Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the overarching term for a series of complex diseases caused by an accumulation of fat in the liver. The liver is an essential organ in the body which carries out many metabolic functions and also removes toxins from the blood. Persistently increased levels of fat in the liver lead to inflammation of the liver and ultimately liver damage and cirrhosis. Cirrhosis is irreversible scarring of the liver which leads to decreased liver function. Cirrhosis was historically known to be caused by alcohol abuse, but with the emergence of obesity as an epidemic concern, fat accumulation in the liver became a new known causative agent of liver cirrhosis.

This diagram depicts the progression of nonalcoholic fatty liver disease (NAFLD) from normal liver tissue to steatosis (which is associated with an accumulation of fat in liver cells) to nonalcoholic steatohepatitis (which is associated with inflammation and liver cell death) to cirrhosis (severe, irreversible liver scarring). NAFLD is the broad term used to characterize these stages and the progression from a normal liver to a cirrhotic liver.
Image from: Cohen, Jonathan C., Jay D. Horton, and Helen H. Hobbs. 2011. “Human Fatty Liver Disease: Old Questions and New Insights.” Science 332 (6037) ( 6–24): 1519–1523. doi:10.1126/science.1204265.

A rise in the prevalence of NAFLD has paralleled the rise in obesity over the last few decades. In developed countries, NAFLD has been reported in 20-35% of adults in the general population and 70-90% in obese populations (Black et al. 2014). In America’s pediatric population, 35% of children are categorized as overweight or obese, and about 10-25% of these children have been diagnosed with NAFLD (Della Corte et al. 2012). The disease is difficult to diagnose because in the early stages, people do not usually present with any symptoms (Della Corte et al. 2012). Yet, if left uncontrolled, NAFLD can progress to liver cirrhosis which can only be treated by liver transplantation.

The cause of increased fat accumulation in the liver and progression of NAFLD are multifactorial. There are several hypotheses surrounding increased fat accumulation in hepatocytes (liver cells), but the primary ones focus on increased dietary intake of glucose and fructose which then stimulates the production of fat in hepatocytes by upregulating enzymes that catalyze lipogenesis (Cohen et al. 2011). The progression of NAFLD to more severe forms like nonalcoholic steatohepatitis and cirrhosis has been attributed to increased cytokine levels which lead to an inflammatory state in the liver (Cohen et al. 2011).

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This image illustrates how fructose leads to increased de novo lipogenesis (the production of fatty acids from fructose) which can then form in lipid droplets and lead to hepatic steatosis. It also displays that increased fatty acids can lead to reactive oxygen damage and inflammation which leads to NASH. Additionally, dietary fats can be broken down into free fatty acids which can also be absorbed directly by the liver.
Image From: Perito, Emily R, Luis A Rodriguez, and Robert H Lustig. 2013. “Dietary Treatment of Nonalcoholic Steatohepatitis.” Current Opinion in Gastroenterology 29 (2): 170–76. doi:10.1097/MOG.0b013e32835ca11d.

At this point, treatments for NAFLD are limited. One option to treat NAFLD is exercise and healthy eating, thereby reducing levels of fat in the body and the liver. Scientists are also trying to discover safe drugs which will act on some of the enzymes that lead to increased production of fat in liver cells in order to combat NAFLD. One recently discovered drug, ursolic acid, is present in the peels of apples. Ursolic acid administration decreases the production of fat and increases the breakdown of fat in the livers of mice and is soon to be investigated in humans (Li et al., 2014). Since drug therapies are limited, it is crucial that individuals take care of their liver by eating well-balanced meals and exercising regularly.

See the links below for more information!

History and Metabolic Context of Nonalcoholic Fatty Liver Disease

The Molecular Basis of Nonalcoholic Fatty Liver Disease

Therapy and Treatment of Nonalcoholic Fatty Liver Disease

Conclusions and Proposals for Future Research

Annotated Bibliography

9 Replies to “Nonalcoholic Fatty Liver Disease”

  1. This entry is a perfect balance of giving enough information, while making it very accessible! One thing that I was curious about was if obesity is the only cause of NAFLD, or if there are other potential causes as well.

