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Interview with Dr. Dawei Zhang

📷 Dr. Dawei Zhang

Journalist: Amy Stewart

AMY: Hello and welcome back to Scisection. I'm your journalist, Amy Stewart for the Scisection radio show broadcasted on CFMU 93.3 FM radio station. We're here today with Dr. Dawei Zhang, a professor in the Faculty of Medicine at the University of Alberta and a lead researcher on less expensive and more effective treatments for high cholesterol, which is a key contributor of heart disease for thousands of Canadians. Thank you so much for coming on the show today!

DR. ZHANG: Thank you, Amy. I'm really happy to have a chance to talk about the cardiovascular disease and the cholesterol metabolism and the research in my lab and how we can develop new strategies to reduce the risk of these high risk diseases.

AMY: So to get us started, how about you give us a little history of your education and your career that brought you to where you are today?

DR. ZHANG: Yeah, so basically, I grew up in China. I got my university degree and master training in China, and then I moved to Canada. I did my PhD at Queen’s University in Kingston. So after that, I moved to the United States to start my post-doc training in a well known Lab in Southwestern Medical Center, which is more like a pioneer, working on the cholesterol metabolism. They have two Nobel laureates who won a Nobel prize due to the discoveries in cholesterol metabolism. So I received the training there and then in 2008, I got a job offer from the University of Alberta, so I moved back to Canada. So, I like the environment in Canada, so that's why, the reason I moved back to Canada, to start my career in Canada.

AMY: So I think to get started, it would be great to give our viewers a basis of what high cholesterol means and what it's caused by and what some of the current treatments are for right now.

DR. ZHANG: Yeah, when we talk about the high cholesterol, but first of all, we need to understand the cholesterol, basically, all of the human beings, all of the living mammals, we need the cholesterol. So cholesterol is a basic structural component of our cells which is the unit to make our bodies. So that's why we need cholesterol. But however, cholesterol, once it's too high, it’s really dangerous, it causes damage. The human bodies develop a system to keep the cholesterol and now the cells in the body, we can destroy the cholesterol once the cholesterol, the molecule is made. So that's why once it's high in the body it's really dangerous. So when we talk about high cholesterolemia, we may focus on the cholesterol in circulation in the blood. So the cholesterol is hydrophobic, it cannot be transported in the blood in a free form. So the body developed a mechanism we call lipoprotein particles, so this has proteins and puts the cholesterol there, to circulate in the body. And then one of the bad things for the cardiovascular disease, we call bad cholesterol. But most people know the good cholesterol and bad cholesterol. So where this cholesterol is associated with, when we talk about bad cholesterol, associated with one kind of lipoprotein particle: we call lower density lipoprotein particles. So that is dangerous. Once it's high, it builds up in the blood vessels, arteries, and then eventually it causes the inflammation and makes the blood vessel harder and layer up. And the build up, we call fatty streaks. So basically it builds a block composed of fat. So the LDL cholesterol is the main cause of that. And eventually this block will grow bigger and bigger, it either blocks the blood flow or it can rupture from the original place and then cause the bleeding of the blood vessel we call hemorrhage. So this will block the blood flow and cause the heart attack and the stroke and cause disease. So the main therapy right now in the market we’re focused on reducing the levels of this bad cholesterol. So the commonly used one is the Statins. Most people know the Statins, so that there are better known Statins: Lipitors, Crestors, they all belong to the Statins. So Statins basically can be enhanced, so we make the bad cholesterol but we also have a way or mechanism to remove this bad cholesterol. The Statins basically enhance the body to clear the bad cholesterol. This is a commonly used one. There is also a relatively new drug, it’s called PCSK9 inhibitors. So, which is really powerful to enhance the clearance of bad cholesterol from the blood that people who have heard of this drug, it is very expensive, because they are a small molecule drug, or what we call SNPs, a shorter nucleotide. Those are very expensive.

