Energy Balance

Time to stop procrastinating and write about this week's content! I'm going to start with BIOC3004, because that seems to be the easiest one to write about (the summary slides are pretty clear on what we need to know). This post will be on energy balance, which unfortunately doesn't involve any kind of magical, mystical energy, but rather simply the balance between the energy we consume and the energy we expend.

Know the units to measure energy intake and expenditure

As you probably know, calories and kilojoules (kJ) are the main units used for energy intake and expenditure. The tricky part is that there are actually two types of calories: scientific calories and food/nutritional calories. Scientific calories are smaller, as scientists are often measuring things on a small scale. 1000 scientific calories (cal) make up a single food calorie (Cal). Note the capitalisation: bigger food calories are denoted Cal, whereas smaller scientific calories are denoted cal. 1000 scientific calories is also equal to 1 kcal.

One food calorie, or 1000 scientific calories, is also equal to 4.184kJ.

Know the energy density of macronutrients (in kcal)

The following lists the amount of energy (in kcal- remember, a kcal is 1000 scientific calories) per gram of a particular macronutrient:

• Carbohydrates - 4
• Proteins - 4
• Alcohol - 7
• Lipids - 9

Be able to explain the different components making up energy expenditure

Aside from physical exercise, there are many different things that we spend energy on each day. These include:

• Diet induced thermogenesis (DIT)/Thermic energy of food (TEF)- Energy expended during the digestion, absorption and storage of food. Accounts for ~10-15% of daily expenditure.
• Basal metabolic rate (BMR)/Resting energy expenditure (REE)- Energy expended in order to keep the body functioning at rest. Accounts for ~60-75% of energy expenditure.
• Non-exercise activity thermogenesis (NEAT)- Energy expenditure when we are just going about our daily business. This includes activities as diverse as simply sitting still, to doing paperwork, to cooking a meal (i.e. basically anything that isn't sleeping or vigorous exercise).

Be able to calculate BMR when given the equation (you do not need to remember the equation)

The Mifflin equation takes weight, height and age into account in order to provide an estimate of an individual's BMR. Here is the equation:

Men: kcal/day = 9.99*weight + 6.25*height - 4.92*age + 5
Women: kcal/day = 9.99*weight + 6.25*height - 4.92*age - 161

I *think* weight is given in kg and height in cm, but I've just emailed my lecturer to double check. (UPDATE: He replied and said that it is indeed in kg and cm. Also he reminded me that we don't need to memorise this equation)

Be able to explain why there are variations in energy expenditure between individuals

There are variations in energy expenditure between individuals due to differences in BMR, as I'll explain later. Additionally, different people partake in different activities throughout their day-to-day lives, and thus NEAT varies between individuals.

Be able to explain why there are variations in BMR between individuals

The BMR varies between individuals, as people have different amounts of muscle, fat and so forth, all of which contribute towards the BMR. Most variation can be explained by differing amounts of muscle. There is still around 26% of the variation that is, as of now, unexplained.

Know which tissue is responsible for most energy expenditure in the body

The muscles and liver contribute the most to overall BMR (around 22% each), with the brain a close second (around 20%).

Be able to explain the different components of physical activity

Physical activity can be classified according to how much energy is consumed per minute. This can be measured in kcal/min, but this is often impractical, so a system called "Metabolic equivalents," or METS, was developed instead. 1 MET is equivalent to the resting metabolic rate, an activity that requires 2 METS requires twice the resting metabolism, and so on and so forth. For example, a "light" activity that requires around 2.5 METS might be cleaning the house or playing table tennis. A "heavy" activity that requires 7 METS might be climbing a mountain or playing football.

Be able to explain why some foods have a higher energy density than other foods

The way a food is cooked can contribute to energy density. For example, a whole potato contains around 70 kcal of energy, but being cooked in fat or oil can increase the amount of energy for what is effectively the same amount of food. The greater the surface area of the potato exposed to the fat or oil, the higher the energy content: a roast potato, which is pretty much just coated on the outside in a small amount of oil, contains around 140 kcal, whereas a bag of potato crisps of the same weight contains around 500 kcal.

Regulation of Lipoprotein Metabolism

Another post on lipids and the cardiovascular system! This post, like the last one, also has a lot of ground to cover, but hopefully you will find it interesting.

