the normal liver : basic metabolic liver fucntion wtf was this lecture rewatch Flashcards
what is glycogenolysis and what is it promoted by?
breaking down stored glycogen to provide glucose for the body in the fasting state — promoted by glucagon
what is gluconeogenesis? promoted by?
produce glucose from “scraps” and makes it available in the fasting state. promoted by glucagon
what is ketogenesis? promoted by? when?
use of acetyl-CoA to produce emergency fuel (ketone bodies). promoted by surplus of mobilised fatty acids in starvation or type 1 diabetes
what does prolonged fasting or starvation trigger the breakdown of?
fatty acids from adipose tissue because this process in suppressed by insulin
what is glycogenesis? driven by? suppressed by?
absorb surplus of dietary glucose and store as glycogen. driven by high blood glucose, suppressed by glucagon
happens in well fed and in absorptive state
describe fatty acid biosynthesis. promoted and suppressed by?
use surplus of carbon substrate to produce fatty acids for delivery to adipose tissue. promoted by insulin and high cellular energy levels (ATP), suppressed by glucagon
liver has filled up its glycogen stores, any further dietary carbs can be turned into FA, these converted to triacylglycerols - go to adipose tissue for long term storage
surplus ammonia arrives in the liver as what? then what happens?
glutamate, glutamine or alanine. de or transaminated. nitrogen eventually disposed as urea
what result from transaminaton and where can these be used?
transaminases need in gluconeogenesis. nitrogen free amino acids result from transamination
eg. a-ketoglutarate, oxaloacetate
AMINO ACID METABOLISM PRODUCES PRECURSORS OF GLUCONEOGENESIS
what are the 2 components of hepatic glucose production (HGP)?
glycogenolysis and gluconeogenesis
what normally suppresses HGP and via what?
high blood glucose normally suppresses hepatic glucose production via insulin
what is the main eason for hyperglycaemia in type II diabetes mellitus?
failure to regulate HGP
when does the liver take up glucose and what happens do it?
- takes it up in high glucose levels via GLUT-2
- converted into glucose-6-P via glucokinase
- then converted to glycogen in glycogenesis
or - converted to pyruvate (glycolysis) then Acetyl CoA then fatty acids then triaglycerols - delivered to adipose tissue
what happens when triaglycerols are hydrolysed?
releases fatty acids that can be broken dow into acetyl coa — this can never be turned back into glucose — instead produces ketone bodies
what is glycolysis?
catabolism (breaking down) of glucose ( and most other carbohydrates via glucose) in all tissues
glycolysis functions
- generation of intermediates for other pathways
- generation of energy and (in aerobic conditions) reducing equivalents
what are the end products of glycolysis and what does it depend on?
depends on O2
- pyruvate under aerobic conditions
- lactate under anaerobic conditions
what facilitates the diffusion of glucose into cells? give 2 examples
a family of glucose transporters (GLUT)
- many are tissue specific
- GLUT-4 in adipose tissue (key insulin target — acts to increase the surface density of this transproter in muscle and adipose tissue to promote glucose uptake) and GLUT-2 in liver
- GLUT-2 can facilitate both glucose entry into liver cells and exit
what is the effect of phosphorylation of glucose?
traps glucose in the cell because the ionic phosphate cannot cross the membrane spontaneously
what is the phosphorylation of glucose catalysed by?
hexokinase/glucokinase
- hexokinase is relatively slow but fully active at very low glucose concentrations
- glucokinase in the liver has a much higher capacity to trap glucose in the liver, but only when glucose concentrations are high eg. after a meal
what is the msot critical regulated step in glycolysis?
fructose-6-P is phosphorylated to yield F-1,6-BP — this commits the molecule for further degradation — want to avoid in fasting state
what happens in the only oxidative step of glycolysis?
GA-3-P is converted to 1,3-BPG.
NADH and H+ are generated - these can be regenerated under anaerobic conditions by reducing pyruvate to lactate. the liver can re-oxidise lactate it pyruvate
what is the net generation of ATP per glucose in glycolysis?
2 ATP
what is the Warburg effect?
the increase in the rate of glucose uptake and preferential produciton of lactate in cancer cells
gluconeogenesis is the production of glucose from what?
pyruvate or oxaloacetate
where is glycogen stored?
mainly in skeletal muscle (1-2% by weight, total 400g) also liver (up to 10% by weight, total 100g)
what are key mechanisms that maintain blood glucose levels and are regulated by what?
- synthesis of glycogen after a meal and degradation during an overnight fast
- regulated by glucagon
glycogen metabolism is controlled hormonal by what?
glucagon and insulin
what are glucagon levels like in a fasting state?
elevated
what affect does glucagon have on glycogenolysis and glycogenesis
glucagon promotes glycogenolysis and inhibits glycogenesis
how does glucagon promote glycogenolysis and inhibit glycogenesis?
