Liver

Sorting and making Carbon compounds

With a bit of guidance from the pancreas

Hepatic Portal Vein

The liver is the sorting station and repurposing station

To do its job the liver gets two supplies of blood, these both then drain into the hepatic vein and then into the vena cava

To clarify:

Artery = Away from the heart

Vein = Return to the heart

Hepatic Vein and Hepatic Portal Vein are different

It goes:

Intestines, Hepatic Portal Vein, Liver, Hepatic Vein, Vena Cava, Heart

Also, for key words

Hepatic = Liver

Mesenteric = Intestines

The Hepatic "Portal" Vein is called Portal because it connects 2 sets of capillaries:

Capillaries in the Villi, to Capillaries in the Liver

It goes:

Capillaries in the Intestines (and Stomach)
Venules
Mesenteric veins
Hepatic Portal Vein
Branches of the Hepatic Portal Vein
Capillaries in the Liver
Branches of the Hepatic Vein
Hepatic Vein
Vena Cava
Heart

Looking at this image of the liver we can see 4 pipes:

Hepatic Artery
Hepatic Portal Vein
Hepatic Vein
Bile Duct
Lymphatic vessels not shown

Hepatic Artery

goes into the Liver carrying oxygen
This circuit goes:
- heart, aorta, hepatic artery, Hepatic Vein, Vena Cava, heart

Hepatic Portal Vein

goes into the Liver carrying nutrients and toxins - goodies and baddies

Hepatic Vein

returns blood to the heart from the liver
This is a combination of the blood from the Hepatic Artery and the Hepatic Portal Vein
It drains into the Vena Cava (the bodies biggest Vein) and then goes to the heart

Bile duct

Collects bile salts and old heme (hemoglobin from old red blood cells) and anything else that needs to be released into the intestines
The liquid moves down the bile duct then into the gall bladder until it is released in response to the presence of fat in the stomach and intestine

Lymphatic Vessels

Collect any water, proteins, fat, minerals, that leaks from around the hepatocytes and returns fluid to the circulatory system
Not shown on most diagrams

An overview of the movement of blood from the heart, through the Intestines, through the liver, back to the heart.

Blood goes from the heart, down then aorta to abdomen.

Arteries branch off and then branch more as they become smaller arteries and arterioles.

These are the mesenteric arteries (artery = away).

The arterioles branch more, becoming tiny capillaries. So small that only one blood cell at a time can fit.

Here the Red blood cells release oxygen, giving oxygen to the cells of the villi.

At the same time, nutrients that have been absorbed from the Small Intestine into the Villi are passed into the blood stream

Also, some Carbon dioxide from cellular respiration of the cells of the villi also passes into the blood

This blood then moves from capillaries into venioles. These combine into Veins (vein = return).

These Veins are called the mesenteric veins

These veins then combine into one big vein called the Hepatic Portal Vein

Hepatic means liver

The Hepatic Portal Vein then enters the liver, where it branches back out into venioles and capillaries.

This branching is so that the liver can work on the nutrients and remove any toxins

Once the blood has been filtered, the capillaries rejoin into venioles and then veins before connecting to the Vena Cava and moving into the Heart

Liver Lobules

This is the second copy of an earlier image

If we look at this image we can see Liver lobules

The lobule has 4 different vessels running through it:

Branch of Hepatic Artery
Branch of Hepatic Portal Vein
Central Vein connecting to Hepatic Vein
Bile Ductule connecting to Bile Duct

The Central vein takes blood to the hepatic vein, this then flows to the vena cava and the heart

The reason all these vessels are running through the liver is because of the cells that live in there

All these pipes are running past cells

These cells are the workers
These cells sort the carbon compounds
These cells deconstruct and reconstruct carbon compounds
These cells are Hepatocytes

Hepato = liver.

Cyte = cell.