Clinical Lipidology: Methods of studying lipoprotein metabolism

Clinical lipidology is, to my understanding, using our knowledge of lipids to aid in the diagnosis of different kinds of dyslipidemia. Having too much of a particular lipid could be due to increased production or decreased clearance, and having too little could be due to decreased production or increased clearance, but this can't be discerned by simply measuring lipid concentrations.

Tracer studies are a common way of finding answers to this question. In tracer studies, the relative concentrations of a tracee and a tracer are measured over time. The tracee is the endogenous molecule that you're interested in, for example glycerol, whereas the tracer is the same molecule but with a label of some description. In the past, molecules were often labelled using radioisotopes, but this raised safety concerns, so nowadays stable isotopes such as deuterium (essentially hydrogen with an extra neuron) are used instead. For example, a tracer for glycerol might be ²H₅-glycerol.

The tracer is first given to the patient by an intravenous bolus or by primed constant infusions (i.e. a constant infusion given immediately after a priming dose). After this is done, the body can begin to incorporate the labelled lipid, amino acid etc. into other molecules. The fraction of molecules that have the newly-introduced tracer as opposed to those that just have the naturally-occuring tracee can be measured by gas chromatography-mass spectometry (GCMS) and given as a tracer/tracee ratio, or TTR. TTR curves can then be drawn to give an indication of the production and clearance of molecules with the tracer. (Or at least that's my understanding of how it works. Correct me if I'm wrong.)

(Note: I've emailed my lecturer asking for clarification on this part, but he hasn't responded yet. Watch this space.)

Lifestyle interventions, lipid changes and metabolic changes

Lifestyle interventions for dyslipidemia include the general "healthy dietary changes" that I've mentioned in BIOC3004: reduce your intake of saturated fat and balance your caloric intake with your caloric expenditure. Additionally, plant stanols/sterols and viscous (soluble) fibre may also help with lowering LDL. I'm not too sure about how fibres achieve this, but stanols/sterols can compete with and bind to cholesterol in order to achieve their effects. Aside from dietary changes, increased physical activity and general weight reduction can also help in the prevention and treatment of dyslipidemia.

n-3 polyunsaturated fatty acids (or n-3 PUFAs for short) may also have a protective effect against CVD and dyslipidemia, though to my understanding there's still some room for debate on this one. n-3 PUFAs include eicosapentanoic acid and docosahexanoic acid, which cannot be synthesised by the body, but can be derived from fish and plants.

Lipid-lowering drugs: Statin therapies

Statins, which primarily lower LDL cholesterol, work by targeting HMG CoA reductase. This enzyme, as I mentioned all the way back in first-year, is the rate-limiting step in cholesterol synthesis. Some statins may also help with raising HDL and lowering triglycerides (rosuvastatin currently being the most effective at both).

Aside from blocking the synthesis of cholesterol, statins also help hepatocytes to take up more LDL from the blood. You see, when the synthesis of cholesterol is blocked, hepatocytes upregulate LDL receptors in order to try and make up for the cholesterol that they're no longer sythesising. A study done on rosuvastatin found that while production of VLDL, IDL and LDL did not change when on the drug, the catabolic rate increased significantly. This is consistent with an increased number of LDL receptors that allow these lipoproteins to be removed from the blood more efficiently.

Statins have been shown to reduce the rates of cardiovascular disease morbidity and mortality. They may even have an anti-inflammatory effect: studies done on statins show reduced concentrations of C-reactive protein (an acute phase inflammatory protein). However, just like every other drug, statins are also associated with a range of adverse effects. Possibly one of the more well-known side effects is muscle pain (myalgia), or even rhabdomyolosis (breakdown of muscle fibres). Other adverse effects include liver damage, gastrointestinal problems and rashes. The jury is also out over whether or not statins may increase the risk of type 2 diabetes or neurological side effects. Just like everything else on this blog, though, don't change or stop your medicine based on what some random blogger is saying: talk to your doctor about it first.

Endothelial Function

Yet another post from PHYL3002 that draws on a lot of stuff from PHYL2001! Ah well, it's always good to have a refresher :)

Explain the structure and function of endothelial cells

Endothelial cells are thin, flattened cells that make up the lining of the blood vessel (i.e. the endothelium). Their size and their ability to overlap with each other and form tubes means that they are good at letting some substances through, but not others. This makes them good at filtering blood, especially at the level of the capillaries, which are made up of only a single layer of endothelial cells (see here).

