Lipid Metabolism Flashcards
Lipids are grouped by their
insolubility in water
Lipids have diverse biological functions:
- Principal source of stored energy
- Major structural elements of biological
membranes e.g. phospholipids, glycolipids
and cholesterol - Play important roles in metabolism:
enzyme cofactors, electron carriers,
emulsifying agents in the digestive tract - Inter- and Intra signalling events:
precursors of steroid hormones
Triglycerides are
lipids mainly used for storage of energy
Triglyceride structure
Glycerol bound to three fatty acid chains
Triglycerides are hydrophilic or hydrophobic?
hydrophobic
Saturated fatty acid chains have
no double bonds between carbon atoms
unsaturated fatty acids chains have
a double bond between carbon atoms
Polyunsaturated fatty acid chains
have more than 1 double bone between carbon atoms
Triglyceride metabolism:
- depending on metabolic requirements there are 2 major metabolic pathways:
- oxidation in the mitochondria to release energy in the form of ATP
- Synthesis of TG from malonyl-CoA (for storage)
What are the 3 stages to achieve complete oxidation of fatty acids to CO2 and H20?
- oxidation of long fatty acid chains to 2 carbon fragments in the form of acetyl co-enzyme A = beta oxidation
- oxidation of acetyl co-enzyme A to CO2 in the citric acid cycle
- transfer of electrons from reduced electron carriers to the mitochondrial respiratory chain
Beta-oxidation of fatty acid chains
- occurs in mitochondria
- successive removal of 2-carbon fragments as acetyl co-enzyme A from fatty acids
- Step 1: fatty acids activated by attachment to co enzyme A (in the cytosol)
- Step 2: transfer of acyl-groups across mitochondrial membrane through a carnitine shuttle
- step 3: progressive oxidation of fatty acids by removal of 2 carbon units to form acetyl co enzyme A, which enters the citric acid cycle.
Each removal of 2C results in the formation of 1 acetyl co-enzyme A, 1 FADH2, 1 NADH, all used to generate energy for the cell
Which step in beta oxidation is the rate limiting step?
Step 2
Transfer of acyl groups across the mitochondrial membrane via a carnitine shuttle
Carnitine shuttle
- activated fatty acids can be transported across the inner mitochondrial membrane
- enzymes called carnitine acyltransferase
- carnitine acytransferase 1 is on the cystolic side of the outer mitochondrial membrane
- removes co-enzyme A and adds carnitine
- passes through the carnitine carrier protein
- carnitine acyltransferase 2 is on the matrix side of the inner mitochondrial membrane
- removes carnitine and attaches co-enzyme A
Beta oxidation process with image:
- Step 1: fatty acids activated by attachment to co enzyme A (in the cytosol)
- Step 2: transfer of acyl-groups across mitochondrial membrane through a carnitine shuttle:
- activated fatty acids can be transported across the inner mitochondrial membrane
- enzymes called carnitine acyltransferase
- carnitine acytransferase 1 is on the cystolic side of the outer mitochondrial membrane
- removes co-enzyme A and adds carnitine
- passes through the carnitine carrier protein
- carnitine acyltransferase 2 is on the matrix side of the inner mitochondrial membrane
- removes carnitine and attaches co-enzyme A
Step 3: progressive oxidation of fatty acids by the removal of 2 carbon units to form acetyl co-enzyme A which enters the citric acid cycle.
Each removal of 2 carbon units forms 1 acetyl co-enzyme A, 1 FADH2, 1 NADH, which are used to generate energy for the cell
Beta oxidation 3 rd step:
Which step is this of what process, when does it stop
3rd step of beta oxidation which is step one of oxidation of TGs into CO2 and H20
once all carbon units are released
MCADD stands for
medium chain acyl Co-enzyme A dehydrogenase deficiency
Mutations oof Acyl-Co-enzyme A Dehydrogenase:
- does?
- results?
- usually diagnosed?
- what type of disorder?
- clinical symptoms?
- observed?
- inhibits the first stage of beta oxidation
- results in MCADD
- usually diagnosed after newborn blood spot testing
- autosomal recessive disorder of the ACADM gene
- symptoms: lethargy, hypoglycaemia, seizures, vomiting
- often observed after common illness or fasting
Co-A in cytosol used for
- other metabolic events and fatty acid biosynthesis
Co-A in mitochondrial matrix used for
fatty acid oxidation/ beta oxidation
Why is it called beta oxidation?
- alpha carbon becomes part of actyl co-enzyme A
- beta carbon remains till next cycle
First enzyme to interact with activated fatty acid in the mitochondrial matrix?