Hepatocyte = Liver Cell

Hepatocytes

Hepatocytes are the Liver Cells

These hepatocytes do a lot of jobs

Move drugs like antibiotics out of the blood stream and into the bile
Move bile salts from the blood and into the bile
Make bile salts from cholesterol
Store vitamins A, B, D, E, K
Store minerals Fe and Cu
Remove iron from heme from recycled red blood cells. The heme once, iron is removed, is now bilirubin. It is disposed of in the bile and causes the color of feces
Turn broken amino acids into Urea
Make the protein albumin and secrete it into the blood to maintain osmotic gradients (this is almost the albumin in eggs that turns white when you cook)
Make protein clotting factors that allow your blood to clot when you bleed
Remove excess protein hormones and Insulin so that the level in the blood can change rather than build up too high
Build and repurpose: Lipids, Proteins, Glucose. In order to balance nutritional demand

There are 3 other cell types we can see in this image

Sinusoidal Cells
- These cells keep the blood cells in the channels and only allow liquid plasma from the blood to get to the hepatocytes for processing
Stellate Cells
- These cells contain fat, they use this to store fat soluble Vitamins, like Vitamin A. They are also involved in forming scar tissue in response to liver injury
Kupffer Cells
- These cells are macrophages that live in the liver (for about 3 days each). They are immune cells, they will capture and destroy any viruses or bacteria or other bad cells that get into the liver.
- Alcohol can trigger the release of damaging oxygen free radicals from kupffer cells. Thus they play a roll in Alcoholic Liver Disease and Cirrhosis

Balancing the Fuels

Fuels for Muscles

Glucose and Fat

Muscles can burn both Glucose and Fat.

If muscles run low on fat, then they will burn amino acids as a last resort. If you go for a marathon run, then about 1% of muscle cellular respiration will be from protein

The image to the side is of a muscle cell (grey) with its Mitochondria (purple).

The image shows that the muscle cell can take in fat (lipid) with it ending being 'burnt' by combining it with oxygen through the process of cellular respiration.

The graph shows the main fuel being burned in the muscles during 3 types of exercises

Walking = Mostly Fat

- 'FFA = Free Fatty Acids - these are the single fatty acids that were cut off Triglycerides by lipase

Jogging = About half Fat and half Glucose from glycogen from in the muscle

Glycogen is the human form of starch

Sprinting = Mostly Glucose from Glycogen.

This is why walking and Jogging is so very good for your health and so very good for reducing body fat and loosing weight. Its also good for your liver and your arteries and for your energy levels overall (due to an increase in mitochondrial density in the muscles)

Evolutionarily, we walked all the time. This sitting thing, where we sit in cars is recent

Evolutionarily, we jogged when hunting. Indeed evidence suggests that we evolved to be joggers. We have one of the longest Jogging ranges of the Large mammals.

Sprinting only happens when we are about to catch our prey. As we sprint, more of our muscle fibers start to do anaerobic respiration, this can only occur with glucose. So at sprinting levels, the contribution of glucose will be higher

Muscles happily burn fat first, as it is very, very high in energy.

Skeletal muscle energy metabolism during exercise - Nature MetabolismHargreaves and Spriet review regulatory mechanisms of ATP resynthesis during exercise and summarize nutritional interventions that target muscle metabolism to enhance athletic performance.

This image is just here to show that muscles are happy to eat Fat and Glucose

They can get their Carbon from either Carbohydrates or Lipids

Either way, they will conduct cellular respiration

Aerobic cellular respiration:

Fuel + Oxygen = Carbon dioxide + Water

This process releases energy, this energy is used to connect phosphate atoms onto Adenosine Diphosphate, recharging the cellular 'battery', and making Adenosine Triphosphate, ATP

Fuel For the Brain

Glucose ... only

The brain is a Fussy eater

It will only eat Glucose

This doesn't mean that you need to though

The liver and the pancreas look after it and will work together to make sure that the brain always has glucose, even if you live in the Artic and only eat meat

Your Liver will make glucose out of fat and if it needs to, protein

Your liver will also make Ketones out of fat when it burns the fat. Fat such as triglycerides and free fatty acids are too big to get through the wall of the blood vessels in the brain, the blood-brain-barrier.

