Although we tend not to give it too much thought (except for a sincere apology sent its way when we drink too much), the liver plays a crucial role in maintaining a state of metabolic homeostasis – that is, it continuously senses the current energetic state of the body, receives signals about the current energetic demands of the body, and makes the necessary adjustments required to maintain a healthy balance.
The ability to perform this monstrous task requires an incredible network of mechanisms, but for our needs this week, we will focus on two primary pathways:
First, as shown in image 1, the liver is the primary regulator of glucose homeostasis. It continuously receives information about the energetic demands of the body via hormones insulin, glucagon, and epinephrine. Based on these signals it may store take in glucose from the bloodstream and store it as glycogen (thus lowering blood glucose levels); or, it may release glucose into circulation by breaking down stored glycogen (thus raising blood glucose levels).
Second, as shown in image 2, the liver takes in all forms of energy-containing molecules (e.g. glucose, fructose, and lipids) and is able to convert all energy forms into triglycerides (3 fatty acids bounded by 1 glycerol molecule), which are packaged together into lipoprotein particles. These particles are then shipped back out into circulation so that they can reach tissues throughout the body that are in need of energy.
Thus, the liver serves to take in all forms of energy and to package this energy in the form that is needed by the body at that time. For instance, if there is an energy surplus in the body, the liver will take in energy-containing molecules, store glucose as glycogen, and package the rest as triglycerides to be shipped around in the body.
Or, if the body is in a fasted state, the liver will release glucose from its stored glycogen so that tissues throughout the body receive the energy they need to maintain functioning.
An important question for us to address is how the liver knows what to do with the energy it receives. How does the liver know whether sugars should be converted to fats or stored as glycogen, and how does the liver know if it should be storing energy or releasing it into circulation?
There are two methods that the liver uses to make this decision. First, the flux of energy-containing molecules, themselves, serve as a signal to the liver about the state of the body. If the liver is receiving an abundant load of glucose, it understands that it needs to convert some of this glucose to lipid so that it can be shipped out via lipoprotein particles. In this way, the glucose, itself, serves as the signal.
The second method the liver uses to make decisions on what to do with energy is hormone signals. The one that you are familiar with if you’ve been following along is insulin. Insulin is released by the pancreas in response to elevated blood sugar, and serves as a signal to the body to work to lower the blood sugar concentration. For the liver, the insulin signal means that glucose needs to be stored as glycogen (or alternatively, converted to lipid).
Many other hormones communicate with the liver to signal specific stories about the current demands of the body. Two other particularly relevant hormones are glucagon and epinephrine. While these hormones are released for different reasons, they serve the same purpose for the liver. They act opposite to insulin, signaling that the body needs more glucose, which means they signal to the liver to release glycogen as glucose.
This is modeled in image 3 below:
Given these basics about the liver, one thing we can understand is that it is of utmost important that the liver is able to effectively communicate with the body. If, for instance, the liver was unable to understand the signal that blood sugar concentrations were elevated, then the liver would not know to store glucose instead of releasing it.
This is, of course, exactly what happens when the liver becomes insulin resistant. A liver that is unable to listen to the insulin signal may continue to release its stores of glycogen instead of storing glucose as glycogen.
This means that when the liver becomes insulin resistant, it may contribute to an increased hyperglycemic condition instead of helping the body to resolve the hyperglycemia.
This is itself should draw our attention, as hyperglycemia is directly damaging to tissues and proteins throughout the body. An individual with chronic hyperglycemia is on a path to loss of tissue function, going as far as loss of vision or loss of limb, as is common with Diabetics.
And yet, the pathology doesn’t end here, as you’ll remember, blood glucose homeostasis isn’t the liver’s only function.
Remember from Image 2, the liver also serves to package and distribute energy in lipoprotein particles. It takes in energy in all forms, converts any excess carbohydrate to lipids, packages all lipids as triglycerides in lipoprotein particles and ships these out into circulation.
So, what happens if the liver is unable to listen to the insulin signal?
Let’s think about that answer: from the glucose function explained above, the insulin signal serves to tell the liver that the body is in a state of elevated glucose. Additionally, as we saw with the adipose tissue in week one, the insulin signal serves as a sort of “energy storage mode” indicator – it tells the body that there is a surplus of energy in the body, and that the body needs to store away this energy so that it is removed from circulation. The liver does this directly by storing glucose as glycogen. The liver also participates in this energy storage with its second function: packaging all energy as lipid in lipoprotein particles, so that this energy can reach the adipose tissue for storage.
Now, as opposed to the glucose/glycogen insulin-resistance pathway that is fairly straightforward, the lipid insulin resistance pathway is not. So, instead of walking you through the gritty details and mechanisms, I am going to take a leap and tell you the pathophysiologic result of an insulin-resistant liver in regard to triglyceride synthesis and lipoprotein particle distribution. If do happen to be interested in those details, see the references at the end of the post.