  2. Thank you for your comment, Kathleen! For my project, I chose to investigate the effects of obesity on NAFLD, but there is a significant body of research right now on some genetic factors that predispose people to NAFLD. One such genetic factor results in a mutation in the gene, PNPLA, and this mutation has been found to lead to NAFLD independent of obesity. However, the PNPLA mutation then leads to an increase of fat accumulation in the liver, suggesting that the mutation leads to obesity which leads to NAFLD. So perhaps, the short answer to your question is that all causes of NAFLD stem from fat accumulation in some way.

  3. This is a really well organized title page. I like how you established what it did, why it is so prevalent, and the mechanism with which it acts. A few questions. What are some of the symptoms of NAFLD (you reference this in the second paragraph)? Second, is the link between fat accumulation and the increased cytokine levels established? You might not have included it for space/complexity reasons, but this could be an interesting area to add. Also, why is the liver, in particular, affected by obesity? I’m assuming it has something to do with the liver’s role in lipogenesis? But overall, this does a very good job of explaining the significance and progression of the disease!

    1. Thank you for your comment, Matt! To answer your first question, most people with NAFLD are asymptomatic. This means that they are only diagnosed with NAFLD during routine blood or liver function tests. If people do present with symptoms, they usually express pain in the upper right quadrant of their abdomen, and very rarely they present with jaundice.
      I have to do more research on your second question since I’ve been wondering that myself. Researchers have found that when fat accumulates in the liver and inflammation occurs, it leads to a more severe form of NAFLD. Yet, there are times when fat accumulation occurs, but inflammation does not. So I guess an additional question is why does inflammation occur some of the time? Therefore, to answer your question (at least a little bit), the link is not established, because fat accumulation does not always lead to increased pro-inflammatory cytokines.
      The liver is affected by obesity for several different reasons, but the biggest reason is because of the increased consumption of fructose. Fructose sends dietary carbons directly to the liver where de novo lipogenesis happens. Additionally, unlike glucose, circulating fructose is almost entirely picked up by the liver (Cohen et al 2011). As we learned in class, fructose is a huge source of our dietary sugars, and we ingest it in abundance, which is why the liver is very affected by obesity.

  4. I found your title page to serve its purpose extremely well! You provided details regarding the background of the disease as well as to why we should care in a very concise yet comprehensive manner. Your information also flowed very nicely, you started off with the big picture and honed into the specific details about the mechanistic action and current state of the disease very schematically. The one thing I was left curious about were the general details about drug therapy. Although I know the nitty-gritty will be described on another page, it may be interesting to briefly mention the specific enzymatic roles and mechanisms of pharmaceutical products. Thanks!

    1. Thank you very much for your comment- it was super helpful! There are several proposed drug therapies in the literature right now, but for now, I will touch on just one. One drug therapy includes the administration of ursolic acid which has anti-inflammatory and anti-oxidative effects. UA is found in several different food sources including the peels of apples! You can also buy UA pills in drug stores. Lee et al (2014) found that administration of UA decreased the expression of SREBP-1c, which is a transcription factor for two rate-limiting enzymes of fatty acid synthesis, by activating PPARalpha, a nuclear hormone receptor. They also saw improvements in inflammation and oxidative stress as a result of UA administration. The team claims that UA reversed hepatic steatosis, and will likely be starting human trials soon. Hope this is a little taste of what is to come in the longer section!

  5. It would be interesting to see studies from a non-western country I regards to this. For example do we see the same occurrence of NFLD in Asian cultures?

    1. Thank you for your comment! They did find that there are significant differences in the prevalence of hepatic fat accumulation among African Americans, Hispanics, and European-Americans. A recent clinical study of over 2000 individuals titled the “Dallas Heart Study” found that hepatic steatosis was present in 45% of Hispanics, 33% of individuals of European ancestry, and 24% of African Americans. Interestingly enough, they found a genetic variant that is present with the highest frequency in Hispanics and and lowest frequency in African Americans. This variant causes a mutation in the gene PNPLA3 which cleaves fatty acids allowing them to be exported from the liver. They found that this mutation decreases the activity of PNPLA3 causing fat to accumulate in the liver with a higher frequency. Therefore, they are linking this mutation with the discrepancies seen among different ethnic populations. I have not found any studies looking at specifically the U.S. versus China versus European countries though.

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