These have only 4 Carbons. C4H6O3. They can be burnt by the brain, and estimates have the normal level of Ketone use by the brain at around 15% of its fuel, with glucose at 85%

If a person is starved for 3 days, this use of ketones will increase to 25% as the stores of glycogen are used up so glucose use drops to 75%

There are no studies beyond 3 days due to ethics, however research indicates that during extreme starvation, the use of Ketones by the brain can increase to half of the fuel. However, the brain will still be burning Glucose

So if a person hasn't eaten for a week, where is the brain getting its glucose from?

One of these is a Ketone

The other is Glucose

Which is which?

What differences are there?

What similarities are there?

You do not have to eat glucose. The Liver will make glucose for the brain

Pancreas

Blood Sugar Controller

The pancreas tries to keep the amount of sugar in the blood to about 1 gram per liter

1 gram of sugar per 1 liter of blood

To put this in perspective, the average person has 5 Liters of Blood, and a teaspoon of honey has about 5 grams of sugar. So, the total amount of sugar in your blood is about the same as the total amount of sugar on a single teaspoon of honey

1 gram per liter is shown differently on different graphs.

1 gram per litre is 100mg per dL (deciliter or 100mL)

1 gram per liter is 5.6mmol/L

This graph shows that blood sugar levels rise up after eating a meal, peaking around 30 min to an hour afterwards, it then decreases.

Here we see the quantity of sugar in the blood as mg per dL

The body wants to keep the blood sugar to around 100mg per dL

The graph shows what happens after eating each food type

The blood sugar for all food types rises up to a peak as the sugar moves from the food, bolus and chyme into the blood

The blood sugar then falls due to the pancreas making Insulin

Rise in blood sugar is highest for Sweet potatoes, white potatoes and Cheerios - why?

Rise is lowest for Lentils and Black beans - why?

These graphs show the 'change in ' blood sugar levels after eating each product

The 'glucose' drink is like a soft drink, like coke

Notice that by 15 minutes sugar has moved into the blood.

The spike for these is around 30 minutes

Notice also that after the high reading from the glucose, how by 120 minutes the line is actually in the negatives, meaning that blood glucose is now too low - this will cause you to crave another glass of coke.

If you hold out and don't have another glass, your pancreas will sense the low level and tell the Liver to make and release human glucose. So you don't need to listen to the craving.

Insulin and Glucagon

The endocrine pancreas is about 2% of the mass of the Pancreas. It releases 2 hormones in response to blood sugar levels

Insulin = Blood sugar is high, Insulin will cause it to be lowered

Glucagon = Blood sugar is low, glucagon will cause it to rise back up

Insulin

Insulin is released by the Pancreas into the blood in response to high blood sugar

Insulin is a key

Insulin = In Sugar In

Insulin binds to the Insulin Receptor on Cells

The Insulin Receptor signals to the GLUcose Transporter - GLUT

Glucose binds to GLUT, and GLUT moves it into the cells

Because glucose is quite a big molecule; C6H12O6 = 24 Atoms

So glucose needs to be transported into the cell. It is Glucose Transporters that do this .

The glucose binds to the Glucose Transporter and it pushes it through into the cell

However, the cell needs to be told when to use the Glucose Transporter

Insulin binds to the Insulin Receptor in the cell membrane this receptor then sends a signal to the Glucose Transporter for it to do its job

Glucose needs to go into cells, without glucose, some cells will die

To maintain the osmotic gradient favoring the movement of glucose into a cell, whenever glucose goes into a cell a phosphate is bound to it's 6th Carbon. This makes Glucose-6-phosphate. Thus there is no 'glucose' in the cell, so diffusion continues to favor the movement of glucose into the cells

Not all Glucose Transporters need Insulin. However, Glucose Transporter number 4, GLUT 4, does. GLUT 4 is the most numerous of the transporters, so its normal operation is extremely important

Diabetes is when the body no longer produces enough Insulin to be able to get blood sugars back down

This is a problem because Insulin is used to get sugar into the cells

Without Insulin these cells starve and start to die

Complications of Diabetes come from two causes

Cell death due to glucose not getting into the cells
High sugar levels in the blood causing damage to the cells that line the blood vessels (Endothelial Dysfunction)

This is related to an increase in the rate of the development of Atherosclerosis and Cardiovascular disease)