Acyl-CoA dehydrogenase
Oxidises alpha carbon
reduces FAD to FADH2 (used to make ATP)
Mutations in what enzyme of beta oxidation can cause SIDs
- acyl CoA dehydrogenase
- sudden infant death syndrome
Where does fatty acid synthesis occur?
Mainly in the liver and adipocytes
In the cytosol
Fatty acid synthesis brief description
long carbon chain molecules built up from 2 carbon unit derived from acetyl co enzyme A and 3c malonyl co enzyme A intermediate
Fatty acid synthesis occurs in the cytosol but acetyl CoA is mainly in the mitochondrial matrix, how does acetyl CoA get out of the mitochondria?
The citrate malate cycle
The citrate malate cycle diagram
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1) pyruvate (6c) gains an CO2 and becomes oxaloacetate
2) pyruvate also becomes acetyl CoA
3) citrate synthase enzyme catalyses the formation of citrate from oxaloacetate and acetyl CoA
4) citrate is transported out into cytosol through Tricarboxylate transporter
5) citrate lyase enzyme converts citate into oxaloacetate and acetyl CoA, which can then be used for fatty acid synthesis
6) Oxaloacetate uses MDH to become malate
7) malic enzyme turns malate into pyruvate, which returns into the mitochondrial matriax via a pyruvate transporter
Fatty acid synthesis after acetyl CoA has been transported to the cytosol
Acetyl CoA + CO2
Enzyme acetyl CoA carboxylase catalyses this reaction to form Malonyl CoA in an irreversible rate limiting step
- malonyl CoA (3C) (ask dr leslie) and acetyl CoA (2C) both bind to enzyme fatty acid synthase
- a repeating series of condensation reactions involving malonyl CoA adds a further 2 carbon units
Fatty acid synthase: how does it add a further 2 carbon atoms
already has it bound
What is the rate limiting step in fatty acid synthesis?
formation of malonyl CoA from acetyl CoA, catalysed by acetyl CoA carboxylase (subject to phosphorylation under the control of glucagon)
Glucagon, adrenaline control over fatty acid synthesis
will phosphorylate acetyl coA carboxylase and hence acetyl CoA will not be converted into Malonyl CoA
Insulin control over fatty acid synthesis
insulin will favour dephosphorylation of acetyl CoA carboxylase and therefore favours fatty acid synthesis
fatty acid syntehsis control
cholesterol
- all cells can synthesis so not needed in diet
- amphipathic lipid (hydrophobic and hydrophilic portions)
- synthesised from acetyl CoA and eliminated as bile acids
- storage form is cholesterol ester found in most tissues
What makes cholesterol molecules amphipathic?
OH
What do cholesterol acyltransferases do?
catalyses the formation of cholesterol esters
Acyl CoA Cholesterol Acyltransferases (ACAT)
ACAT stands for and does?
Acyl-CoA Cholesterol Acyltransferase (ACAT) makes cholesterol esters inside hepatocytes and lethicin cholesterol acyltransferase (LCAT) makes cholesterol esters in the bloodstream to trap cholesterol inside lipoproteins for transport.
Emulsify definition
Emulsify – breaking up fats to from a suspension of tiny fat droplets in an aqueous medium. This increases the surface area of the fats available for enzymatic digestion.
Bile acids
- produced from cholesterol by the liver and excreted into the gall bladder for release into the small intestine
- bile acids are relatively hydrophilic cholesterol derivatives and act as emulsifiers
- most bile acids are reabsorbed by the gut and returned to the liver and recycled
Cholesterol biosynthesis
- mainly in the liver, some in intestine and adrenal cortex
- target site for statins
!0 synthesis of mevalonate from acetate
2) conversion of mevalonate from two activated isoprenes
3) condensation of six isoprene units to form squalene
4) cyclisation of squalene to the four ring steroid nucleus
cholesterol biosynthesis
primary point of metabolic control of cholesterol
HMG CoA Reductase which converts HMG CoA into mevalonate
Glucagon and adrenaline inhibit
Insulin favours
Why do we transport lipids around the body?
- brings dietary lipids to cells for energy production or storage
- moves lipids from storage in adipose tissue for use in energy production
- provides lipids from the diet to cells for synthesising cell membranes
- carry cholesterol from peripheral tissues to the liver for excretion
How are lipids transported in the blood?
