The normal liver - metabolism (lecture series) Flashcards
What are the main functions of the liver ?
- controls metabolism of fats, proteins, carbs
- produces bile
- produces cholesterol + bilirubin
- produces proteins (albumin + clotting factors)
- filters blood
- destroys old RBCs
- stores glycogen, vitamins, minerals
Where does the liver receive blood from ?
- spleen
- stomach
- pancreas
- duodenum
- mesentery
pretty much whole GI tract except rectum
Which vessel transports blood from the GI tract into the liver ?
the portal vein
Which hormones does the liver primarily respond to ?
- glucagon
- insulin
What are the key metabolic roles of the liver when the body is in a fasting state ?
- glycogenolysis
- gluconeogenesis
- ketogenesis
What is glycogenolysis ?
Breaking down stored glycogen to release glucose when body is in a fasting state
Which hormone promotes glycogenolysis?
glucagon
What is gluconeogenesis ?
Producing new glucose from scratch in the fasting state, using scraps of other nutrients
Which hormone promotes gluconeogenesis ?
glucagon
What is ketogenesis ?
producing emergency fuel (ketone bodies) using Acetyl-CoA in the fasting state
What triggers ketogenesis ?
prolonged fasting causes breakdown of fatty acids from adipose tissue
Which hormone suppresses ketogenesis ?
insulin
What can ketogenesis be a sign of? why?
Type 1 diabetes
because ketogenesis is usually suppressed by insulin, so an increase in the process would suggest a decrease in insulin
What are the key metabolic roles of the liver when the body is in a fed/absorptive state ?
- glycogenesis
- fatty acid biosynthesis
- removing surplus ammonia (AA metabolism)
- producing gluconeogenesis precursors (AA metabolism)
What is glycogenesis ?
storing absorbed surplus dietary glucose as glycogen
What drives glycogenesis ?
high blood glucose
What hormone suppresses glycogenesis ?
glucagon
What is fatty acid biosynthesis ?
Use surplus carbon substrate to produce fatty acids for delivery to adipose tissue
What promotes fatty acid biosynthesis ?
- insulin
- high cellular ATP levels
Which hormone suppresses fatty acid biosynthesis ?
glucagon
How does amino acid metabolism dispose of surplus ammonia ?
- surplus ammonia arrives in liver carried by glutamate, glutamine or alanine amino acids
- transaminase hydrolyses the excess amino acids to release nitrogen
- N is disposed as urea eventually
How does amino acid metabolism produce gluconeogenesis precursors ?
- transaminase release N from amino acids
= N-free amino acids are the precursors for gluconeogenesis
What are the 2 methods of hepatic glucose production in a fasting state ?
- gluconeogenesis
- glycogenolysis
Which hormone usually suppresses hepatic glucose production ?
insulin
What is the main reason for hyperglycaemia in type 2 diabetes ?
failure to regulate hepatic glucose production
Which cells can perform glycolysis ?
almost all cells in the body
What process is the main player in carbohydrate metabolism ?
glycolysis
What is glycolysis ?
breaking down carbohydrates/glucose
What substance is produced by the end of glycolysis, if in aerobic conditions ?
pyruvate
What substance is produced by the end of glycolysis, if in anaerobic conditions ?
lactate
How does glucose enter cells ?
using glucose transporters via co-transport
transporters are tissue specific
Which glucose transporter is used to let glucose in/out the liver ?
GLUT-2
What stage of carbohydrate metabolism traps glucose within the cell ?
phosphorylation
Which enzyme catalyses carbohydrate phosphorylation?
hexokinase
What conditions are required for glucokinase to be effective at trapping glucose in the liver ?
glucose levels must be high - e.g after a meal
What is the liver variant of hexokinase called ?
Hexokinase-IV or glucokinase
What are the first 2 steps of glycolysis ?
glucose —> fructose-6-Phosphate (F-6-P)
F-6-P —> fructose-6-bisphosphate (F-6-BP)
Which step of glycolysis is the most critically regulated step ?
F-6-P ——> F-6-BP
uses ATP
What is the net result of glycolysis in aerobic conditions ?
- 2 pyruvate
- 2 ATP
- 2 NADH
What is the structure of glycogen like ?
