12 - Lipid Metabolism & ketones Flashcards
what does increased fat intake without appropriate energy expenditure lead to?
- increase in numbers of adipocytes
- more fat in adipocytes
= obesity
what does control of energy balance in body depend on?
- genetically linked factors e.g. protein messengers regulating appetite
- environmental factors e.g. food abundance, fashionable foods
what is fat required for?
- energy source = more energy than carbs & proteins
- for some essential fatty acids (that you can’t make in body)
- for fat soluble vitamins (to absorb vitamins, fat absorbed at same time)
what can occur if fat intake or absorption is inadequate?
secondary deficiencies
what are fat soluble vitamins?
vitamins A,D,E,K
= absorption of these vitamins is closely linked to that of fat (vitamins absorbed same time as fat)
- lipids required to carry vitamins around the body
what are lipids made of?
- predominantly hydrocarbon
- usually contain long chain fatty acids
- insoluble in water = important for their biological function
what are essential fatty acids?
- some polyunsaturated fatty acids cannot be made by the body
- deficiencies can lead to membrane disorders, increased skin permeability, mitochondrial damage
what are different types of lipids?
lipids are collection of different compounds like:
- simple lipids (fatty acids, triglycerides, waxes)
- compound lipids (phospho-, glyco-lipids, lipoprotein)
- steroids (cholesterol, steroid hormones)
what is structure of triglyceride?
glycerol with 3 fatty acid tails
= hydrophobic
- compact & don’t require concomitant storage of water
what are the main natural fatty acids?
- palmitic acid
- stearic acid
- oleic acid (has kink so makes space in cell membrane allowing other molecules to be there = fluidity)
what is structure of fatty acid chains?
- Mainly straight chains
- Aliphatic (no rings)
- Usually contain an even number of C atoms (2 - 20 or more)
- Branched chains and odd numbers of C are rare
- Can be
- saturated (no double bonds)
- unsaturated (one double bond)
- polyunsaturated (several double bonds)
- Double bonds usually in cis configuration
what is saturated, unsaturated and polysaturated?
- saturated (no double bonds)
- unsaturated (one double bond)
- polyunsaturated (several double bonds)
what is example of polyunsaturated fatty acid?
linoleic acid (can’t be synthesised by body)
what is fatty acid nomenclature?
count the carbons starting at ester group, COO- = carbon 1 and the count all the way to omega carbon
what does omega 3 fatty acid look like?
omega (ω) 3 fatty acid – double bond 3 carbons in from ω carbon terminus
what is relationship between temp and solid/liquid?
Fatty acids with up to 8 C atoms are liquid at room temperature, longer ones are solid
- Double bonds lower melting point (longer = less double bonds = higher)
what type of acids are mainly in plant and animal fats?
- Plant fats contain large proportions of unsaturated fatty acids 🡪 liquid
- Animal fats contain mostly palmitic and stearic acid 🡪 solid
what are main products of fat digestion?
- glycerol
- readily absorbed in intestinal epithelial cells
- fatty acids
- monoglycerides
how are different acid types absorbed into mucosal cells of intestine?
- short and medium-length fatty acids enter portal blood
- longer chain fatty acids and monoglycerides are re-synthesised to triglycerides
where are chylomicrons and why are they there?
large lipoprotein particles that transport dietary lipids, primarily triglycerides, from the intestine to other tissues in the body
how do longer chain fatty acids enter mucosal cell with chylomicrons?
- Enter lymph, then the blood stream
- At muscle and adipose tissue, chylomicrons are attacked and cleaved by lipoprotein lipases
- There, free fatty acids are:
- re-synthesised into triacylglycerols (in adipose tissue, for storage)
- oxidised to provide energy (in muscle)
- depends on amount available
what is lipolysis?
breakdown of fats
what is the initial cleavage of stored fat?
by hormone sensitive lipases (e.g. adrenaline-sensitive)
- releases free fatty acids & glycerol - occurs when energy is needed
where is fat stored?
adipose tissue
what needs to happen before fatty acids can be oxidised to generate energy?
they have to be converted to CoA derivatives. have to be tagged with CoA
= occurs in cytoplasm and requires 2 ATP
fatty acid + CoA →acetyl-CoA
where does further oxidation of fatty acids occur?
in mitochondria so need to be transported by special carrier mechanism (carnitine shuttle)
what is carnitine shuttle?
- Acyl-carnitine transporter in inner membrane:
- facilitates antiport of acyl-carnitine into the mitochondrion and carnitine out
- In the cytoplasm, fatty acids are transferred from acyl-CoA to acyl carnitine
- Net result: acyl-CoA located in mitochondrial matrix
= acyl carnitine goes in at same time carnitine goes out
what are the products of each cycle of beta oxidation?
- 1 acetyl-CoA
- 1 FADH2
- 1 NADH + H+ (not yet ATP)
- 1 fatty acyl-CoA, shortened by 2 carbon atoms
what happens in beta oxidation?
cleaves carbon from carbon 1 and every 2 carbons down fatty acid chain
how to calculate number of cycle for fatty acid chain?
