Bio Sci

The male reproductive system is quite complex to look at, yet has quite a simple function: to create gametes and transport them into the external environment.

(simplified diagram)

The male gonalds are called testes. Phenotypically normal males have two testes (singular: testis) These are contained within a fleshy pouch called the scrotum, which is split into two compartments by the thickening of the scrotum skin in the middle called a raphe. Each testis is contained in a separate scrotal cavity which limits the chances of inflammation or infection affecting one testis to reach the other.

Each testis subdivides into a series of lobules. Each lobule contains around 800 seminiferous tubules, each around 80cm in length. Seminiferous tubules are the sites of sperm production. As the name tubule implies, they are tubes with a hollow lumen in the middle. Around each tubule are Leydig cells which produce androgens like testosterone to enable sperm maturation.

SPERMATOGENESIS

Spermatogenesis is the process of sperm cell formation. It begins at the outermost layer of cells within the tubule and moves towards the lumen as maturation occurs.

First, primordial germ cells are stimulated by growth factors to become spermatogonia - specific male gamete sperm cells. Upon activation, these spermatogonia divide by mitosis into two daughter cells; one remains a spermatogonium and the other turns into a primary spermatocyte. Primary spermatocytes have 46 chromosomes and are diploid. These then divide by meiosis to form two secondary spermatocytes containing 23 haploid chromosomes each.

These two secondary spermatocytes undergo further meiosis to produce four haploid spermatids, each with 23 chromosomes. Interestingly, cytokinesis does not occur until relatively late, meaning all 4 spermatids are connected by a bridge of cytoplasm which ensures equal distribution of nutrients to ensure synchronised growth.

Spermatids are surrounded by the cytoplasm of Sertoli cells, or nurse cells, which promote development into mature spermatozoa by providing nutrients and chemical stimuli. They are also heavily involved in the maintenance of the blood-testis barrier by their tight junctional joining which creates two layers in the seminiferous tubule: an outer basal conpartment which contains the spermatogonia and a luminal compartment which meiotic divisions occur. The blood-testis barrier enables a micro-environment to be created in the interstitial fluid, separate from the blood, which contains androgens and amino acids to stimulate growth. The blood-testis barrier is also important in the prevention of immune response: sperm cells have specific sperm antigens which are not seen in somatic cell membranes and would cause an immune response if they were ever exposed to the immune system.

SPERMIOGENESIS

Spermiogenesis is the final step of spermatogenesis in which the spermatids undergo maturation to become mature sperm cells, or spermatozoa. The golgi apparatus is compressed to form an acrosome (a cap-like structure which contains enzymes needed for fertilisation), all organelles except mitochondria and centrioles are expelled, and the cytoplasm is shed and ingested by Sertoli cells to create a highly streamline cell with a flagellum to propel itself through fluid; the only example of a human cell to have a flagellum. Because sperm cells lack glycogen, they gather their energy from fructose in surrounding fluid.

At spermiation, the mature sperm cell deteaches from the Sertoli cell, which has been nourishing it, and enters the lumen of the seminiferous tubule.

EPIDIDYMIS

From the lumen of the tubule, the sperm cells are transported to the epididymis: a large tube that sits atop each testis, connecting the external reproductive organs to the internal ones. Although sperm cells have flagella, they cannot use them just yet (they need to be capitated) and are pushed along the epididymis by fluid currents and peristaltic contractions. Amazingly, the epididymis is around 7 metres (23 feet) long, but tightly convoluted to take up very little space. It takes around two weeks for sperm cells to pass through the epididymis. In the mean time, the epididymis breaks down defective sperm cells, monitors and adjusts the composition of the fluid produced by the seminiferous tubules. Sperm leaving the epididymis are functionally mature, but still cannot move independently.

VAS DEFERENS

Upon leaving the epididymis, the sperm enter the vas deferens - a very long tube that transports them into the body. The walls contain a thick layer of smooth muscle which pushes the sperm forward with peristaltic contractions. It passes three types of gland as it moves along the tract:

• Seminal vesicle: secretes prostaglandins, fibrinogen and fructose into the vas deferens to mix with the sperm, creating semen. Prostaglandins stimulate further smooth muscle contractions, fibrinogen creates a temporary semen clot when it reaches the external environment, and fructose enables capitation which allows sperm to beat their flagella for the first time.
• Prostate gland: Amongst a cocktail of compounds of uncertain purpose, the prostate also releases seminalplasmin into the vas deferens. Seminalplasmin is an antibiotic protein which decreases the chances of urinary tract infections in men.
• Cowper’s glands: These two glands release pre-ejaculate before the semen reaches them. As many of you probably know, pre-ejaculate lubricates the head of the penis upon erotic stimuli. It also lubricates the inside of the urethra and neutralises any urinary acids that may be in there (it is alkali). It may also serve as a neutraliser for the acidic environment of the female reproductive tract. 