Suffice it to say, an insulin-resistant liver will produce a pro-atherogenic lipoprotein particle distribution. That is, lipoprotein particles that are produced from an insulin-resistant liver are more likely to go on to cause atherosclerosis and the development of cardiovascular disease.
Given that an insulin-resistant liver leads to hyperglycemia and a pro-atherogenic lipid profile, we should probably be asking ourselves what it is we can do to ensure that we do not send our own bodies down this path of dysregulation, dysfunction and disease.
How does the liver become insulin resistant?
If you remember from (or refer back to) last week’s post, you already know one answer to this question. Last week we discussed how insulin-resistant adipose tissue and lipid overflow can lead to an insulin-resistant liver. This occurs when adipose tissue fills up and begins leaking fat and pro-inflammatory cytokines into circulation.
The important question for us, with this post, is how exactly does this occur? That is, what is it about lipid spilling over into the bloodstream that drives insulin resistance in the liver?
To help answer this question, remember these 4 key characteristics of the lipid overflow system:
1. Hyperlipidemia – results as adipose tissue reaches capactiy and lipid spills over into the bloodstream
2. Systemic Inflammation – the pro-inflammatory signal accompanies this excess lipid as a signal to the body for help
3. Hyperinsulinemia – the initial cause of the over-filled adipose tissue
4. Hyperglycemia – an initial cause of, and also a potential result of, insulin-resistant adipose tissue
As outputs of the lipid overflow system, we can think of these 4 characteristics as inputs into the liver. We can do this because the body is one entire system – a system connected by the bloodstream.
Thus, we can examine the liver within a system comprised of hyperlipidemia, systemic inflammation, hyperinsulinemia, and hyperglycemia as one that is primed for insulin-resistance. Again, I ask the question of how, exactly, these characteristics cause the liver to lower its ability to respond to the insulin signal, thus becoming insulin-reistant.
To answer this question, let’s put ourselves in the liver’s shoes:
As I keep (and will keep) stating, above all else, the liver needs to ensure that a healthy blood sugar balance is achieved. Secondary to this, it needs to conduct the packaging and distribution of all forms of energy as triglycerides in lipoprotein particles.
But what happens if, while trying to perform 1 (manage sugar concentrations), the secondary function starts to become a problem? That is, what happens if lipid starts to accumulate in the liver because it isn’t devoting enough resources to this task?
Let me ask what you would do. Say you have two tasks, and you have been given strict orders that task 1 is to take priority. But, in doing so, task 2 seriously starts to build-up. You have so much incoming work from both tasks that you cannot devote the time you need to manage both. You do your best to devote some time to task 2, but you can’t devote enough time so it builds up.
Do you ever reach a point where you have to re-evaluate your priorities?
I don’t know what your answer is as it probably depends on the consequences of task 1 vs. 2. But, I can tell you the answer that nature chose for this particular task:
Generally speaking, the body has been programmed to focus primarily on maintaining a healthy blood sugar concentration. All else comes secondary to this, including lipid homeostasis. The reason for this is the acute toxicity of elevated blood sugar, and the energy-deprivation of life-supporting tissues if blood sugar drops. The bottom line: if blood sugar concentration is not maintained in a tight window, the individual is at risk of death.
However, if lipid begins to accumulate, it too poses a serious danger. At first, the threat isn’t terrible, but as the liver fills up with lipid, it too begins to pose a threat to the individual’s life.
So, what does the liver do?
Image 6 shows us the answer:
As lipid accumulates in the liver, caused by elevated lipid in the bloodstream in combination with hyperinsulinemia (and its cause, elevated blood sugar), the liver has no choice but to stop listening to the signal to manage blood sugar so that it can shift its efforts to managing the lipid accumulation problem. That is, it becomes insulin-resistant.
To simplify:
Elevated blood lipids + elevated blood sugar + insulin —-> Insulin Resistance
Before jumping into the most important part of this article – the actionable information – I want to introduce you to one more concept. I know, we’ve already walked through a whole bunch of physiology and you’re probably ready for the actionable advice. But, there’s one piece of actionable advice that I want to give you, and you won’t be able to understand it fully without this one last piece.
Fructose:
These past two weeks I have discussed two primary forms of energy-containing molelces: sugars and lipids. In regard to sugar, I have focused our attention on glucose, a six-carbon signal that serves as a primary source of energy for all tissues throughout the body.
What I have yet to bring up is a similar molecule, fructose.
Here are two facts to know about sugar:
First, sugar comes in all different forms (the white grainy stuff, high-fructose corn syrup, agave, honey, etc.) – but, all these forms, at their core, have the same chemical composition: sugar is a 50/50 combination of glucose and fructose.
At this point you are familiar with glucose – glucose elevates insulin, a signal to tissues throughout the body to work as and team to lower blood glucose concentration. Glucose is managed by all tissues throughout the body, is an important source of fuel for the body, and it is also the body’s priority in regard to its responsibilities.
Fructose is a little different. Fructose can be used as an energy source for tissues throughout the body, but when it comes to any excess, there is only one specific part of the body that has the ability to manage it.
Any guesses what that one component may be?