- highly branched
- glucose polysaccharide
- alpha-1,4 linked backbone
- alpha-1,6 linked branches
What are the 2 main glycogen store in the body ?
- liver
- skeletal muscle
Are glucagon levels elevated or decreased in a fasting state ?
elevated
Are insulin levels elevated or decreased in a fasting state ?
decreased
What is glucagon’s effect on glycogenesis ?
glycogenesis = inhibited by glucagon
What is glucagon’s effect on glycogenolysis ?
glycogenolysis = promoted by glucagon
Describe how glucagon regulates formation/destruction of glycogen stores ?
increases cellular Protein Kinase A (PKA) which….
- directly inhibits glycogen synthase = stops glycogenesis
- indirectly activates glycogen phosphorylase (via phosphorylase kinase) = activates glycogenolysis
What are the body’s primary and secondary methods of regulating blood glucose in periods of fasting/starvation ?
primary:
- glycogenolysis
- glycogenesis inhibiton
secondary:
- gluconeogenesis
What are the substrates used to form new glucose in gluconeogenesis ?
- Lactate re-oxidised into pyruvate via Cori Cycle
- Glycerol released by lipid hydrolysis
- amino acids metabolised to alpha-keto acids
When does glucogneogenesis occur ?
when the body is well into starvation mode and glycogen stores have already been used
glycogenolysis can sustain an overnight fast but not much longer, so gluconeogenesis kicks in
Which hormone is the main regulator of gluconeogenesis ?
glucagon
How does glucagon increase gluconeogenesis ?
increases availability of PEP (molecule converted into pyruvate in glycolysis) by…
1. increasing expression of PEP carboxykinase
2. decreasing expression of pyruvate kinase
Increases glycolysis by activating F-6-P into F-6-BP (the early steps of glycolysis)
What happens to levels of insulin and glucagon after a meal ?
- insulin increases/spikes dramatically
- glucagon decreases dramatically
What processes does insulin up-regulate ?
- glucose uptake
- glycogenesis
- protein synthesis
- fat synthesis
What processes does insulin down-regulate ?
- ketogenesis
- lipolysis
- gluconeogenesis
- glycogenolysis
What processes does glucagon up-regulate ?
- ketogenesis
- lipolysis
- gluconeogenesis
- glycogenolysis
- amino acid uptake
What processes does glucagon down-regulate ?
- glycogenesis
- fat synthesis
What factors affect the regulation of metabolism ?
- availability of substrates
- allosteric control (metabolites bind to allosteric site to modulate activity of enzyme)
- regulatory phosphorylation (phosphorylation of glycogen synthase etc)
- changes in transcription of enzymes that control each process
Which enzyme catalyses the reaction of F-6-P —> F-6-BP in glycolysis ?
PFK-1
phosphofructokinase-1
What is the rate limiting (slowest) step of glycolysis ?
F-6-P —> F-6-BP
How is PFK1 activated ?
- allosterically by activated AMP
- by F-2,6-BP (fructose-2,6-bisphosphate)
How is PFK1 repressed ?
by ATP + Citrate
What is the interaction between PFK1 and PFK2 ?
- PFK1 is activated by AMP and F-2,6-BP
- F-2,6-BP is the product of an activated PFK2 molecule
Which hormone
a) activates PFK 2?
b) deactivates PFK2?
activates = insulin
deactivated = glucagon
active in well-fed state
Is PFK2 active in the fasting or well-fed state ?
well-fed state
What is the link reaction ?
Pyruvate + CoA + NAD —> Acetyl CoA + NADH + CO2
What are the products of the link reaction ?
Acetyl CoA + NADH + CO2
What happens to pyruvate in the link reaction ?
it is oxidised into acetate
What are the 4 main carbon compounds in the krebs cycle, in order from the 6c molecule ?
6c = citrate
5c = α-ketoglutarate
4c = succinate
4c = oxaloacetate
Where does the krebs cycle take place ?
mitochondrial matrix
Which molecule needs to be present in order for Acetyl CoA to enter the krebs cycle ?
Oxaloacetate (OAA)
What is lipolysis ?
triglycerides —> fatty acids + glycerol
what is lipogenesis ?
glycerol + fatty acids —> triglycerides
