Leanne Hodson: Liver Fat Metabolism
Understanding liver fat metabolism is extremely important because of the associated risks of fatty liver disease – diabetes, heart disease and liver cancer being a few. Developments in techniques to measuring liver fat, and the use of stable isotopes to monitor fat metabolism are bringing us closer to developing new treatments.
Q: Why does fat accumulate in the liver in some people?
LH: In health, we have a certain amount of fat in our body; we need it and it is really important that we have it for normal functioning such as for insulation and for energy. Ideally we want that fat to be stored under our skin in adipose tissue. It seems that as we get more obese or put on weight the fat under our skin doesn't seem to function as it should. When we have a fatty meal such as fish and chips, that fat doesn't get taken up and stored under your skin where we want it to be - it tends to go to other organs. One of those organs is the liver, and we really don't want fat to be stored in the liver; it is not what it is designed to do. The liver is a very metabolically active organ, it sees lots of fatty acids coming in during the day - if you think over the course of a day you eat three meals, maybe more, and the fat comes in, it mixes in a big pool with fat coming from adipose tissue, and the fat the liver is making, and then it gets exported out to a new destination. The liver, in my mind, is sort of a big central post office in the UK; there are letters coming in from different destinations, they go into a big sorting pile and then they go out on new pathways to new destinations. That is what happens to the fat except in some cases, as we know in the postal system in the UK, some letters get left behind in the back room and they start accumulating and there seems to be more and more letters accumulating particularly around busier times of the year. That is what seems to be what happens in the liver; as we start eating more fat or we gain more weight, we have more fat coming into our liver but it is not all going back out through the liver. It seems to be staying there and that is really not healthy. We define a healthy liver as less than 5% liver fat and that is ideally what we want in people. When we get over 5% liver fat that is known as fatty liver disease.
Q: How can we measure it?
LH: We can measure it by a few methods; a very simple method, which isn't very specific, is to actually take a blood sample. You can have a high amount of fat floating around your blood and that would give us an indication that maybe you have some fat accumulating in your liver; that is not very specific. Another way of doing it very non-invasively is to give you an MRI scan; that is basically laying you on your back and going into a big magnet and lying there for twenty minutes while we take some pictures of your liver. It can be a bit noisy but there are no needles involved. We take pictures of your liver and look for a specific signal for the fat and we can quantify how much fat is in your liver. Another way is if you go to your doctor they may send you for an ultrasound which is again non-invasive, lying on your back and having probe over your abdomen. Ultrasound is not very sensitive: you have to have more than 30% fat in your liver, which is a very large amount, for the ultrasound to be able to pick it up. So the last way we can do it and that is very invasive is to send you for a liver biopsy. This is where a doctor will take a small slice of your liver while you are under anaesthetic in surgery and then put it under a microscope and look at how may fat droplets are in that section. That is the most invasive way. In research we tend to use the MRI scanner to quantitate liver fat, partly because it is very quick but also a lot less invasive.
Q: Does this increase the risk of developing diseases like diabetes or heart disease?
LH: It does increase the risk of developing these metabolic diseases. It has become quite clear in the last few years that, as your liver starts to accumulate more fat, you increase your risk of heart disease and diabetes. These seem to be associated with obesity as well. The reason we know that it increases your risk is because as your liver starts getting more fat, it starts producing more fat and sending that out into your blood. High amounts of blood fat, or triglycerides, are associated with a higher risk of heart disease so it is not a good thing to have happen.
Q: What are the most important lines of research that have developed over the past five or ten years?
LH: We have known for a long time, or the surgeons have known, that fat does accumulate in the liver and that is not healthy. I think that one of the more important things we are now able to do is quantitate it through non-invasive methods, so take you for an MRI scan. More recently we can start looking at the metabolism and how it affects your metabolism through the use of special labelled atoms which we call stable isotopes. So we can either introduce them as part of a meal and feed them to you (because they are not radioactive they are very safe), or we can introduce them into the blood stream by an intravenous infusion. These particles then go through the liver and come out in the molecules and particles secreted by the liver, so we can take some blood samples and see what pathways they have been through. This really gives us a good indication or metabolic picture of where those nutrients are going in the body and through the liver, and then what functions less well as you accumulate more liver fat. So that is one of our major developments: understanding liver metabolism within a human.
Q: Why does your line of research matter, why should we put money into it?
LH: Fatty liver disease is a very silent disease because most people don't get diagnosed. We do know that one in four middle aged adults who have had ultrasounds, that is defining them as greater than 30% fat infiltration in their liver, have fatty liver disease; that is very high. We also know that of people who have type-2 diabetes and who are obese and middle aged, 50-70% of them have fatty liver disease. Because we are not diagnosing people there is a very large proportion of the population that would have greater than 5% fat in their liver and we haven't picked them up yet. Fatty liver disease is also important because it is just the very start of a spectrum of liver disease which may progress. The liver fat accumulating in your liver is not healthy, it has metabolic consequences and may raise your blood fat, but it can also progress on and affect your liver and make it more inflamed and become very unhealthy; some cells may die and you could end up with very serious liver disease. It has been shown recently that you can go on to get liver cancer, you are more at risk. It is a very important area where we can stop the progression of those more nasty diseases of the liver by looking at lowering liver fat in individuals. The other thing that is quite important and is becoming more of a problem is that the number of livers available for transplant, that are good to transplant, is far less because the more fat that is in the liver the less likely they will succeed in a transplant situation.
Q: How does your research fit into translational medicine within the department?
LH: We need to understand the liver, but it is very hard to look at a liver in a human because it is tucked away in your abdomen and you can't always take a biopsy. So we start by getting some cells from human donors and we can look at specific pathways in those cells. Then we can take our humans and study them by giving them stable isotopes, and we can merge together data from the cell model and human data and that really gives us a good picture of drug targets that we can start looking for. This may lead to new medications that will help lower liver fat and lower the risk of accumulating liver fat, and therefore make everyone a bit healthier.