Death can occur due to very high levels of Ketones in the blood

Ketones arise when we burn fat, this is only small in most situations (like going for a run)
In a diabetic patient who has not been taking insulin, the sugar in their blood is not getting into the cells. So instead the cells will burn Fat, just fat. Remember from the earlier graphs of exercise, that muscles will burn both fat and sugar. However, here it is just fat. So the production of Ketones is huge, far more than the Liver can handle. So these ketones which are acidic, make the blood acidic. This acidity kills the organs of the body. This process is called Ketoacidosis. If a diabetic person isn't there usual self, ask them have they remembered to take their insulin and offer them something sweet like chocolate (incase they have taken too much insulin). If the person passes out, if any person passes out for any reason, call an ambulance.

Below is an overview of Glucose including Insulin, GLUcose Transporter 4, Insulin Receptor and the effect of attaching a Phosphate to Glucose. This clip is made by a past student of mine. Watch it, Its really good. :-)

Glucagon

What happens when the glucose levels drop below 1 gram per liter?

What happens when "Glucose are gone"?

When glucose are gone, the pancreas's Alpha Cells will release Gluc-a-gon.

This Glucagon signals to the Liver to release stored Glucose and to start making glucose form other things, such as from Fat.

This is a brilliant overview of Blood sugar regulation by the pancreas and its communication with the Liver, muscles and brain through the hormones Insulin and Glucagon

Pancreas uses Insulin and Glucagon to

balance Blood Sugar

The pancreas watches the Blood sugar

When blood sugar is higher than 100mL per deciliter, it releases Insulin from pancreatic beta cells

Insulin binds to insulin receptors on Muscle and Fat cells, allowing Glucose Transporters, in particular GLUT 4, to transport Glucose into cells

Excess Insulin is deconstructed into amino acids by the liver

When blood sugar is too low, Glucagon is released from Pancreatic Alpha cells

Glucagon goes to the Liver where the liver is told to increase the glucose levels

The liver does this by

1. Releasing glucose that has been stored as glycogen.

2. Making glucose from Fat

3. Making glucose from proteins as a last resort

Glycogen

The liver, repurposing Carbon Compounds

This shows a molecule of Glucose an Amino Acid (protein) and a Lipid (Triglyceride)

The atoms for these are Carbon, Oxygen and Hydrogen. The amino acid also has some Nitrogens

Muscles that aren't getting enough oxygen will create lactate from glucose, this lactate will then move to the liver where it can be turned back into glucose.

Looking at the chemical formula you can see that lactate is exactly half a glucose molecule. So 1 glucose = 2 lactate

C6H12O6 = C3H6O3 + C3H6O3

Glucose = Lactate + Lactate

If we look at the 3 core fuels for the body, they are all carbon based

The liver is very hard working, it can turn any of those fuels into Fat, and into Glucose

If you eat a lot of protein shakes, your liver will turn the excess amino acids into fat.

The Nitrogen from amino acids that are converted into Fat or Glucose are released as urea in Urine

So, if you eat lots of glucose, the liver will turn it into Fat, and it will store some of it as Glycogen

Glycogen is the human and animal version of Starch

If you go for a while without eating any Starch or Sugar, then your Liver will start to release glucose from its Glycogen store

The liver will also turn any lactic acid floating around in the blood due to any of your muscles doing anaerobic respiration, into glucose.

If you go for even longer without eating any starch or sugar, then the glycogen store will start to run low, and your liver will start to turn Fat into Sugar

As your fat supplies start to run low, your Liver will increase the conversion of amino acids into glucose. This is the 'muscle wasting' that occurs in prisoners of war

All to keep your brain supplied with Glucose

In this diagram, we can see all the things that the liver is involved in

At the top you have food entering, it is divided into 3 fuel types, Fats, Carbohydrates and proteins

At the bottom are the two metabolism buckets. We can see that 'Metabolism in most tissues' can burn fat and glucose. But we can see that 'Brain metabolism' can only burn glucose

However, we can also see pipes connecting the 3 'pools'. We see words ending in -lysis. This means to break. We also see words ending with '-genesis' this means to create.

