case 5 - liver function Flashcards
where does the liver receive blood from
via the portal vein, receives blood from the spleen, and most of the GI tract
what does the liver respond to
insulin and glucagon
what does glycogenolysis do
makes glucose available in the fasting state
what is glycogenolysis promoted by
glucagon the hormone
what does gluconeogenesis produce
glucose from scraps and makes it available in the fasting state
what is gluconeogenesis promoted by
glucagon
what is ketogenesis
the use of acetyl-CoA to produce emergency fuel
what is this emergency fuel
ketone bodies
what is ketogenesis promoted by
the surplus of mobilised fatty acids in starvation or T1D
when does ketogenesis run
in the fasting state
what are the ketone bodies
acetoacetate and hydroxybutyrate
what does glycogenesis do
absorbs surplus of dietary glucose and stores as glycogen
what is glycogenesis driven by
high blood glucose
when does glycogenesis run
in the healthy state
what does fatty acid biosynthesis use
surplus carbon substrate to produce FA for delivery to adipose tisse
what is fatty acid biosynthesis promoted by
insulin and high cellular energy levels - ATP
what is fatty acid biosynthesis supressed by
glucagon
what does amino acid metabolism result in
the production of gluconeogenesis precursors
what are the precusors for gluconeogenesis
ketoglutaraten and oxaloacetate
when does the liver take up glucose
only at high glucose levels and uses some of it to produce glycogen
what happens to the rest of the glucose
degraded into acetyl-CoA first and then into fatty acids and triacylglycerols to deliver to adipose tossie
how does the liver produce and then release glucose into the blood stream in the fasting stat
It does this by breaking down glycogen and later by dementating amino acids to produce building blocks for gluconeogenesis
what does the hydrolysis of triacylcylcerols release
fatty acids that can be broken into acetyl-CoA
can acetyl-CoA ever be turned back into glucose
no
what is acetyl-CoA’s contiribution to fasting metabolism
via the production of ketone bodies
what is at the heart of carbohydrate metabolism
glycolysis
what does glycolysis do
catabolism (breaking down) of glucose (and most other carbohydrates via glucose) in all tissues
Generation of intermediates for other pathways
Generation of energy and (in aerobic conditions) by reducing equivalents
what is the end product dependent on
oxygen -produces pyruvate under aerobic conditions and lactate under anaerobic conditions
what facilitates the diffusion of glucose into cells
the family of glucose transporters - GLUT
where is GLUT4 specific for
adipose tissue
where is GLUT2 specific for
the liver
what can GLUT2 facilitate
both glucose entry into the liver cells and exit
what does phosphorylation do
traps glucose in the cell because the ionic phosphate cannot cross the membrane spontaneously
what is this phosphorylation catalysed by
enzym hexokinase
when are the enzyme variants in more tissues fully active
at low concetrations of glucose
what has a much higher capacity to trap glucose in the liver and when
Hexokinase-IV or glucokinase, in the liver has a much higher capacity to trap glucose in the liver, but only when glucose concentrations are high - especially after a meal
describe the steps in glycolysis
glucose 6-P is isomerised to fructose-6-P
F-6-P is phosphorylated again to yield F-1,6-BP in the most critical regulated step
this phosphorylation commits the molecule for further degradation
So this is something to be avoided in the fasting state when we want to preserve glucose
The next steps up to PEP are fully reversible
The energy from burning glucose as fuel depends on oxidation, but glycolysis is only the preparation for that
In the only oxidative step of glycolysis, GA-3P is converted into 1,3-BPG,
NADH + H+ generated in this oxidative step can be regenerated under anaerobic conditions by reducing pyruvate to lactate
The liver can re-oxidise lactate to pyruvate
Accounting for the investment of 2 ATP per molecule glucose early on, there is a net generation of 2 ATP per glucose in glycolysis
what is the Warburg effect
Compare 2 vs 28 ATP excessive glucose consumption of tumours. Aerobic glycolysis is inefficient but fast
what is glucose greatly preferred for
Glucose is greatly preferred as energy source by brain and nervous tissue, and essential for the adrenal medulla, testes and mature erythrocytes
the liver is the main tissue in performing what two maintenance mechanisms
gluconeogensis and glycogenesis
what is glycogen
is a highly branched, all glucose poly-saccharide with an alpha 1,4 linked backbone and alpha-1,6 linked branches
Is the storage form of glucose, mainly in skeletal muscle and liver
what is glycogen synthesised
after a meal and degradation during an over night fast as key mechanisms that maintain blood glucose levels