= divide length of chain by 2 (as take 2 per cycle) then -1 (as left with 2 carbons at the end)
where does beta oxidation occur?
mitochondrial matrix
where is carnitine shuttle found?
inner mitochondrial membrane
what is different about beta oxidation fro unsaturated fatty acids?
different route
what is total ATP yield of stearic acid in beta oxidation?
120 ATP
- look at notes on how to calculate
what is pathway to breakdown glycerol?
- requires ATP, generates NAD and redirected to glycolysis pathway
- Activated to glycerol-3-phosphate by glycerol kinase
- present in liver and kidney but absent from adipose tissue, skeletal and heart muscle - Dehydrogenated to dihydroxyacetone phosphate
- normal intermediate of carbohydrate metabolism
where are ketone bodies formed?
in liver mitochondria from acetyl Co-A from beta oxidation (happens because acetyl CoA that usually used in TCA cycle can’t be used up due to lack of glucose starting TCA cycle so in liver and muscle where acetyl-CoA accumulates ketosis occurs)
what normally happens with acetyl CoA?
- fatty acid oxidation yields acetyl-CoA
- enters citrate cycle if fat and carbohydrate degradation are balanced
- depends on oxaloacetate (C4 compound) for formation of citrate
- oxaloacetate can be provided as a side-product of glycolysis
what happens with acetyl CoA in starvation?
- oxaloacetate is consumed for gluconeogenesis
- fatty acids are oxidised to provide energy
- acetyl-CoA is converted to ketone bodies
- high levels in blood
- too much for extrahepatic tissue (i.e. heart, brain, etc.)
- ketone bodies are moderate acids
- accumulation leads to severe acidosis (blood can’t buffer any more)
- impairs tissue function, particularly central nervous system
- smell of acetone can be detected in breath
where do ketones diffuse to?
into the blood stream and to peripheral tissues
what is lipogenesis?
fatty acid synthesis
where does lipogenesis occur?
De novo synthesis of fatty acids occurs mainly in liver, kidney, mammary glands, adipose tissue and brain (mainly takes place during excess energy intake)
what happens when excess carbohydrate taken in?
- conversion to fatty acids and triglycerides in the liver
- free fatty acids are transported in plasma bound to albumin
- triglycerides formed in the liver are transported to adipose tissue by VLDL for storage (VLDL = very low density lipoprotein)
is lipogenesis reductive or oxidative process?
reductive process = electrons required
what is mechanism for converting carbohydrates to fat?
dietary starch -> glucose ->pyruvate->acetyl CoA -> fatty acids -> triglycerides
what happens when citrate is present at high concentrations (accumulates) in mitochondria?
transported to cytoplasm - citrate formation is first step of TCA cycle
what is activated form of acetyl CoA?
malonyl-CoA
what is rate limiting for fat synthesis?
acetyl-CoA carboxylase
what does malonyl Co-A do?
donates carbon atoms to new lipid
what converts acetyl CoA to malonyl CoA?
Acetyl-CoA carboxylase
= mainly in liver & adipose tissue
what is function of fatty acid synthase?
= 4 subunits that assembles fatty acid
by 4 steps:
1. Condensation
2. Reduction
3. Dehydration
4. Reduction and release
what is fatty acid synthase?
multi-enzyme complex – exists as a single polypeptide chain with 7 distinct enzyme activities. Can homodimerise through sulfhydryl cross bridges
what is the 2nd enzyme in fatty acid synthesis process?
fatty acid synthase = outcome is to generate acyl chain that is then transported elsewhere in cell for storage (transported in acyl-carrier protein)
what is required as electron donor for lipogenesis?
NADPH as electron donor
what is growing acyl chain attached to?
acyl-carrier protein (ACP)
what has Essential role in regulating fatty acid synthesis and degradation?
acetyl-CoA carboxylase
what conditions are when fatty acids are made?
Synthesis is maximal when carbohydrate and energy are plentiful, and when fatty acids are scarce
what signals the fed state?
insulin = stimulates storage of fuels and synthesis of proteins (glucogenesis & preferentially fatty acid synthesis - activating acetyl-CoA carboxylase)
what signals the starved state?
- Glucagon signals starved state, epinephrine signals requirement for energy:
- mobilise glycogen stores
what does high citrate levels mean?
citrate levels are high when acetyl-CoA and ATP are abundant
when is palmitoyl-CoA abundant?
when fatty acids in excess
what happens in synthesis of triglycerides?
- Requires glycerol-3-phosphate (G-3-P)
- Liver produces G-3-P from glycerol
- Adipose tissue produce G-3-P from glucose
- Adipose tissue production of triglycerides only during the fed state
- insulin stimulates adipose tissue uptake of glucose
- Triglyceride formation involves esterification
- Liver also synthesises phospholipids, cholesterol and lipoproteins