The liver can do all of the pipe things:

Lipogenesis - turning glucose into fat
Lipolysis - cutting triglycerides into free fatty acids, monoglycerides and glycerol
Glycogenesis - binding up glucose in glycogen stores
Glycogenolysis - breaking glucose off the glycogen stores
Gluconeogenesis - making new (neo) glucose from Amino acids.

not shown on this diagram, gluconeogenesis will also make new glucose from Fat
also not shown on this diagram, gluconeogenesis will make new glucose from Lactate

Liver and Pancreas partnership

The liver works with the Pancreas to ensure that the Brain has a constant supply of Glucose

You do not have to eat glucose for your brain to have glucose. Your liver will make it out of fat and protein.

Your pancreas monitors the level of Glucose in the Blood, keeping it to around 1 gram per Liter of blood.

A teaspoon of honey has 4 grams of sugar

The part of your pancreas that does this is called the Endocrine pancreas.

The Endocrine pancreas accounts for only about e% of the size of the pancreas

The pancreas releases 2 different hormones in response to blood sugar levels

Insulin - made in pancreatic Beta Cells. This is the key that lets Glucose into Muscle cells by binding to insulin receptors and activating Glucose Transporters

Glucagon - made in pancreatic Alpha Cells. This tells the liver to make Glucose for the blood

So, in response to Sugar levels:

Insulin is released in response to higher Sugar levels
Glucagon is released in response to lower Sugar levels

The liver 'listens' to the pancreas

Receives Insulin

Stores glucose as Glycogen
Turns excess glucose into Fat

Receives Glucagon

Releases glucose from Glycogen
Makes Glucose from Fat
Makes Glucose from Lactate
Once Fat supplies run low, will make glucose from Amino Acids

Lactate to Glucose to Lactate

Muscles release Lactate during anaerobic respiration, this lactate travels to the Liver where it is turned back into Glucose, this then travels back to muscles, where it can be turned back into Lactate. This process uses more energy from the body overall as more ATP is used to create the glucose from the lactate, than the amount created by turning glucose back into lactate. So, your body will want those muscles to rest

Amino Acid Synthesis

The liver can also make some amino acids out of glucose for carbon and other amino acids for the nitrogen

The liver can also make some amino acids out of other amino acids, this is the main way that the liver keeps a balance of the 20 different amino acids. Importantly though, the liver can only make some of the amino acids. These are called 'non-essential' amino acids. They are called this because you don't need to eat them, the liver can make them. There are also 'essential' amino acids. You have to eat these ones, because the liver cannot make them.

Liver functions

The liver does many jobs, many more than we will cover on this page.

These clips here are a good recap of what the liver does

Liver and The Diet

The brain burns glucose. Muscles can burn glucose and fat.

Because the brain needs glucose, the liver will make glucose out of Fat and Amino Acids if there is not enough glucose in the blood stream

With our 'Western diet' we always have glucose in the blood stream, so the excess glucose is turned into fat in fat cells and by the liver

Diets very high in sugar and fat result in fat cells growing in size and multiplying.

Individuals that have these high fat high sugar diets will also have more fat stored in their liver. This decreases the effectiveness of the Liver

Liver Disease

Here are some clips looking at Liver diseases. They show how vital the liver is for overall health and life

Metabolism and Nutrition

Hank Greens Crash course lectures are really good and tie nicely to the whole topic

If you haven't watched these clips yet, now would be a good moment to watch. You'll be able to tie what he talks about to what you have learnt

Exercise

Exercise is a really good place to look at to see how the pancreas and liver work together to maintain glucose levels. So that the brain can burn glucose while the muscles can burn glucose and fat.

These graphs compare several things

They get people to exercise in the grey shaded area for 1 hour. The exercises are:

Endurance = Running

Resistance = Lifting Weights

They then looked at the level of Glucose (A) and Lactate (B) in the Blood at the end of the exercise and then during recovery

Endurance = Running for an hour

From looking at graphs A and B we can see that:

Endurance blood sugar is slightly lowered but returns to normal quickly. - This shows that the pancreas and liver worked together to keep blood sugar stable I

There is a slight increase in lactate. Lactate forms during anaerobic respiration, this gives the 'burn' feeling. This shows that the muscles were getting enough oxygen, so they did aerobic respiration. There was a very small about of anaerobic respiration.