AMY: Very interesting. I feel like I have studio Statins a fair bit in a few of my classes so I'm sure our viewers will have heard of them before. I feel like they’re always regarded as a “cure all” for high cholesterol but as I came up on your research, you’re looking at different ways to target high cholesterol. Can you talk about some of the pathways and mechanisms that your lab is studying?

DR. ZHANG: Yes. So we talked about, you know, the clearance of bad cholesterol and in bad cholesterol there is the production and the clearance. So far there is no good way to inhibit the production because once we inhibit the production then we cause the fatty liver and the fat accumulates in the liver which is also no good. So then we tried to enhance the clearance. So Statins and PCSK9s, they’re two commonly used ones. So the LDL cholesterol is mainly cleared by one protein we call the LDL receptor. So the liver, it is highly expressed in the liver. 75% of the bad cholesterol in the circulation - in the blood - is cleared by this protein. So both Statin and the PCSK9 can increase expression of LDL receptors. But it is well known that the receptor on the cell surface, there is another protein that functions like scissors and it can cut this protein off. Once it is cut and it makes this protein inactive. So even with Statins or PCSK9 there are more proteins and then more proteins can be cut by another protein, so we call proteinase. So, we don’t know what is the proteinase that targets the LDL receptor, so the research in our lab,

we identify that proteinase which is called MT1MMP - membrane type 1 matrix metalloproteinase - and that is a metalloproteinase. So this protein can cut the LDL receptor and once this receptor is cut, it becomes inactive. So the bad cholesterol - LDL cholesterol - in the blood is increased and then it can increase the risk for cardiovascular disease. So our finding, we would like to inhibit this proteinase so that we can increase that LDL receptor even combined with treatments of Statins or PCSK9 inhibitors. That’s indeed what we found.

So that is promising for the future therapeutic use of this proteinase inhibitor as a treatment.

AMY: That is very interesting and I bet it is going to become very useful, because as I was reading your lab website, people can become intolerant to Statins or it may no longer be effective up to a certain point. So the fact that you can combine these two therapies is very exciting to treat these people with treatment resistant high cholesterol.

DR. ZHANG: Yeah, there are about 15-30% of patients with Statin treatment that cannot stick with Statin treatment. Statin treatment is a lifetime treatment, so that’s why once you’re on Statins you have to keep taking it, you cannot drop it.

AMY: That’s very impressive that you guys are coming up with a new way to deal with those problems. The next thing I wanted to talk about is, your lab also studies Progressive Familial Intrahepatic Cholestasis Type 2. Can you give a little run down of what that disease is and what some of your findings are?

DR. ZHANG: So yes, I am glad you brought this up because this is a rare disease, probably many people don’t know it very well. We would like more people to get to know it. It is a rare disease, but it is a very severe disease. Especially, it is more prevalent in some certain populations, we surveyed ethnic backgrounds. So the disease is basically, you know, the cholesterol in the liver can be converted into a thing we call bile salts. Bile salts are important for us to digest the food, without the bile salts we cannot digest the food we cannot absorb the lipids or the nutrients. So the liver makes this bile salt from the cholesterol but the bile salt is a detergent, it cannot be stored in the liver, otherwise it will destroy the liver cells. So it has to be transported to a thing we call the gallbladder. So the bile salt is stored in there and waits until we intake food and then the release of bile salt into the intestines to help us digest food. So then the liver has one protein we call ABECB11 to help with the transport of the bile salts into the gallbladder once it is made. Then if this protein is mutated the bile salt cannot be pumped out from the liver cells and will accumulate in the liver cells and eventually, because this is a detergent, eventually it will destroy the liver cells and cause liver failure. So unfortunately for these patients, there’s no cure, like cardiovascular disease we have really powerful Statins. For all of these patients right now there are no good medicines. So eventually almost all of them end up with liver failure and a liver transplant. And we know the liver transplant has various side effects and there’s the limitations of the resource. So if they don’t go through that step, the patient will die at a very early age. So now we only have a little bit of what we call an approach to relieve the symptoms so that the patient can have time to wait for the liver transplant eventually. But in most of the patients unfortunately they don’t have that resource available for the liver transplant. So that's why at the lab we also try to work on if we can find a way to help the body to reduce the accumulation of these bile salts in the liver. At least if it's not a cure, at least if the patient has a longer time to wait for the availability of the liver transplantation.