- short chain fatty acids are transported bound to blood proteins like albumin
- bulk transport of neutral lipids, which are insoluble in water require special carrier proteins called lipoproteins
- lipoproteins are composed of hydrophilic, hydrophobic and amphipathic molecules
Apolipoproteins
- specific carrier proteins combine with lipids to form several classes of plasma lipoproteins
- each has a specific function determined by:
- point of synthesis
- lipid composition
- apolipoprotien content
apolipoprotein content acts as signals targeting
tissues or activating enzymes that act on lipoproteins
Major classes of plasma lipoproteins: chylomicrons:
- largest (50-200nm)
- least dense
- exogenous lipid transport: synthesised from dietary fats from intestinal tissues
- ApoE, ApoC-II
Major classes of plasma lipoproteins: VLDL:
- very low density lipoprotein (28-70nm)
- endogenous lipid transport: originates in live transport lipids to muscle and adipose tissue
- ApoE, ApoC-II
Major classes of plasma lipoproteins: LDL:
- low density lipoprotein (20-25nm)
- endogenous transport: carry cholesterol to muscle adrenal glands and asipose tissue
- ApoB-100
Major classes of plasma lipoproteins: HDL:
- high density lipoprotein
- reverse transport: originates in the liver and small intestine and is involved in bringin cholesterol back to the liver
- ApoE
Digestion and Absorption of triglycerides
- emulsified by bile acids
- hydrolysed by enzyme pancreatic triaglycerollipase
- absorbed by intestinal mucosa
Lipid transport exogenous pathway
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Exogenous transport of lipids from the intestine as dietary fat through the intestinal mucosa where it is packaged as chylomicrons.
These travel to tissues where the apoC-II apolipoprotein stimulates tissue bound lipoprotein lipase enzymes to released triacylglycerides.
Remnants are endocytosed by the liver which recognises them by their ApoE apolipoprotein.
how does the liver recognise the contents of chylomicrons?
remnants of particles by their ApoE content and takes them up in endocytosis
Lipid Transport Endogenous Pathway
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Endogenous transport of lipids from the liver to the adipose/muscle tissues as VLDL lipoproteins. ApoC-II activiates tissue-bound lipoprotein lipases which releases fatty acids. Triacyl glcyeride depleted remnants of VLDLs from IDL (intermediate density lipoproteins) which on further loss of triacylglycerides become low density lipoproteins. These cholesterol/cholesterol ester rich lipoproteins are taken up by endocytosis within the extrahepatic tissues by binding of the ApoB-100 apolipoprotein to the LDL receptors on the cell surface of the liver and extrahepatic tissue.
Lipid Transport - Reverse Transport:
Endogenous cholesterol and cholesterol esters are transported from the extrahepatic tissues back to the liver via HDL (high density lipoproteins). These do not enter the liver by endocytosis but instead bind to scavenger receptors (SR-B1) on the cell surface that media transfer of cholesterol into the cell.
LDL (cholesterol) uptake by cells
- mediated by LDL receptors on cell surface binding to ApoB-100
- LDL receptors separated from LDL and recycled back to cell surface
- endosome fuses with lysosome: lytic enzyme degrade ApoB-100 releasing amino acids fatty acids cholesterol and cholesterol esters
Regulation of intracellular cholesterol
short term: regulation achieved by modifying HMG CoA reductase activity: controls biosynthesis of cholesterol
Long term: regulation achieved by modifying numbers of molecules involved in maintaing cellular cholesterol
What happens to transcription and protein production when there is low cholesterol levels?
increases
what happens to protein degradation of HMG CoA and LDL receptros when high cholesterol
increases to reduce number so less absorbed into the cells
summary exogenous pathway of lipid transport
Dietary lipids are packaged into chylomicrons; fatty acids are released from TAG by lipoprotein lipase to adipose and muscle tissues. Chylomicron remnants are taken up by the liver.
Summary of endogenous pathway of lipid transport
lipids synthesized or packaged in the liver are delivered to peripheral tissues by VLDL. Extraction of lipid from VLDL gradually converts them to LDL which delivers cholesterol to extrahepatic tissues or returns to the liver.
summary of reverse cholesterol transport
via HDL lipoproteins that pick up excess cholesterol released from peripheral cells and return to the liver.
atherogenesis
LDL adherence to extracellular matrix of arterial epithelial cells attract monocytes, take up the LDL eventually forming foam cells; undergo apoptosis leading to progressive occlusion by plaques (extracellular matrix material, scar tissue and foam cell remnants)
Lipoprotein classes: in decreasing size
Chylomicrons >VLDL>LDL>HDL.
vary in lipid content