The endothelium is also important in the inflammatory response. You can read more on inflammation here.

Endothelial cells are sometimes supported by other cells called pericytes. These are small mesenchymal-like cells that are relatively undifferentiated, but can differentiate into fibroblasts, smooth muscle cells or macrophages. They are important in angiogenesis and stability of the blood-brain barrier.

Describe the processes and determining factors of filtration and absorption across the capillary

See earlier post: Microcirculation and Blood Flow

Explain the role of the lymphatic system in systemic circulation

Again, see my earlier post on microcirculation and blood flow.

Wow, that was easy...

Diabetes part two

Yup, BIOC3004 had a lecture on diabetes that covered much of the same ground as my previous post on the subject. There is some new stuff, though, so let's get started!

Understand the concepts of hyperglycaemia and hypoglyacemia

Hyperglycaemia = high blood sugar, while hypoglycaemia = low blood sugar. Diabetic ketoacidosis, which has many of the symptoms of hyperglycaemia, and insulin shock, which shares symptoms with hypoglycaemia, are discussed in that earlier post on diabetes.

Know the different types of diabetes: cause, risk factors and treatment

The main differences between the two types, as well as treatments, are covered in my earlier post, though in that post I didn't go too much into the cause or risk factors. Type I diabetes may have a genetic component, but sometimes the autoimmune response against the beta cells is triggered by an environmental factor, such as a viral illness. Type II diabetes may also have a genetic component, but environmental factors, such as obesity and a sedentary lifestyle, are also linked to diabetes.

Be able to explain how diabetes is diagnosed

Diabetes is generally diagnosed through the Oral Glucose Tolerance Test (OGTT), which I conveniently wrote about for PHAR3303.

Be able to explain how blood glucose levels are controlled

Guess I'm back to linking to that old post about diabetes again...

Know the normal range for fasting glucose

Quick easy question: ~3.5 - 5.5 mmol/L

Be able to explain protein glycosylation

Since diabetics have high blood glucose, that glucose can become added to proteins via glycosylation. Free amino groups are especially prone to this. Haemoglobin has many exposed amino groups which can become glycosylated, thereby compromising its ability to deliver oxygen around the blood. This increases the risk of many complications of diabetes, such as renal failure and damage to blood vessels and nerves. Glycosylated haemoglobin can also be used in diagnostic testing (see here).

Membrane Events of the Action Potential and Ion Channel Function

Understand the IV curve for gated ion channels, the concept of rectification and importance of channel opening probability

Yup, we're going back to IV curves again!

Remember, the IV curve is a graph of current against voltage, according to the equation I = V/R or I = VG (basically a rearrangement of Ohm's Law, V = IR). Since I = VG, where G = conductance, the higher the conductance, the higher the current. Conductance increases when ion channels open, so the more ion channels are open, the steeper the slope.

Things get a bit more complicated when voltage-gated ion channels are involved, because an increase in voltage will increase the number of open ion channels, and therefore also increase the slope of the curve. If a whole bunch of ion channels were to open at exactly the same voltage, the curve would look something like this:

In reality, though, channels do not open at once: some will open slightly earlier and some will open slightly later. As voltage increases, the chance of a channel opening increases, until you reach the point at which all channels have a pretty much 100% chance of being open. This results in a graph that looks something like this:

You probably noticed that in the above graph, there is no current into or out of the cell below the membrane potential at which the channels start to open. This is because, if the channels are closed, ions can't pass through the membrane. (Technically, I probably should have done that for the first graph too, but I have the lamest excuse ever: for some reason, the graph on the slides is like that too, so I went all "monkey see, monkey do" on it, and now I can't be bothered changing my Paint diagram. So deal with it.)

Explain experimental methods used to study ionic mechanism of the action potential

Back in my first post, I gave you the equation I_x = G_x(V_m - E_x). Well, now it's going to come in handy! Measuring the current at a known voltage will give us Gx, or the conductance, which is related to the number of open ion channels (remember, conductance is the ease at which an electric current passes, and ion channels make things a helluva lot easier).