AMY: That’s a path of research a lot of students may overlook when they are trying to find what field to go into, is a lot of people think about curing diseases but sometimes we need this approach as well to extend that time we have before you can get a treatment like a liver transplant or something like that. So that’s very interesting and a disease I’ve definitely never heard of.

DR. ZHANG: Yeah, so that’s why I am so glad you brought it up so that the public can know more, because it is a rare disease.

AMY: So for my last question, you work in a field that has a lot to do with health and proper diet and exercise, like that’s very commonly associated with cardiovascular disease. So what is a common misconception in your field that you would like to clear up for the general public?

DR. ZHANG: Ok yeah that’s a good question, these are really great questions. So the one thing you talk about exercise and the diet, yes that is really important. We know we have plenty of sufficient food to eat, it's very different from ancient times. But the human body developed during harsh times, the body developed to store energy. And

due to the progress of modern medicine, medication,so probably, it takes much longer time for the human body to develop another mechanism to fit in the current environment. So that’s why the cardiovascular disease risk increased dramatically because we have plenty of food, almost unlimited intake of food if we don’t control ourselves. And we play on our phones, games and a loss of physical activities, the risk has increased dramatically for cardiovascular disease and other diseases like type II diabetes.

So I have to emphasize that activity is really important. So we talk about bad cholesterol, so I wanted to bring up another concept. When you go to the physician to do a physical exam they always test the good cholesterol - HDL cholesterol. So the HDL cholesterol can protect us from the development of cardiovascular disease especially when people have high levels of bad cholesterol. Exercise can increase the good cholesterol dramatically so that’s why we emphasize that exercise is important. So especially when we take western food which is high cholesterol content food and then we increase our bad cholesterol. And there is one thing we can do, we can exercise to increase the good cholesterol.

AMY: You make an excellent point. I think it goes without saying for treating all types of diseases, but especially when it comes to hypercholesterolemia, a holistic approach, coming at it form a medicinal side likes Statins or new treatments like the ones you’re developing, but also diet and exercise are also very important facets, you can’t just pick one and focus on one, you kind of have to look at the whole picture.

DR. ZHANG: Yeah, the other misconception I wanted to bring up:

we know that women are protected for cardiovascular disease, atherosclerosis, that is true. But there is the one thing, when we talk about women we are always most of the time we mean pre-menopause women. So, post-menopause women they have a similar cardiovascular risk as men.

So estrogen does protect the development of cardiovascular disease, it has a protective role. So when we talk about women, some females will say “ok I’m a woman so I’m protected from cardiovascular disease, so I don’t need to watch my cholesterol, because even if it’s high I don’t worry because I have a lower risk”. Yes that is true, but you have to consider your own situations, even the post-menopause, because then your risk is the same as men.

AMY: That is very interesting. I didn’t know that and that is such a great example of bias in medicine. I feel like I have heard that women are at a lower risk of cardiovascular disease but if you’re not including all ages of women then it definitely isn’t a very representative statistic. Wow, thank you so much, Dr. Zhang. I feel like I have learnt so much today. I really enjoyed having you on the show to talk about all these misconceptions but also to tell us what is going on at your lab and the rare diseases you’re researching and the new treatment that you're coming up with. It's very exciting and I can’t wait to see what your lab does in the future.

DR. ZHANG: Thank you very much, yeah I’m really happy to have a chance to talk about this disease and hope it can help the public understand more of what we are doing in the lab.

AMY: That’s it for this week of SciSection. Make sure to check out our podcast available on global platforms for our latest interviews.


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