- glucagon triggers the production of cAMP in cells, which in turn activates protein kinase A (PKA)
- PKA phosphorylates glycogen synthase directly, and glycogen phosphorylase via phosphorylase kinase
- phosphorylation has opposite effects on the 2 enzymes : glycogen synthase becomes inactive, while glycogen phosphorylase is activated by phosphorylation
- as a result, glucagon PROMOTES GLYCOGENOLYSIS and INHIBITS GLYCOGENESIS
where is gluconeogenesis and when?
in liver during an overnight fast and in the kidney after prolonged fasting
gluconeogenesis regenerates glucose from what?
non-carbohydrate precursors
- LACTATE from skeletal muscel is re-oxidised to pyruvate (this liver muscle cycle is called Cori Cycle)
- GLYCEROL is released by the hydrolysis of fat (TAGs) in adipocytes
- AMINO ACIDS from tissue protein are metabolised to a-KETO ACIDS like oxaloacetate and a-ketoglutarate (via transamination)
what’s the main regulator of gluconeogenesis?
glucagon
how does glucagon affect gluconeogenesis?
- represses pyruvate kinase, thus increasing the availability of PEP for gluconeogenesis
- increases the expression of PEP carboxykinase
- represses the formation of F-2,6-BP = a repressor of F-1,6-BP in gluconeogenesis (while it is an activator of PFK-1 in glycolysis)
what is pyruvate kinase?
- enzyme in gluconeogenesis
- it is the point of no return
- glucagon represses it therefore PEP can still be recycled easily into glucose
in gluconeogenesis, why would we rather start from phosphoenolpyruvate than pyruvate?
pyruvate requires several steps and 2 ATP to turn it into oxaloacetate therefore much mroe expensive
opposing regulation of metabolism via insulin vs glucagon
what is PFK-1?
- phosphofructokinase-1
- acts after isomerisation of glucose-6-P to fructose-6-P and catalyses the most important regulated step of glycolysis — it is the rate limiting step
what is PFK-1 allosterically activated by and inhibited by?
- activated by AMP (signal for serious energy depleting in cell)
- repressed by ATP and citrate (reflect well-fed cell state)
- activated by fructose-2,6-bisphosphate whose biosynthesis in turn is regulated by insulin and glucagon
what does fructose-2,6-phosphate promote and suppress?
promotes glycolysis by activating PFK1 and suppresses gluconeogenesis in opposite directions via F26P in well fed state
wtf
what is the pyruvate dehydrogenase complex?
a gigantic multi-enzyme complex with dozens of each of 3 enzymes E1, E2, E3
helps shuttle pyruvate into mitochondria
when is the pyruvate dehydrogenase complex inhibited?
when ATP, NADH or acetyl CoA are plentiful
shut down via phosphorylation when glucose needs to be preserved
all TCA (Krebs/Citric acid) cycle reactions happen in ________ and require ______ to recycle the reduced coenzymes ____________
- mitochondria
- oxygen
- NADH+H+ and FADH2
what feeds 2 carbons into the kreb cycle
acetyl-CoA
the TCA cycle provides for full oxidation of acetyl coa to what?
2 CO2
kreb cycle : oxidation of NADH and FADH2 in the mitochondria generates how much ATP per molecule glu she and how many GTP?
- 28 ATP
- 2 GTP
four intermediates of the TCA cycle are amino acid metabolites. this allows what?
their conversion to glucose by gluconeogenesis
most of the FAs needed by the body are provided within a normal diet. ant carbohydrates or proteins in excess of the body’s needs can be converted to fatty acids in the liver and ultimately stored as what?
fats in adipocytes — triacylglycerols, TAGs
where must acetyl-CoA be shuttled for lipogenesis?
to cytoplasm from mitochondria
what is burned off in TCA cycle when we need energy, but is re-routed into FA production in times of plenty
acetyl CoA
TAGs and FAs can be used by most tissues, but de novo synthesis is mainly in what?
liver
what is hepatic lipogenesis regulated by?
- availability of substrate : carb-rich meals provide carbon (pyruvate/acetyl-CoA) and NADPH via the pentose phosphate pathway
- insulin stimulates lipogenesis via transcriptional activation of L-PK, ACC, and other enzymes leading to TAG
what is the rate limiting and regulated enzyme in fatty acid synthesis?
acetyl-CoA carboxylase (ACC)
what is ACC activated by?
citrate
what is ACC inactivated by?
directly by fatty acyl-CoA and by phosphorylation by AMPK
via regulation of ACC phosphorylation , _____ indirectly activates ACC, ____ and ____ inactivate ACC
- insulin
- glucagon and AMP
lipogenesis is inhibited by what?
starvation signal - glucagon and AMP both acting by protein phosphorylation
citrate promotes re-routing of what towards lipogenesis instead of breakdown?
acetyl coa
what is acetyl-CoA converted to in FA synthesis?
malonyl-CoA
rewatch lecutre none of jt makes sense
ok
the B oxidation of what produces large amounts of energy?
fatty acids
long chain fatty acids broken down how many carbons at a time?