So, how do we measure the current? We can use the voltage-clamp technique, which I outlined here. Normally, a voltage clamp record will give us a transient inward current, followed by a delayed outward current. But how do we tease out which parts are caused by which ion channels? Thankfully, scientists have ingenious ways of figuring it out.

The first method is to change the Na⁺ concentration gradient by changing the concentration of Na⁺ in the extracellular fluid. It was found that if the cell was in a Na⁺-free solution of choline, the transient inward current was lost, and was instead replaced with a small outward going current. This is what we would expect to happen if Na⁺ channels opened first and the concentration gradient was such that [Na⁺]_i > [Na⁺]_o.

Another method for testing this is by using selective blockers. When tetrodotoxin (TTX), a Na⁺-channel blocker, was used, the initial inward current was lost, but the outward current remained. When tetraethyl ammonium (TEA), a K⁺-channel blocker, was used instead, the inward current remained, but the outward current was lost.

Altogether, these methods supported what we know today: Na⁺ channels open first, followed by K⁺ channels.

Describe the different behaviour of voltage-gated Na⁺ and K⁺ channels including Na⁺ channel inactivation
Describe recent advances in understanding the mechanism of Na⁺ channel gating

In a nutshell, voltage-gated Na⁺ channels open first, but they are only open transiently. K⁺ channels, on the other hand, take longer to open, but they will remain open until the membrane becomes polarised again.

Na⁺ channels have three major states: closed, open and inactivated. This is because they actually have two "gates": an activation gate and an inactivation gate. This was discovered by studying mutated ion channels which could become active, but, unlike normal Na⁺ channels, they could remain active for a long period of time. In the closed state, the activation gate (m-gate) is closed, but the inactivation gate (h-gate) is open. In the open state, both gates are open. In the inactivated state, the activation gate is open, but the inactivation gate is closed.

At normal resting potential, around 40% of Na⁺ channels are inactivated. This number decreases as the cell becomes more negative (hyperpolarised). It's because of this that a previously hyperpolarised cell can undergo "post-inhibitory rebound firing" (increase in amplitude and frequency of action potentials) once they are depolarised again. Another phenomenon related to this is "nerve accommodation"- if the membrane becomes depolarised at a very slow rate, a greater proportion of Na⁺ channels can become inactive, so that when it is time for an action potential to occur, the cell can hardly do anything (i.e. it is unexcitable).

I'll finish this off with a quick note on why all of this is important. As I just noted, the proportion of inactivated and available channels can affect excitability. If there are issues here, there might be abnormally high or low levels of excitability. Channel mutations might be responsible for issues such as epilepsy.

Metabolism of Protein and Carbohydrates

In my last post for this unit, I wrote a fair bit about fats. Now I'm going to write up about the other main nutrients: proteins and carbohydrates!

Proteins

1. Know the potential fates of amino acids

Amino acids, as you really should know by now, are the building blocks of proteins. Aside from simply being incorporated into proteins as they are, they can also be converted into other amino acids first. The carbon backbone that makes up amino acids can be synthesised into fat, or enter the citric acid cycle in order to generate ATP. It's pretty good that amino acids have so many different functions, because otherwise they'd just go to waste (they can't be stored).

2. Know the difference between a ketogenic and gluconeogenic amino acid

As I mentioned above, amino acids can enter the citric acid cycle. Depending on where they enter and what they end up producing, they can be classified as gluconeogenic (used to generate glucose), ketogenic (used to generate ketone bodies) or both. Leucine and lysine are only ketogenic, phenylalanine, tryptophan, tyrosine, isoleucine and threonine are ketogenic and gluconeogenic, and all other amino acids are only gluconeogenic. (Sometimes you might see the gluconeogenic amino acids classified as "glucogenic" instead.) (NOTE: I'm pretty sure that you do not need to remember which amino acids fit into which categories.)

3. Know the difference between an essential and non-essential amino acid

An essential amino acid is an amino acid that cannot be synthesised by the body and thus must be consumed in the diet. These include histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threnonine, tryptophan and valine. There are also six conditionally essential amino acids which can be produced by the body, but in some cases not in adequate amounts. These include arginine, cysteine, glutamine, glycine, proline and tyrosine. Finally, there are five non-essential amino acids which can easily be produced in the body. These include alanine, aspartic acid, asparagine, glutamic acid and serine. (NOTE: Once again, I'm pretty sure that you do not need to remember which amino acids fit into which categories.)

