Week 3 - Lipids Part 2 Flashcards
What does MCAD cause ?
Liver damage at an early age due to the inability to metabolise fats during fasting leading to hypoglycemia.
What process does MCAD limit?
Gluconeogenesis
What is the treatment for MCAD?
Frequent feeding, avoidance of fasting and carnitine supplementation
What are the main characteristics of Zellweger Syndrome?
Defects in the import of enzymes into peroxisomes.
Accumulation of very long chain fatty acids in neuronal tissue.
What is the treatment for Zellweger Syndrome?
Fibrates - a class of hypolipidemic drugs that act by inducing peroxisomal proliferation in the liver.
An increased peroxisome number leads to an increased?
VLCFA turnover
What are the two types of fatty acid?
- double bonds 3 carbons from methyl end (w-3 fatty acids)
- 6 carbon from the methyl end (w - 6 FA) - are required for the synthesis of eicosanoids
What are eicosanoids a derivative of?
Arachidonic and eicosapentaenoic acids which are generally taken in from the diet and incorporated into membranes.
What are eicosanoids?
They are poly unsaturated FAs
The precursor PUFA of eicosanoids is released from what and by the action of what?
membrane phosphatidylcholine by the action of phospholipase A2
Eicosapentaenoic acids competitively inhibit the oxygenation of arachidonic acid by enzymes?
Cyclooxygenase and lipoxygenase
What responses do the eicosanoids alter in the body?
Inflammatory, hypersensitivity and allergenic responses
How do eicosanoids act through?
They act through GPCR - have tissue specificity.
Do eicosanoids act on close cells?
Yes, those in close proximity
What are the 3 families of eicosanoids?
Prostaglandins, thromboxanes and leukotrienes
Are eicosanoids stored in cells?
They are not stored within cells, but are synthesized as required in response to hormonal stimuli.
What is the role of Cyclooxygenase I?
in healthy tissue, it is expressed in all tissues and in particular blood cells - responsible for the synthesis of prostaglandins and thromboxane’s including A2
What is the role of Cyclooxygenase II?
Activates the immune system
Activation induces pain, heat, fever, swelling, inflammation through the overproduction of prostaglandin H2
What enzymes are targetted by aspirin?
Cyclooxygenase I (low dose aspirin used to prevent stroke + heart attack) and II
What are some of the roles of sterols?
- structural lipids that are present in all cell membranes
- serve as precursors to steroid hormones, bile acids and vitamin D.
- amphipathic lipids
What is the major sterol in human tissues?
Cholesterol
What are the two ways in which cholesterol enters the body?
- diet
- de novo biosynthesis
What are the 2 cholesterol transporters in the intestine?
- NPC1L1 (treats hypercholesteremia) suppressed by drug ezetimbe
- Reverse cholesterol transport
Where do most catabolic pathways exist?
In the mitochondria
Where does cholesterol synthesis occur?
In the cytoplasm
Can cholesterol be broken down/oxidised to CO2 and H2O in humans ?
No cholesterol cannot be excreted
What is cholesterol synthesised from?
Acetyl Co A
Which form is cholesterol usually circulating in ?
esterified form
Is cholesteryl soluble?
Cholesteryl esters are very hydrophobic, they are so insoluble they are transported in association with protein - lipoprotein particles
Why can cholesterol not be degraded?
Due to the sterol ring of cholesterol it cannot be degraded and is instead excreted in bile, or returned to the liver as bile acids or used to make steroid molecules: steroid hormones, vitamin D.
Which step does cholesterol biosynthesis share with ketone body synthesis?
They result in the production of HMG CoA
What is the difference between ketone synthesis and cholesterol synthesis?
Cytosolic enzymes are involved in the cholesterol synthesis whereas the mitochondrial enzymes function for the ketone body formation
What is the rate limiting step in cholesterol synthesis?
The synthesis of mevalonate
What is the committed step and rate limiting reaction of cholesterol synthesis?
HMG CoA reductase, feedback inhibition of mevalonic acid and CoA production
What is cholesterol synthesised to when in excess?
Bile
What is the transcription factor which binds to the promoter region of HMG CoA reductase and increases gene expression?
SREBP
High sterol level - SREBP is held at ER
Low sterol level - SREBP is transported to the nucleus
HMG CoA reductase is inactivated by ? What is it activated by?
cAMP- activated protein kinase
Phosphoprotein phosphatase
HMG CoA reductase gene expression is inhibited by and promoted by what?
Inhibited by - glucagon
Promoted by - insulin
What is the role of statin drugs?
These are competitive reversible inhibitors of HMG –CoA reductase
What is the first step in cholesterol biosynthesis?
The synthesis of mevalonate from acetate
What does mevalonate yield in cholesterol biosynthesis?
2 activated isoprenes
What are isoprenes?
They are a simple 5C subunit and are a common structural motif in biological systems
After a series of isoprene condensation steps, what is produced?
Squalene
The oxidation and ring closure of squalene leads to the biosynthesis of?
Cholesterol
What are the three routes from which Acetyl CoA is derived?
- Beta oxidation of long-chain FA
- dehydrogenation of pyruvate
- oxidation of ketogenic amino acids such as leucine and isolecuine
What is the reducing power involved in cholesterol biosynthesis?
NADPH
Where do all reactions occur in cholesterol biosynthesis?
All reactions occur within the cytoplasm
What three units is farnesyl pyrophosphate made up of?
Three isoprene units
How many molecules of AcetylCoA yield mevalonate?
