This is probably the first lecture this year that's had a significant amount of new content, so hold onto your hat!
Cardiovascular disease: How bad is it in Australia? What are CVD risk factors?
Cardiovascular disease is pretty bad in Australia, where it's actually the leading cause of death. There are a whole host of risk factors for CVD, some of which are modifiable (smoking, poor dietary intake, obesity etc.) and some of which are non-modifiable (family history, age, gender etc.). In this blog post, we will focus on three main modifiable causes: obesity, type 2 diabetes and dyslipidemia.
Cardiovascular disease risk factors
Obesity
Obesity is, essentially, an excess of body fat. This is usually measured via the BMI scale or by waist circumference, but there are many other ways to measure body fat. These include skin-fold measurements, underwater weighing, bioelectrical impedance analysis (a special scale that can measure body fat- not sure how it works though), X-ray absorptiometry, ultrasound, CT, MRIs and so on. Obesity is a major problem in many wealthy countries due to the abundance of food.
Type 2 diabetes
I've already written a fair amount about diabetes in a post appropriately titled "Diabetes Mellitus." The main tests for diagnosing type 2 diabetes are the oral glucose tolerance test (in which your glucose levels are taken after fasting, then you're given a glucose drink, and your glucose is tested again after two hours) and by measuring haemoglobin A1c (HbA1c). HbA1c is glycated haemoglobin, which reflects exposure of haemoglobin to plasma glucose over a long period of time. As HbA1c turns over relatively slowly, it acts as a marker for average glucose concentrations over the past few months.
Dyslipidemia
Dyslipidemia is defined as having abnormal levels of lipids and lipoproteins in the plasma. The main types of these are high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides, which can be thought of as "the good," "the bad" and "the ugly," respectively, in terms of what they do to your health. There are different patterns of dyslipidemia, which I will go into here.
When total cholesterol and LDL cholesterol are high, this results in hypercholesterolemia, or hyperlipidemia. This may be due to environmental factors, but may also be due to genetic factors. A genetic condition called familial hypercholesterolemia involves a lack of or a reduction in the number of LDL receptors, which take up LDLs from the blood. Without these LDL receptors, LDL is increased in the blood, potentially resulting in cholesterol deposits in the hands, feet and other places. This is particularly bad if the sufferer is homozygous for the condition.
High triglyceride levels are known as hypertriglyceridemia. There is evidence suggesting that hypertriglyceridemia may be a risk factor for CVD, but this is still controversial. It does, however, increase the risk of pancreatitis. This can be caused by genetic conditions such as familial chylomicronemia, familial lipoprotein lipase deficiency or apolipoprotein C-II deficiency.
If triglyceride and LDL cholesterol levels are high, this condition is called combined hyperlipidemia. If this is caused by a genetic condition, this is known as familial combined hyperlipidemia.
If triglyceride levels are high, and HDL levels are low, this is called atherogenic dyslipidemia, so-called because both of these are factors that lead to an increased risk of atherosclerosis. CVD risk is increased in atherogenic dyslipidemia.
Another pattern of dyslipidemia involves an increase in small dense LDL particles. These arise as a consequence of remodelling LDL particles by lipases and transfer proteins, as well as high levels of triglycerides. These are also highly atherogenic.
Lipoprotein metabolism: step-by-step description
Lipoproteins: Structure, content and classification
Lipoproteins are, essentially, a lipid and protein complex. They contain cholesterol and triglycerides in their centre and have a phospholipid membrane, which is surrounded by apolipoproteins (essentially just the protein component of lipoproteins). These proteins include structural proteins, such as ApoB-100 (the major structural protein for LDL) and ApoA-I (the major structural protein for HDL). There are also enzyme modulators, such as ApoC-II (a co-activator of lipoprotein lipase activity) and receptor ligands such as ApoE and ApoB, which bind to the LDL receptor (which I mentioned when talking about familial hypercholesterolemia).
Lipoproteins can be classified in two main ways. Usually, they are classified based on density and size. Generally, chylomicrons are the largest and least dense, followed by VLDL, IDL (intermediate density lipoprotein), LDL and HDL. They can also be classified based on their lipid and apolipoprotein compositions.
Pathways of lipoprotein metabolism
There are three main pathways of lipoprotein metabolism: the exogenous pathway, the endogenous pathway and reverse cholesterol transport.
The exogenous pathway involves the uptake of dietary cholesterol and the formation of chylomicrons, which are basically lipoproteins that take triglycerides and cholesterol from the GI tract to the liver. The process kicks off when structures called mixed micelles carry cholesterol and triglycerides to the intestinal brush border for absorption.
Cholesterol is absorbed into enterocytes (gut cells) via the NPC1L1 transporter. From there, it can undergo esterification via an enzyme called ACAT to become cholesteryl ester, or it can be re-secreted into the gut via the ABCG5/G8 transporters. Triglycerides, on the other hand, are absorbed into the cell in their component parts (i.e. fatty acids and monoglycerides), which can then re-form in the enterocytes thanks to an enzyme called DGAT. Triglycerides and cholesteryl ester can then be packaged together by MTPs (microsomal transfer proteins) to form chylomicrons, which are excreted from the cell.
Once the chylomicron has left the enterocyte, it can pick up other apolipoproteins, such as apoC-II, which as I said earlier, is a co-activator of lipoprotein lipase. Lipoprotein lipase can then hydrolyse the triglycerides carried by chylomicrons back down into their fatty acid components, which can then enter adipose tissues or muscle to be stored as triglycerides. Other remnants of chylomicrons can then be taken up and cleared by liver receptors.
The endogenous pathway, which involves the formation and secretion of VLDL by the liver, initially involves many of the same processes as the exogenous pathway. Triglycerides and free cholesterol are taken up into the cell, the cholesterol is esterified to form cholesteryl ester, and cholesteryl ester and triglycerides become packaged together thanks to the help of MTP. They also associate with apoB, which as I mentioned earlier, is the main structural protein for LDL.
Once in the circulation, VLDL can secure other apolipoproteins, such as apoC-II, apoC-III and apoE. apoC-II hydrolyses triglycerides carried by VLDL into fatty acids (though this process can be inhibited by apoC-III). This results in the formation of IDL. Further hydrolysis of remaining triglycerides by HL (hepatic lipase) results in the formation of LDL. Fatty acids can enter adipose tissues or muscles for energy storage. They can also be taken up by macrophages, which become foam cells after taking up cholesterol. Alternatively, LDL particles can be taken up by LDL receptors on the liver and cleared. This process is facilitated by receptor ligands such as apoB and apoE.
Reverse cholesterol transport involves transport of cholesterol from the tissues and back to the liver. The process kicks off when apoA-I, secreted by the liver and intestines, recruits cholesterol from macrophages. This results in nascent HDL. The cholesterol in the nascent HDL is then esterified via LCAT to form cholesteryl ester. At this stage, the HDL is now mature. It can then return to the liver either directly via uptake by the receptor SRB1, or indirectly via transfer of the cholesterol to LDL and VLDL by the action of CETP (cholesteryl ester transfer protein).
Whew! That was a lot. The next lecture for this unit also covers a fair bit of ground, so I hope you've still got some energy left!
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