4. Know factors defining protein quality

Protein quality is determined by two main factors: digestibility and amino acid profile. A "higher quality protein" will have higher amounts of the essential amino acids.

5. Know why protein quality of plant sources is lower than animal sources

Plant protein sources are considered to be of lower quality than animal sources as they tend to be more deficient in essential amino acids. These include lysine, sulfur amino acids (i.e. cysteine and methionine) and, to some extent, threonine.

6. Be able to describe the health outcomes associated with plant and animal proteins

Although plant sources of proteins are considered to be of lower quality than animal sources, this isn't considered to be a health issue. Vegetable protein has been found to be linked to lower blood pressure, but this could be due to a variety of other factors. As long as vegetarians and vegans take in enough calories and ensure adequate amounts of the essential amino acids, they should be fine.

Carbohydrates

1. Be able to describe the different types of carbohydrates

The main types of carbohydrates are fibres, sugars and starches. Fibres are non-digestible forms of carbohydrates, which help to provide satiety. Fibre might also help protect against cardiovascular disease, obesity and type 2 diabetes. Information on sugars and starches can be found here.

2. Know the potential fates of glucose

Glucose, which is a monosaccharide (single sugar) molecule, can be consumed directly or produced as a breakdown product of a larger sugar or starch (chain of sugars). It can be stored as glycogen in the liver or muscle, converted to body fat or oxidised to produce ATP. Glucose is the main energy source for the brain, CNS and red blood cells.

3. Know the factors defining carbohydrate quality

Carbohydrate quality can be looked at in several different ways: whole grain vs. refined grain, glycemic index and glycemic load. I'll look at these one at a time:

4. Know the difference between whole grain and refined grain

A whole grain is, well, the whole grain. A grain consists of the bran, endosperm and the germ. The bran is the "outer shell" of the seed, which contains fibre, B vitamins and trace minerals. The germ nourishes the seed, and contains antioxidants as well as E and B vitamins. Finally, the endosperm, which is the bit in the middle, essentially just contains carbohydrates and proteins. As you can see, a whole grain contains quite a few vitamins and good stuff.

A refined grain, on the other hand, only has the endosperm remaining. This gives you all the energy without any of the good stuff. Unfortunately, refined grains are a common source of starch in Western diets.

5. Be able to explain glycemic index

Glycemic index, or GI, is a measure of how quickly blood glucose levels rise after eating a particular food. A high-GI food causes blood glucose levels to rise rapidly, whereas a low-GI food causes blood glucose levels to rise more slowly. Low-GI foods are considered to be healthier, and have been associated with better outcomes for many chronic illnesses, such as diabetes. GI can be measured by giving someone a standard amount of a food and measuring their blood glucose levels over time. This is compared to a control food.

6. Know what factors affect glycemic index

Glycemic index can be affected by the type of starch, as a more branched starch with a larger surface area can be broken down more rapidly, resulting in a higher GI. For example, amylose, which is a long chain, takes longer to break down than amylopectin, which is branched. If starch molecules are trapped within the food, making them take longer to digest, this can also lower the GI. Also, soluble dietary fibre can slow the gastric emptying rate, once again slowing down the speed of digestion and lowering the GI.

7. Know the difference between glycemic index and glycemic load

Glycemic load is essentially glycemic index but corrected for the percentage of the food that actually contains carbohydrates. After all, a high-GI food might not be too much of an issue if there's only a tiny amount of carbohydrates in there. For example, a carrot has a glycemic index of 71, but a glycemic load of 4, whereas a banana has a glycemic index of 53 and a glycemic load of 21. Glycemic load can be calculated as (glycemic index * carbohydrate (g))/100.

8. Be able to explain the health consequences of carbohydrate consumption

I've already noted above that fibre can be beneficial for us. As for sugars, perhaps not so much. They are a vital source of energy, but many of us consume too much of them. This may lead to a high risk of chronic disease. Carbohydrates are not 100% good or bad per se, but you should definitely try and substitute whole grains for refined grains and limit added sugars.

9. Know the recommendation for added sugars

This is a relatively quick question to answer. The recommendation here is that no more than 10% of calories per day should be from added sugars.

Lipid and Lipoproteins: Structure, Function and Metabolism

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!