3 molecules of Acetyl CoA
In de novo synthesis of cholesterol, what is the first closed cyclic structure to resemble cholesterol?
Ianosterol
What are some of the different fates of cholesterol?
- converted to cholesteryl esters/plasma lipoproteins
- converted into bile acids
- incorporated into membranes
- a precursor for steroid hormones
Cholesterol can be converted to oxysterol by …. of its side chain?
Oxidation
What happens to excess cholesterol?
- converted to bile acids and bile salts
- secreted into bile and then excreted
Where is bile made, secreted into and stored?
Bile is made in the liver, secreted in the duodenum and is stored in the gall bladder
Bile acids are conjugated via an amide bond to either?
glycine or taurine before they being re-secreted into the bile canaliculi as a bile salt
What enzymes synthesis bile acid?
Cytochrome enzymes from cholesterol
Which hormone is involved is the post-meal release of bile salts?
Hormone Cholecystokinin
What to free bile acids influence?
Secondary and tertiary bile acids are also signalling molecules that influence the gut and metabolic status
Which receptor is involved in the gut to liver signalling via bile acids.
Farnesoid X Receptor.
Which receptor is involved in the gut to liver, gut to adipose tissue and macrophage signalling via bile acids?
TGR5
Cytochrome P450 enzymes are a part of the family of ? what is their function?
Heme proteins which catalyse the monooxygenation of a large variety of compounds
Can the substrates for cytochrome P450 enzymes be endogenous or exogenous?
Either
What is the rate limiting step in bile acid synthesis in the liver?
Rate limiting enzyme: CYP7A1
Involved in the hydroxylation of cholesterol.
What is the name of the novel mitochondrial cholesterol transporter involved in bile acid synthesis?
StAR 0 steroidogenic acute regulatory protein.
Bile acid is synthesised in the liver by cytochrome enzymes from cholesterol rate-limiting one?
Cyp7A1
Cyp27A1 - mitochondria
Where are bile acids recycled and reabsorbed back into the body?
In the terminal ileum (95%) is reabsorbed here
What is the purpose of bile acids in gut health?
- emulsify fats
- activate lipases
- induce pancreatic enzymes, solubilise cholesterol, remove cholesterol from the body and signal back to the liver and to other organs and tissues
What directs the complexity of bile acids?
Gut microbiota
What are three disorders in which the bile acid reuptake/transporters are affected?
- Crohns Disease
- CRC (colorectal cancer)
- BAD (bile acid diarrhea)
What amount of bile salts are secreted from the liver each day?
15-30g, only 0.5% is lost daily in the faeces
What is the role of bile acids?
- emulsify fats
- acts as an excreting fluid
- digestive enzyme
Bile acid INRs regulate?
SREBP, cholesterol and fatty acid synthesis
When cholesterol is modified by bacteria what is it modified to and what is it joined to make up?
Coprostanol and cholestanol
Joined to make up fecal sterols
Cholesterol is made in the liver and is converted to cholesterol esters that are transported to?
Secreted lipoprotein particles
Cholesterol is the precursor to which hormones?
Oxysterols: glucocorticoids, progesterone, testosterone and estrogen
The cholesterol to phospholipid ratio if greater than 1:1 and is not flushed down the bile duct leads to the development of?
Gall Stones cholelithiasis - these cause irritation and obstruction of the common bile duct
What is an inhibitor of cholesterol reabsorption?
Cholestryamine
The transfer of excess cholesterol from the liver to bile requires ?
- phospholipids
- bile salts
Does cholesterol regulate the ileal bile acid transporter allosterically at the DNA level?
Yes it does via transcription activation
What is endocrine?
This is when the hormone travels through circulation to reach a distant target cell.
What is paracrine?
This is when the hormone is secreted by a cell and travels a short distance to interact with cognate receptors on neighbouring cells
What is autocrine?
This is where the cell that produces the hormone is also the target for that hormone.
What is an example of a paracrine hormone?
Prostaglandin E1 (PGE1)
What are non-steroid hormones based on?
Amino acids
Steroid hormones are … and are based on the synthesis from cholesterol.
Liphophilic
What are the 2 satiety/hunger hormones?
Leptin and Ghrelin
Steroid hormones are hydrophobic so they need a transport protein partner, give an example?
Albumin
What are the 2 classes of steroid hormones?
- adrenocortical
- sex and progestational hormones
What is the initial and rate-limiting reaction of steroid hormone synthesis involves the conversion of cholesterol to?
21-carbon pregnelolone
What protein mediates the mitochondrial import of cholesterol?
StAR
Issues with progesterone production results in?
3 beta hydroxysteroid dehydrogenase deficiency
Issues with 17 alpha production results in ?
17 alpha hydroxylase deficiency
21 hydroxylase deficiency results in the what two coids being virtually absent?
Minearlcorticoids and glucocorticoids.
11 beta 1 hydroxylase deficiency results in a decrease in?
- serum cortisol
- aldosterone
- corticosterone
Which fat soluble vitamins can be toxic when in excess?
A and D
What is the retinoic acid receptor known as?
Nuclear retinoid receptors
What can severe vitamin A deficiency lead to?
Permanent blindness
Vitamin D is made from … stored in the skin?
7 - dehydrocholesterol stored in the skin
What is calcitrol?
a potent active form of Vit.D also made in the bone and the placenta
Vitamin D influences which 3 processes?
cell proliferation
differentiation
apoptosis
Vitamin D and PTH stimulates an increased?
Plasma calcium and phosphate concentrations