what is glycogen synthesis regulated by
glucagon
what is glycogen metabolism controlled by
glucagon and insulin
what does glucagon trigger
the production of cAMP in cells, which in turn activates protein kinase A -PKA
what does PKA do
phosphorylates glycogen synthase directly, and glycogen phosphorylase via phosphorylase kinase
what does glucagon do
promotes glycogenolysis and inhibits glycogenesis
what does phosphorylation have
Phosphorylation has opposite effects on the two enzymes: glycogen synthase becomes inactive, while glycogen phosphorylase is activated by phosphorylation
what is gluconeogenesis
a pathway active in the liver that regenerates glucose from non-carbohydrate precursors
this can happen in the kidney after prolonged fating
describe lactate
from skeletal muscle is re-oxidised to pyruvate
this liver-muscle cycle is called the cori cycle
what is glycerol released by
the hydrolysis of fats (TAGs) in adipocytes
what are amino acids from tissue protein metabolised to
alpha-keto acids
what is the main key regulator of gluconeogenesis
glucagon
how does glucagon act
by repressing pyruvate kinase, thus increasing the availability of PEP for gluconeogensis
what can glucagon also do
increase the expression of PEP carboxykinase
what does glucagon also repress
finally, glucagon represses the formation of F-2,6 BP, which is a repressor of fructose-1,6-biphosphatase in gluconeogenesis (while it is an activator of PFK-1 in glycolysis)
what does insulin increase the levels of
glucose uptake
Protein synthesis
Glycogen synthesis
Fat synthesi
what does insulin decrease the levels of
ketogenesis
Lipolysis
Gluconeogenesis
Glycogenolysis
what are the regulatory mechanisms
availability of substrates e.g glucokinase
Allosteric control (regulatory metabolites bind outside of the active site of enzymes and modulate activity) e.g PFK1 regulation by F2,6-BP
Regulatory phosphorylation e.g phosphorylation of glycogen synthase and phosphorylase kinase by PKA
Changes in transcription e.g increase in expression of glycolytic enzymes triggered by insulin; suppression of gluconeogenesis in the liver
what is PFK1
phosphofructokinase
when does PFK1 act
PFK1 acts after isomerisation of glucose-6-P to fructose-6-P and catalyses the most important regulated step of glycolysis
what is the rate limiting slowest step in glycolysis
PFK1
what is PFK1 allosterically activated by
AMP and repressed by ATP and citrate
what else is PFK1 activated by
PFK-1 is activated by fructose-2,6-biphosphate whose biosynthesis in turn is regulated by insulin and glucagon
what is the pyruvate dehydrogenase complex
The PDC complex is a gigantic multi-enzyme complex with dozens of copies each of three enzymes, E1,E2,E3 and end product is Acetyl-CoA - in the mitochondria
what is the TCA cycle
the TCA cycle is a central ‘metabolic roundabout’ with multiple entry and exit points.
Several of the intermediates are involved in gluconeogenesis, amino acid and heme metabolism
The oxidative catabolism of carbohydrates, lipids and amino acids comes together here
where do all TCA reactions happen and what do they require
All TCA cycle reactions happen in mitochondria and require oxygen to recycle the reduced co-enzymes NADH+H+ and FADH2
what starts off these TCA reactions
Acetyl-CoA
what does the TCA cycle produce
the TCA cycle produces a full oxidation of acetyl-CoA to 2 carbon dioxides
what does the oxidation of NADH and FADH2 in the mitochondria generate
28 ATP per molecule of glucose and 2 GTP
what are four intermediates of the TCA cylce
amino acid metabolites
what does this allow
their conversion to glucose by gluconeogenesis
where are TAGs stored
adipocytes
what does fatty acid and TAG synthesis start with
cytoplasmic acteyl-CoA
where is acetyl-CoA generated and what does this mean
Since most acetyl-CoA is generated in mitochondria and cannot cross the membrane, a shuttle is needed
what is the regulation of hepatic lipogenesis by
Regulated by availability of substrate: carbohydrate rich meals provide carbon (pyruate/Acetyl-CoA) and NADPH via the pentose phosphate pathway
what stimulates lipogenesis
Insulin stimulates lipogenesis via transcriptional activation of L-PK, ACC and other enzymes leading to TAG
what is the next step and what is a feature of it
the next step, catalysed by acetyl-CoA carboxylase (ACC) is rate limiting and regulated:
at is this step activated by
a citrate
what is ACC inactivated directly by
ACC is inactivated directly by fatty acetyl-CoA and by phosphorylation by AMPK
what happens via regulation of ACC phosphorylation
Via regulation of ACC phosphorylation, insulin indirectly activates ACC; glucagon and AMP inactive ACC
the beta oxidation of fatty acids produces what
large amounts of energy:
Per 2-carbon unit, one FADH2, one NADH and one acetyl-CoA are produced. Ultimately, these produce 2,3 and 12 ATP, respectively.