I bet you guessed it – the liver.
Which brings us to the second fact to understand about sugar: The liver is the only part of the body that has the ability to deal with an abundance of fructose. Any fructose that is consumed gets shipped to the liver, and any fructose that isn’t immediately used as energy has to be managed by this one organ.
So, what does it do with this abundance of fructose?
Quite simply, the liver turns fructose into lipid, packages it as triglyecerides, and ships it out into circulation in lipoprotein particles.
This means that, when you consume sugar, the glucose component elevates insulin and puts the body in a pro-energy storage mode. This also means that the liver gets tasked with taking in fructose and converting it to fat.
Now, understand that this isn’t necessarily a bad thing. The liver is equipped to manage this task, given that the total load of energy is low. if we consume some fructose, say, by eating an apple or adding a bit of honey to our toast, the liver will convert this fructose to fat and ship it out to the body. That fructose energy will be managed appropriately and serve to fuel the body as it carries out its daily operations.
But, what happens when we consume sugar in the amounts that are regularly consumed. Say, when we eat a carbohydrate-based breakfast item with 20+ grams of sugar. What happens if we then consume a snack containing more sugar (maybe a banana or bagel with jam?). And then, at lunch we eat a meal with more refined grain and refined lipid (a sandwich, perhaps?)…. and then another snack in the afternoon, and then dinner, and then dessert, all containing sugar and refined carbohydrate.
I’ll let you take a shot at this answer – what happens when we regularly consume high-carbohydrate foods that additionally contain sugar? What does the liver receive from this meal?
Do you have your answer?
When our diet is based on foods that contain refined grains, sugar, and may additionally contain fat, the body is put in an insulin-elevated, glucose-focused mode. Because these foods are typically consumed regularly, throughout each and every day, this means that the body understands that it needs to be storing energy – and that it needs to be doing this all day every day. This does two things:
This means that any excess energy is put into storage as fat, thus initiating the lipid overflow pathway discussed last week.
This also means that the liver is put under a heavy load: it now has to deal with managing glucose homeostasis, while also packaging excess glucose and lipid as triglycerides in lipoprotein particles.
And, finally, we now add fructose to the system: the liver, which is already under a heavy load of energy, now becomes the only organ that can manage this fructose, of which it converts directly to fat.
So, if we consume industrially refined foods, especially ones that contain sugar – and if we do this regularly over time – what happens?
You guessed it – the liver cannot handle the load, begins to accumulate fat, and, ultimately, becomes insulin resistant:
Clarifying External Inputs:
The most important part of all this – what actions can we put into place to avoid these pathophysiologic pathways?
Now that we understand the internal pathways driving a fatty, insulin-resistant liver, we can clarify what we can do to avoid these pathways to an insulin-resistant liver and the resulting hyperglycemia and pro-atherogenic lipid profile?
Of course, if you were paying attention in the last section, or tuned in last week, you already know the answer.
The simple take away, as always, is this: the path to insulin resistance is via the regular consumption of industrial not-so-foods (i.e. foods that are made of refined carbohydrate and additionally may contain fats and sugars).
Industrial not-so-foods are made of refined carbohydrate. The regular consumption of these items send a burst of glucose into the bloodstream, resulting in the spiking of insulin. Industrial not-so-foods may also contain fat, and when fat enters a system with elevated insulin, then all of this energy is sent into storage. When this is done over time, adipose tissue fills up, leading downstream to elevated lipid, elevated glucose, and elevated insulin at the site of the liver, which we now know is a recipe for insulin resistance.
And now, finally, we understand that when we add the consumption of sugar to the system (i.e. glucose + fructose), there is an additional load of glucose to the system, while the liver also recieves a load of fructose, of which it must convert to fat.
If you desire a healthy body, one that is capable of effectively regulating energy supply and demand, begin by focusing on the avoidance of industrial not-so-foods, especially those that contain sugar.
Instead of these industrial not-so-foods, focus on consuming real, whole foods.
References:
Biddinger, S. B., Hernandez-Ono, A., Rask-Madsen, C., Haas, J. T., Alemán, J. O., Suzuki, R., … Kahn, C. R. (2008). Hepatic Insulin Resistance Is Sufficient to Produce Dyslipidemia and Susceptibility to Atherosclerosis. Cell Metabolism, 7(2), 125–134. https://doi.org/10.1016/j.cmet.2007.11.013
Packard, C. J. (2003). Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. Biochemical Society Transactions, 31(Pt 5), 1066–1069. https://doi.org/10.1042/BST0311066
Adiels, M., Olofsson, S. O., Taskinen, M. R., & Borén, J. (2008). Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(7), 1225–1236. https://doi.org/10.1161/ATVBAHA.107.160192
Chapman, M. J., Ginsberg, H. N., Amarenco, P., Andreotti, F., Borén, J., Catapano, A. L., … Watts, G. F. (2011). Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: Evidence and guidance for management. European Heart Journal, 32(11), 1345–1361. https://doi.org/10.1093/eurheartj/ehr112