How were the pancreas and liver were able o maintain such a flat line of glucose? In graph C we see that insulin levels actually reduced. Although insulin is used to get glucose into muscle cells, it is more important to save glucose for the brain. So the glucose intake into the muscle cells is supplemented heavily by the glycogen stored in the muscles themselves and by Fat. That way the brain keeps getting its glucose. Also, helping the brain get glucose is its specialized GLUTs that don't actually need insulin to let glucose in)

The Glucagon levels skyrocketed. Glucagon levels increased 4 fold. This glucagon released from the pancreas alpha cells told the liver to release glucose from stored glycogen. It also told the liver to make more glucose (gluconeogenesis). It will do this mainly from Fat. But it will also do this to any lactate floating around.

Resistance = Lifting Weights for an hour

An hour of lifting weights has a different effect. We already know this because of our own experiences in the gym. How many pullups can you do before you feel the 'burn'. The burn is caused by lactate. You can jog for an hour before you feel the burn, but you can't do an hour of pullups.

This is because you are not using all of the power of your leg muscles each time you strike the ground to run forwards. However you are using almost all of the power of your biceps to do a pullup. The more of the muscles power you use the more oxygen it will need to do cellular respiration, and the more likely it will run out of oxygen (called an oxygen debt). Thus it will go into anaerobic respiration sooner and start making the big C3H6O3 lactate out of C6H12O6 glucose.

From looking at graphs A and B we can see that:

Resistance exercise resulted in an increase in blood sugar and a huge increase in Lactate. For glucose 100mg/dl is the same as 5mmol/L. So after an hour of lifting weights, you have more lactate in your blood than glucose. Your liver turns this lactate back into glucose, you can see this with the fast drop in lactate levels once exercise has finished. 3 hours later lactate levels are back to near zero.

The reason Lactate increases so much is because lifting weights is an Anaerobic exercise

During these maximum lifts your muscles will only burn glucose, not fat.

You can see this in the graph at the bottom.

So how does the Pancreas and Liver respond to this anaerobic exercise? You can see in graph C that there is an increase in Insulin levels, this is to force more blood glucose into the muscles so that they can do their anaerobic respiration.

There is a slight increase in glucagon to tell the liver to increase production of glucose from stored glycogen, fat and lactate. A lot of the lactate being made will not be from blood glucose, but from glucose that is already in the muscles and stored as glycogen. This makes even more sense when you remember that graph A and B show that blood lactate levels increase to twice the concentration of blood sugar, so where did the sugar come from for the creation of that lactate? It came from sugar stored in the muscles as glycogen.

It seems like an oxymoron that insulin levels are increasing and blood sugar is increasing, however some of this increase in blood sugar is due to the conversion of lactate back into sugar by the liver.

You'll also see that Insulin levels remain high for another half an hour as the body tries to push glucose into the muscles to restock the glycogen. This correlates with a decrease in blood sugar levels back to normal.

Lactate is lactic acid without a hydrogen ion. This decreases the pH of the muscles and causes muscles to 'burn' and eventually stops you from exercising. When you take a rest and let oxygen back into the muscles, most of this lactate and lactic acid goes into aerobic respiration and is burnt down to CO2 and H2O. Most of the Lactate left over at the end of the exercise will be burnt by the muscles, with the liver only converting some of it to glucose. This contributes to the fast drop in lactate and the slow drop in glucose (why burn big glucose molecules when the muscles can burn the 3 carbon lactate instead).

Muscles that have worked out like this will continue to need oxygen and fuel to repair themselves from the work out, which is why the arteries and veins on those muscles will remain large for quite a while and why the muscle can be a little bit swollen due to all the extra blood running through it.

Remembering that no matter what the muscles are doing, the brain has to have oxygen and glucose.

If you find exercise metabolism interesting, have a look through the Nature article below. Its from the recent Tokyo Olympic Games

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