Per 16-carbon (palmitoyl)-CoA, that’s 129 ATP!
what are ketone bodies
ketone bodies are an ‘emergency fuel’ that the liver can produce to preserve glucose. The liver itself cannot use ketone bodies though
what is a sign of ketoacidosis
Some will randomly become acetone and a sign of ketoacidosis
what does lack of insulin do
lack of insulin lifts repression of hormone-sensitive lipase in adipocytes > TAG is hydrolysed and fatty acids are released
what does the acidity of ketone bodies do
The acidity of ketone bodies lowers blood pH (ketoacidosis)
what is spontaneous production of acetone from acetoacetate noticable as
fruity breath
what happens early in untreated T1D
Early in untreated T1D, lack of insulin means that glucagon promotes gluconeogenesis in the liver > hyperglycaemia
what does the catabolism of most amino acids begin with
the removal of the alpha amino group
what happens to the amino group
The amino group is transferred to alpha-ketoglutarate in a transaminase reaction
when alanine is converted into pyruvate, alpha-ketoglutarate is converted into glutamate
what do most transaminases transfer their amino group to
alpha-ketoglutarate
why is ASP an exception that is not fully reversible and does not strongly favour one direction
ASP is an exception. The alpha amino group of glutamate that has come from many other amino acids is passed on to oxaloacetate to form aspartate , and from here is fed into the urea cycle
what is the specific indicator for liver damage
ALT
at is more sensitive and why
serum AST is more sensitive because the liver contains larger amounts of AST rather than ALT
what is excess ammonia converted to in peripheral tissues
glutamine
what can glutamine carry
2 nitrogen atoms
what happens in the liver
In the liver, two molecules NH3 can be released from glutamine by glutaminase and then glutamate dehydrogenase
what is the second route for delivering ammonia to the liver
a second route for delivering ammonia too the liver is via the alanine-glucose shuttle. Alanine from muscle delivers NH3 via ALT; resulting pyruvate goes into glyconeogenesis; glucose is returned to the muscle
what else can ammonia also be transferred to
Ammonia can also be transferred to oxaloacetate by aspartate transaminase. The resulting aspartate feeds into the urea cycle
what happens to the mitochondria, ammonia and CO2 in the liver
In liver mitochondria, ammonia and CO2 are joined by carbamoyl phosphate synthetase I. Two molecules of ATP are required to drive the process.
what does glucokinase do
The low affinity, high-capacity glucokinase can channel glucose into glycolysis only when glucose is abundant
what do high levels of glucose-6-phosphate promote
glycogenesis
promote NADPH production in the pentose phosphate pathway
what happens to glucolysis and gluconeogenesis after this
Glycolysis is promoted and gluconeogenesis suppressed by a high insulin’glucagon ratio: PFK1 activation by F-2,6-BP, dephospho rylation (=activation) of pyruvate kinase and PDH
what are surplus carbohydrates from a meal converted into
Surplus carbohydrates from a meal are converted to acetyl-CoA and then mainly channelled into fatty acid synthesis:
what does high ATP do
high ATP inhibits isocitrate dehydrogenase, leading to an accumulation of citrate in mitochondria and export to the cytoplasm
what does ATP-citrate lyase do
ATP-citrate lyase restores acetyl-CoA in the cytoplasm, and ACC is activated by dephosphorylation and by citrate
what is TAG synthesis promoted by
TAG synthesis is promoted by the high availability of fatty actyl-CoA both from de novo fatty acid biosynthesis and from dietary Fats
what happens to the surplus amino acids
Surplus amino acids are recycled, redistributed or degraded into pyruvate, TCA cycle intermediates or acetyl-CoA
where are branched chain amino acids only used
by muscle
what is the number one priority of the liver during fasting state
to maintain blood glucose levels for the glucose dependent tissues
at does glucagon do
Glucagon stimulates the activation of glycogen phosphorylase via PKA mediated activation of phosphorylase kinase
what does the liver specific enxyme glucose-6-phosphatase do
The liver specific enzyme glucose-6-phosphatase produces glucose from G-6-P. Glucose is released into the bloodstream
what does glucagon also do
Glucagon also triggers a reduction in the concentration of fructose-2,6-biphosphate by shifting PFK-2 towards phosphatase activity
what does the reduction in F2-6-BP mean
The reduction in F2,6-BP means that gluconeogenesis is favoured over glycolysis; the key enzyme fructose-1,6-biphosphatase is no longer inhibited by F-2,6-BP
what are the main sources of carbon for gluconeogenesis
lactate from muscle and glycogenic amino acids
what does the hydrolysis of TAGs do
the hydrolysis of TAGs in adipose tissue supplies the liver with fatty acids
what is ACC directly inhibited by an indirectly
The key enzyme of fatty acid biosynthesis, ACC is inhibited directly by abundantly fatty acyl-CoA and indirectly by phosphorylation (mediated by AMPK and glucagon)
what does ACC inhibition do
ACC inhibition lowers malonyl-CoA which in turn activates beta-oxidation
what does the abundant acetyl-CoA do
The abundant acetyl-CoA activates pyruvate carboxylase (for gluconeogenesis) and inhibits degradation of pyruvate (inhibition of PDH)
what does the liver produce during prolonged fasting
during prolonged fasting, the liver produces the ketone bodies aceto-acetate and 3-hydroxy-butyrate that can be used as emergency fuel by all tissues, even the brain
