Lecture 29: Tissue differences

Gluconeogenesis occurs

liver mitochondrial matrix and liver cytoplasm

-maintains blood glucose around 5mM

Liver’s responsibility

storing glycogen, as well as for converting glycogen back to glucose and sending it back to bloodstream to be transported to muscles and brain

muscle’s role

have a small amount of glycogen, which is
used up by them (not involved in gluconeogenesis

brain’s role

feeds only on glucose, relies on liver to supply it

direction of glucose in liver

bidirectional glucose handling as glucose can go into the liver from blood and glucose can also go out of liver into blood

Hormonal interpretation

insulin high: glucose goes into liver and is stored as glycogen

glucagon high: glycogen gets broken down and glucose goes back into blood

glucagon function

triggering the liver to convert stored glycogen into glucose (glycogenolysis) and creating glucose from non-carbohydrate sources (gluconeogenesis) during fasting or exercise

receptor expression difference

insulin, glucagon, and epinephrine are water soluble hormones so they need receptors but glucagon receptors are only present in liver so only liver can respond to glucagon not muscle

liver is the organ responsible for

converting glycogen back to glucose and sending glucose into the bloodstream

enzyme expression difference

liver has the enzyme Glucose-6-phosphatase that is crucial for gluconeogenesis but muscle does not have the enzyme so it can’t complete gluconeogenesis

isozymes

enzymes that differ slightly in amino acid sequence but perform a similar function and often in different tissues/organs

-allow for fine tuning of metabolism

Irreversible glycolysis steps: 1, 3, and 10

1. glucose → glucose-6-phosphate

-enzyme: hexokinase

3. fructose-6-phosphate → fructose-1,6-bisphosphate

-enzyme: phosphofructokinase

10. PEP → pyruvate

-enzyme: pyruvate kinase

Liver and Muscles have different

pyruvate kinase isozymes

Liver pyruvate kinase

when epinephrine is secreted, liver pyruvate kinase gets phosphorylated and is inactivated

Muscle pyruvate kinase

not phosphorylated by epinephrine so its not affected the same way

pyruvate kinase isozymes big idea

liver pyruvate kinase is regulated by phosphorylation

muscle pyruvate kinase is not modified the same way by epinephrine

High Km means

low substrate binding affinity

Low Km means

high substrate binding affinity

glucokinase

the liver isozyme of hexokinase

hexokinase

muscle form of the enzyme

liver glucokinase Km value

high value bc its responsible for maintaining about 5mM glucose in blood, only works strongly when glucose is high

-under substrate level control

liver has to make sure there is enough glucose for

blood, brain, and muscles

muscle hexokinase Km value

low value around 0.1mM bc muscle must work even when glucose low bc muscles have to function always

-high affinity, low Km

Regulation difference

Liver glucokinase is regulated by substrate level

Muscle hexokinase is regulated by feedback inhibition

Muscle hexokinase is regulated by

feedback inhibition, glucose-6-phosphate (G6P) is the allosteric inhibitor

Liver glucokinase is regulated by

substrate level, it needs enough glucose to be active

Liver glucose transporters

always present on membrane because liver must be ready to take glucose in and send glucose out

Muscle glucose transporters

come to the membrane only when insulin is present and after bringing in enough glucose, they can be endocytosed, and then they stay inside until the next insulin signal

glucose transport into liver vs muscle

muscle transporters are insulin-dependent in membrane localization

liver transporters are constitutively present

Cori cycle (AKA lactic acid cycle)

a metabolic pathway where lactate produced by anaerobic glycolysis in muscles travels to the liver to be converted back into glucose via gluconeogenesis, which then returns to the muscles to fuel further contraction

Why Cori cycle matters

The body has limited pools of NAD+, NADH, FAD / FADH2, and ATP / ADP

glycolysis needs NAD+ to keep going, so how do we recycle NADH ack to NAD+ when oxygen is limited

under aerobic conditions,

ETC recycles NAD+ bc oxygen is the final electron acceptor

If oxygen is not available:

ETC cannot handle the recycling but glycolysis still needs NAD+ so the cell uses fermentation

In muscle anaerobic conditions

pyruvate is reduced to lactate which allows NADH → NAD+ and lets glycolysis continue

fermentation is used to make ATP but to also recycle NAD+

why muscles make lactate

During strenuous exercise, muscles may not get enough oxygen but glycolysis can still give a little ATP so muscle keeps going with anaerobic glycolysis, pyruvate becomes lactate and NADH becomes NAD+

Liver’s role in anaerobic conditions

Muscle sends lactate to the liver where lactate is oxidized back to pyruvate and NAD+ is reduced to NADH, then pyruvate undergoes gluconeogenesis and glucose can be sent back to muscle

Pathways involved in Cori cycle

glycolysis, fermentation, and gluconeogenesis

NAD+/NADH ratio in muscle

pyruvate is reduced to lactate so NADH gets oxidized to NAH+ so more NADH than NAD+

NAD+/NADH ratio in liver

lactate is oxidized to pyruvate so NAD+ is reduced to NADH so there is more NAD+

pyruvate and lactate structures

pyruvate has a ketone so its more oxidized and lactate has an alcohol so its more reduced

pyruvate → lactate = reduction

lactate → pyruvate = oxidation