The vas deferens becomes the urethra at the base of the bladder. The urethra serves a dual purpose in men: the transportation of both urine and semen. It travels up the entire length of the penis and leaves by ejaculation through the external urethral orifice. Whether it ends up inside a vagina or not is a completely different matter :D

MALE ENDOCRINOLOGY

• The hypothalamus released gonadatrophin-releasing hormone (GnRH) at a steady rate around once an hour, all the time.
• The release of GnRH stimulates the anterior pituitary gland to synthesis and release follicle-stimulating hormone (FHS) and leutinising hormone (LH).
• LH causes the secretion of testosterone, the primary androgen, from Leydig cells around the outside of each seminiferous tubule. High testosterone levels inhibit the release of GnRH from the hypothalamus, causing a reduction in LH by negative feedback. 4-10mg of testosterone is created a day. Testosterone is needed to support Sertoli cells to stimulate sperm maturation. Sertoli cells modify testosterone into DHT - dihydrotestosterone.
• FSH binds to FSH receptors on Sertoli cells and, in the presence of DHT, promotes spermatogenesis and sperm maturation. Sertoli cells also release androgen-binding protein (ABP) which elevates local concentrations of androgens (such as testosterone), stimulating further growth. A hormone caleld inhibin is released when sperm maturation is rapid, inhibiting FSH release from the pituitary gland by negative feedback.

Erythrocytes, or red blood cells, are the most abdundant type of cell in the blood, accounting for 99% of all the formed elements. These cells give blood its distinctive dark red colour.

• We have arond 5x10^12 RBCs per litre of blood.
• One cubic millimetre of blood contains 4.5 - 6.3 million RBCs in men, and 4.2 - 5.5 million RBCs in women.
• Function is to carry oxygen to somatic tissues and carry carbon dioxide back to the lungs.
• Mature RBCs are anucleate. In fact, they don’t have any of the typical cell organelles you would expect to see.
• They are a disc-shaped biconcave cells around 7.8 x 1.7μm.
• The biconcave shape has three major effects on RBC fucntion:

1. Creating a large surface area to volume ratio
2. Enabling the creation of rouleaux which allows a string of RBCs to travel through a narrow blood vessel, preventing blockages.
3. Enables RBCs to be flexible when entering narrow capillaries, allowing them to change shape to fit into capillaries less than half their size.

• Primarily utilise anaerobic metabolism.
• Convert glucose into lactate to create 2 ATP molecules.

• Erythropoiesis, the creation of new RBCs, is stimulated by hypoxia. Erythropoeitin is released from the peritubular endothelial cells of the kidney which binds to the membranes of primitive erythroid cells within the bone marrow, stimulating them to develop further.
• Every RBC contains around 250 million molecules of haemoglobin.
• Haemoglobin is a quaternary protein with two alpha and two beta chains of polypeptides.
• Nestled within each chain is a molecule of haeme, each of which contains a ferrous iron ion (Fe2+) and protoporphyrin.
• Iron combines reversibly with oxygen, making it the oxygen-carrying part of the haemoglobin molecule.
• Affinity for O2 depends on the pH levels of tissue fluids and the status of other subunits.
• Co2 lowers blood pH and stimulates the release of O2 from the RBCs in exchange for Co2.
• If O2 binds to one subunit in a molecule of haemoglobin, the affinity for the other three subunits increases. Haemoglobin rapidly fills up with oxygen.
• Erythrocytes circulate for around ~120 days before removal in the spleen.
• At ~100 days they start to show signs of aging: glycolysis activity decreases and less ATP is produced and the membrane starts to become more rigid and less flexible.
• At ~120 days, following cues still unknown, they migrate to the spleen where they are destroyed by phagocytes. Their molecular components are either recycled or excreted in the urine.

Anaemia

• Can be caused by a loss of erythrocytes (such as bleeding), an increase in erythrocyte destruction (haemolytic anaemia) or dilution of cells (hypersplenism).
• A decrease in erythrocyte production can be caused by nutrition factors (lack of iron primarily but also B12 and folic acid).
• Can also be caused by ineffective erythrocytes, such as those in sickle cell anaemia or thalassaemia).
• Causes tiredness, lethargy and decreased concentration with a feeling of general malaise in less severe cases. Severe cases exhibit tachycardia, cardiac ventricular hypertrophy and can cause heart failure.

Leukaemia

• Leukaemias are malignancies of white blood cells - specifically leukocytes.
• Cells are trapped in an early differentiation state and uncontrolled division occurs.
• Accumulation of these immature cells prevents the bone marrow from producing healthy mature leukocytes, which leaves people open to infection.
• There are several different types which affect different white blood cells in different ways.

Lymphoma and Myeloma

• Lymphoma: cancer of lymphatic cells
• Myeloma: cancer of plasma cells

Polycythaemia and Thrombocythaemia

• Polycythaemia is a significant rise in erythrocyte production brought on by hypoxia or abnormal erythropoietin.
• Thrombocythaemia is a significant rise in platelet levels.

Haemorrhage (bleeding)

• Decreased coagulation factor synthesis can cause haemorrhage as can blood-thinning drugs such as warfarin and aspirin.
• Thrombocytopaenia (decrease in platelet levels) is also a cause, and puts you at risk of further injury causing bleeding.
• Liver disease can cause haemorrhage.
• Genetic conditions such as haemophilia cause haemorrhage.

