Last week, Nick introduced the concept of fat buildup in the liver from alcohol, and alluded to the downstream problems that can result. What many may not realize is that a parallel process can occur from sources other than alcohol, such as diet, to constitute a condition known as non-alcoholic fatty liver disease (NAFLD). Now, before you shrug this off as something uncommon or inconsequential, here are some fast facts:
According to the Mayo Clinic, NAFLD affects about one-quarter of the U.S. population. Yes, it is estimated that one in four people in the United States have NAFLD. I would also imagine that this is an underestimate, given how few individuals actually test for liver function and detect liver fat buildup in its early stages.
Non-alcoholic steatohepatitis (NASH), an inflammatory complication of advanced NAFLD, is now the leading cause for liver transplant in the United States, surpassing hepatitis C infection.
Tying into our recent post on research inequities, rates of NAFLD are disproportionately higher in the Hispanic-identifying population, so much so that 50% of obese males in this population have fatty liver. This is suspected to be due to a mutation in a protein called PNPLA3.
NAFLD is associated with virtually every chronic disease, including type 2 diabetes, obesity, liver failure, metabolic syndrome, cancer, hypertension and cardiovascular disease, and even Alzheimer’s disease
While these facts may sound like a grim prognosis for our population, the good news is that this is undoubtedly a preventable disease. Many concrete elements of the pathogenesis of NAFLD have been identified, and one of the main culprits is clearly fructose consumption. Fructose is a sugar, and one that is increasingly prevalent in the standard American diet (appropriately abbreviated as the SAD). It can be found in natural sources such as fruits or honey, or it can be found attached to glucose in refined or “added” sugars (a molecule known as sucrose). The principal villain here is this added sugar, particularly because it shows up in unnatural forms without the fiber that one would find in fruit. As we’ve previously discussed, this can lead to harmful spikes in blood sugar and absorption of overwhelming quantities of sugar, especially when it is consumed in sugary drinks.
So, why is fructose problematic for liver health? To answer that question, we need to think about the flow of fat through the liver. Like anything, to get the total amount of liver fat, we must consider the inputs and the outputs. There are two key inputs to think about: exogenous fat consumption (i.e. dietary fat intake) and de novo lipogenesis (DNL, in which our livers make fat themselves). The two key outputs, on the other hand, are fat oxidation (i.e. burning fat as a fuel source) and export to the rest of the body through the blood. Upon examination of these four factors, the cause for the surge in NAFLD seen over the last few decades is undoubtedly the extreme upregulation of DNL. We are consuming so much sugar, specifically fructose, which is incredibly conducive to liver fat production.
Figure 1: Generic pathway of fructose metabolism compared to glucose. Note that KHK stands for ketohexokinase, also known as hepatic (liver) fructokinase. This enzyme consumes vast amounts of ATP in an unregulated fashion, which further exacerbates liver fat production from dietary fructose. In contrast, glucose metabolism is regulated by ATP levels, with the negative feedback of ATP inhibiting phosphofructokinase (PFK). (Image: Cantley and Lyssiotis, 2013)
Biochemically, the mechanisms of this are both fascinating and consistent with our evolutionary history. First, fructose metabolism generates a significant amount of uric acid. On top of other pathologies that uric acid has been shown to drive, the metabolite citrate accumulates with high uric acid levels and induces additional fat production in the mitochondria. Another driver of fat production from fructose metabolism is the massive consumption of adenosine triphosphate (ATP), the cell’s energy currency, by the enzyme fructokinase. When this enzyme causes a large drop in cellular ATP levels, it triggers a sort of emergency signal to conserve energy sources. This causes our cells to adopt an anabolic state of metabolism and build up fuel reserves, including fat, rather than expend energy.
Lastly, the most intriguing means of fat buildup from fructose metabolism to me is the amplification of the AMP deaminase (AMPD) pathway. This pathway gets stimulated by the drop in intracellular phosphate from fructose, which fructokinase utilizes from ATP. When ATP loses a phosphate group, it becomes ADP (adenosine diphosphate) and then AMP (adenosine monophosphate). So, when we’ve used up the energy of this molecule all the way, it has two choices: it can either enter the AMPD pathway or the AMP kinase (AMPK) pathway. You may recognize the latter from an earlier post on metformin, which stimulates AMPK activity. These two pathways are virtually opposed to one another. AMPD converts AMP to uric acid, and can downstream increase fat stores, cause insulin resistance and obesity, and more. Meanwhile, AMPK induces downstream effects that are largely seen as beneficial like burning fat and combating diabetes.
Though it’s highly unlikely that we want to be constantly engaging the AMPK pathway and never the AMPD pathway, it seems our modern society has an imbalance in our stimulation of these two enzymes. In general, we could all use more AMPK activity than AMPD. Among other things, this can be accomplished with exercise, caloric restriction, and of course, limitation of fructose consumption. In a follow-up to this post, we will discuss further measures for prevention of NAFLD, as well as why this disease is detrimental to so many aspects of our health.
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