2
per 2 carbon unit in fatty acid B oxidation (catabolism), what are produced?
one FADH2, one NADH, one acetyl-CoA — ultimately these produce 2,3, and 12 ATP respectively
synthesis vs degradation of fatty acids: greatest flux through pathway
- synthesis = after carb-rich meal
- degradation = in starvation
synthesis vs degradation of fatty acids: hormonal state favouring pathway
- synthesis = high insulin/glucagon ratio
- degradation = low insulin/glucagon ratio
synthesis vs degradation of fatty acids: major tissue site
- synthesis = primarily liver
- degradation = muscle, liver
synthesis vs degradation of fatty acids: sub cellular localisation
- synthesis = cytosol
- degradation = primarily mitochondria
synthesis vs degradation of fatty acids: redox enzymes
- synthesis = NADPH
- degradation = NAD+, FADH2
synthesis vs degradation of fatty acids: product
- synthesis = palmitate (C16)
- degradation = acetyl-CoA
hormone sensitive lipase in adipocytes is repressed by what?
insulin
what are ketone bodies?
- an emergency fuel that the liver can produce to preserve glucose — but the liver itself cannot use ketone bodies
- ketone bodies are highly soluble and unlike lipids can be transported without carriers
name an enzyme in muscle tissue that can regenerate acetoacetyl CoA by adding CoA
thiaphorase
some of the acetoaceteate in the blood will spontaneously disintergrate to form ________, which is volatile. has a smell fo nail varnish remover - in clinical practise is a sign of serious _______ or ___________, can be detected on breath of _____________ or ______________
some of the acetoaceteate in the blood will spontaneously disintergrate to form acetone, which is volatile. has a smell fo nail varnish remover - in clinical practise is a sign of serious ketosis or ketoacidosis, can be detected on breath of poorly managed or undiagnosed type 1 diabetics
describe ketone body production in T1D
- lack of insulin lifts repression of hormone-sensitive lipase in adipocytes —> TAG is hydrolysed and fatty acids are released
- the ability of the liver to oxidise fatty acids released from adipocytes may be limited. the liver produces ketone bodies and releases them into the blood for peripheral tissues
- increased levels of ketone bodies in blood (ketonemia) and urine (ketonuria) are observed in uncontrolled type 1 diabetes mellitus. the acidity of ketone bodies lowers blood pH = ketoacidosis
- spontaneous prodution of acetone from acetoacetate is noticeable as ‘fruity breath’
- early in untreated T1D, lack of insulin means that glucagon promotes gluconeogenesis in the liver —> hyperglycaemia
what happens to excess amino acids and why?
degraded and the generated nitrogen excreted largely as urea — because amino acids have no storage form
most amino acids can be used in what?
gluconeogenesis (they are glucogenic), but some are partially of fully keto genetic = the only form acetyl-CoA or acetoacetate
the catabolism of most amino acids begins with what?
the removal of the a-amino group
the amino group in aa metabolism is transferred to what?
a-ketoglutarate in a transaminase reaction
describe the process of transamination (the method by which the catabolism of most amino acids is carried out)
- an amino radical is transferred to the a-keto acid
- the keto oxygen is transferred to the donor of the amino radical
reaction is promoted by transaminase enzymes
ALT vs AST
ALT — fully reversible and does not favour one direction
AST — an exception. the a-amino group of glutamate that has come from many other amino acids is passed on to oxaloacetate to form aspartate, and from there is fed into the urea cycle
ALT is quite a specific marker for liver damage, but AST is more sensitive because there is so much more AST in the liver than ALT
AST : ALT ratio is diagnostic for different types of liver damage.
high ratio over 2 - liver damage caused by _________________
alcoholic liver injrhy
amino acid metabolism: in peripheral tissues, excess ammonia is converted to what?
glutamine — shuttled to liver
amino acid metabolism: in the liver, 2 molecules of NH3 can be released from glutamine by what?
glutamine and then glutamate dehydrogenase
amino acid metabolism: ammonia can also be transferred to oxaloacetate by what? the resulting _____ feeds in the ______?
aspartate transaminase (AST)
the resulting aspartate feeds into the urea cycle
amino acid metabolism: a 2nd route for delivering ammonia to the liver is via what shuttle? describe
alanine-glucose shuttle — alanine from muscle delivers NH3 via ALT, and the resulting pyruvate goes into gluconeogenesis. glucose is retuned to muscle
in the urea a total of what are converted to urea?
2 molecules ammonia and one bicarbonate
what is the total cost of one round of the urea cycle?
4ATP
read rest
ugh
