxidation?
Each turn produces 1 FADH2, NADH and acetly CoA (2 carbons)
How is ATP produced as a result of beta-oxidation?
Acetyl CoA if further oxidised to yield ATP - TCA/oxidative phosphorylation
What is the benefit of using beta-oxidation?
High yield of ATP
- C16 yields 106 ATP vs 36 for glucose
Fatty acids excellent source of ATP
Fatty acids can be stored densely
ATP also available from glycerol backbone
How are triglycerides synthesised?
Through the esterification of 3 fatty acids and glycerol
What are the main enzymes involved in triglyceride synthesis?
> Lipoprotein lipase
> Diacylglycerol Acyl Transferase
What is the role of Lipoprotein lipase?
Hydrolyses circulating TAG in chylomicrons/VLDL
Extracellular enzyme
What is the role of Diacylglycerol Acyl Transferase?
Re-esterifies FFA and glycerol to TAG
Intracellular enzyme
How is glycerol obtained?
From glycolysis - DHAP
Normally synthesised from glucose rather than breakdown of TAG
What is lipolysis?
The breakdown of triglyceride into glycerol and 3 fatty acids
What enzyme has an important role in lipolysis?
Hormone sensitive lipase in adipose tissue
What are the regulatory measures for hormone-sensitive lipase?
Activated by cAMP-dependent phosphorylation in response to adrenaline in fasted state
Inhibited by insulin by stimulating cAMP breakdown
Describe lipolysis
Adipose tissue is highly innervated with noradrenergic nerves (release NA)
In fasting -> release NA, raising intracellular cAMP and causing activation of PKA -> phosphorylates and activates HSL to stimulate lipolysis
When does lipolysis occur?
In the fasted state
What happens to the products of lipolysis?
FFA are delivered to the liver for gluconeogenesis?
What tissue type like FFA as a fuel?
Muscle, particularly red fibres
How are fatty acids synthesised?
From glucose
Built 2C at a time (max 16C)
What are the regulatory enzymes in fatty acid synthesis?
Acetyl CoA carboxylase (ACC)
Fatty acid synthase
What is the role of Acetyl CoA carboxylase (ACC)?
Forms malonyl CoA (3C structure)
Malonyl CoA also inhibits FA oxidation -> prevents FA oxidation while FA are being synthesised, as this would waste energy
Reciprocal regulation
How is Malonyl CoA formed?
By Acetyl CoA carboxylase (ACC)
Uses biotin (vitamin b7) deficiences are rare, but will cause disregulation of lipid metabolism
How does Malonyl CoA inhibit FA oxidation?
> Acetyl CoA is coupled to malonyl CoA
- uses energy that would otherwise produce ATP
> 7 consecutive steps by multifunctional enzyme
- Fatty acid synthase
> Requires NADPH (pentose phosphate pathway)
> Occurs in cytoplasm
Why are ketones produced?
Ketone formation is an “overflow” pathway for acetyl CoA use if there is not enough oxaloacetate for acetyl CoA to enter krebs
What dietary condition leads to ketone formation?
Diets with very low carbohydrate content
What are ketone bodies?
3 water soluble molecules produced by the liver from fatty acids
> Acteoacetate
beta hydroxybutyrate
Acetone
How are ketone bodies formed?
Acetyl CoA + Acetyl CoA => acetoacetyl CoA
acetoacetyl CoA - CoA => Acetoacetate
Acetoacetate can be converted to acetone and beta hydroxybutrate
What tissues use ketone bodies as an energy source?
The brain
The heart
How are phospholipids synthesised?
Same as beginning steps of triglyceride synthesis to form DAG, which is then combined with an alcohol
From this you get different phospholipids
What are the different phospholipids formed?
Phosphatidylethanolamine Phosphatidylserine Phosphatidylglycerol Phosphatidylinositol Phosphatidylcholine
Which cells have high levels of phospholipid synthesis?
Rapidly-dividing cells as they have to make lots of membranes
NB - potential target for new cancer drugs?
What are essential fatty acids?
Fatty acids that cannot be synthesised
Obtained from the diet (originally classed as vitamin F)
Polyunsaturated w-3 or w-4
(depends on location of double c-c bond on fatty acyl chain)
What are the functions of essential fatty acids?
Cell membrane formation
Required for proper growth and development
Required for brain and nerve function
Precursors for eicosanoids - prostanoids & leukotrienes - in inflammatory response
What is the link between w-3 fatty acids and CVD?
some evidence for protection against hear and circulatory disease
reduces plasma TAG
What is the link between w-6 fatty acids and CVD?
May lower low-density lipoprotein (LDL)
Some evidence that high levels may lower HDL (detrimental effect)
What are the hormones regulate lipid metabolism?
Insulin and noradrenaline
How does insulin regulate lipid metabolism?
Stimulates FA synthesis, TAG synthesis
Suppresses lipolysis
Insulin stimulates: > GLUT4-mediated transport of glucose > Acetyl CoA carboxylase activity > Increases expression of FAS > Increases activity of LPL (in adipose only)
Inhibition of lipolysis by:
stimulates breakdown of cAMP
How does noradrenaline regulate lipid metabolism?
Stimulates lipolysis
Noradrenaline stimulates:
> cAMP synthesis
> cAMP-dependent protein kinase (PKA) activation
> PKA-mediated phosphorylation and activation of HSL
What are the levels of LPL in different tissues in the fed state?
increased LPL synthesis and activity in adipocytes
decreased LPL synthesis and activity in skeletal and heart muscle
What are the levels of LPL in different tissues in the fasted/exercised state?
decreased LPL synthesis and activity in the adipocytes
increased LPL synthesis and activity in the muscle
What are potential affects of elevated FA with obesity?
Lipolysis is overactive and adipose storage capacity for TAG is exceeded
FA are taken up and stored in liver and possibly muscle
How can elevated FA levels lead to the development of T2DM?
Metabolites of FA impair insulin signalling, driving the extreme insulin resistance that causes diabetes
- primarily cause by impact in the liver
Causes impaired insulin action in liver, adipose and muscle
- increased lipolysis, gluconeogenesis
- decreased glucose uptake, glycogen synthesis
Excess FA may also directly impair insulin secretion by the beta cell
Hyperglycaemia results