Thrombosis and Embolisms

• Formation of a blood clot which gets so big it blocks blood flow to organs and interstitial tissues.
• An obstruction which blocks 90% of the arterial or venous lumen can cause tissue death through oxygen deprivation and waste product build-up - infarction (a form of necrosis).
• Atherosclerosis, diabetes, hypertension, blood coagulation factors and a sedentary lifestyle can all cause thrombosis. Sitting down for long periods of time also carries a risk of a particular subtype called deep vein thrombosis. People that fly regularly are susceptible to DVT and are advised to wear bloodflow-stimulating DVT socks.
• Blood clots which detatch from their original site of origin and travel in the blood stream are called embolisms, and can be lethal. Embolisms which manage to reach the brain are highly likely to cause a stroke.

Haematology is the study of blood and its components. Blood is an important health indicator as a blood sample can provide a picture of your overall health. It is a normal first point of investigation for most diseases.

Functions of blood

Everyone should know these already but…

• Distribution of oxygen and removal of carbon dioxide
• Distribution of nutrients and removal of waste products
• Immune response
• Carries messages between organs
• Prevention of infection during injury

Blood has two major components: formed elements (cells) form 37-53% of the blood and plasma forms 46-63%.

Cells of the Blood

Red blood cells, or erythrocytes, form 99.9% of the cells in the blood. White blood cells, leukocytes and lymphocytes, form <0.1% as do platelets (nb: given the sheer number of blood cells in the body, 0.01% is still a large number). All these cells are formed in a process called haemotopoiesis. The body has a few thousand multipotent stem cells at birth which can both divide and differentiate into different blood cell types. Haematopoiesis is stimulated by growth factors from mature cells and cytokines. There are other factors which depend on what sort of blood cell it is (more on this later).

Cells form in the yolk sac for the first 0-2 months of life before shifting to the liver and spleen, which operate as cell factories from 2-7 months. At 8 months, just prior to birth, the responsibility of cell creation switches to the vertaebra and the pelvis (all your life), the ribs (production starts to wane between 20-40 years old) and the femur and tibia (production wanes at around ~25 years, but can be up to 30).

Erythrocytes

• Primary functions: distribution of O2, removal of CO2 via the specialised protein haemoglobin.
• 5x10^12 erythrocytes per litre of blood - 99.9% of all cells in blood.
• Circulate in the bloodstream for around ~120 days, a distance of over 300 miles(!), before being removed by the spleen.
• Primarily anaerobic in operation.
• Mature erythrocytes contain no organelles.
• Highly flexible membranes to squeeze through the narrow capillary lumen.
• Multipotent stem cells > BFU-E (blast forming units - erythro__) > CFU-E (colony forming units - erythro___) > Mature erythrocytes
• Maturation controlled by erythropoietin; a growth factor released from peritubular endothelial cells in the kidneys. Hypoxia, a lack of oxygen, increases the amount released.
• Erythropoietin binds to the membranes of BFU-Es (also known as erythroids).

LEUKOCYTES

Neutrophils

• The most common type of white blood cell (leukocyte).
• Identifiable by their multi-lobed nucleus and granular cytoplasm. The granules contain cytotoxic proteins which destroy pathogenic microorganisms that the neutrophil ingests by a process called phagocytosis.
• Bloodstream lifespan approximately ~12 hours, can be longer in organs like the spleen, but not longer than ~24 hours.
• Primarily combats tissue infections. Neutrophils are called to the site of infection by chemicals released by pathogenic bacteria and other leukocytes - chemotaxis. (check out www.youtube.com/watch?v=I_xh-bkiv_c for a video of chemotaxis/phagocytosis in action)
• Unfortunately, whilst phagocytosis destroys the invading microorganism and prevents us from getting an infection, the neutrophil dies almost immediately after ingestion.

Monocytes

• Circulate in the bloodstream before entering tissues where they undergo changes to become macrophages.
• They produce cytokines: chemical messages which are used to recruit other white blood cells to the site of infection.
• Unlike neutrophils, monocytes survive phagocytosis.
• Very large kidney-shaped nucleus. 

Eosinophils

• Target macroparasites and larger pathogenic organisms.
• Two-lobed nucleus
• Granular cytoplasm
• Numbers of eosinophils are increased in allergies such as hay fever.

Basophils

• Basophils are the least numerous of all the leukocytes.
• They are mediators of acute inflammation, such as that in IBS.
• Granules contain histamine (produces the symptoms of allergy reactions) and heparin (an anticoagulant).

LYMPHOCYTES

T-Cells

• T-cells form 75% of all lymphocytes.
• Provide cell-mediated immunity.
• Originate within the bone marrow but undergo selective maturation within the thymus.
• Three subtypes: helper cells which express surface marker CD4, cytotoxic cells which express CD8 and supressor cells which assist in the supression of the otherwise enthusiastic cell-killing actions of natural killer cells.

B-Cells

• Originate and mature in bone marrow.
• Provide humoural immunity by producing antibodies called immunoglobins.
• Differentiate into B-memory cells and B-plasma cells.
• Memory cells allow a fast response to reinfection. They live for years, waiting for reinfection to occur.
• Plasma cells synthesise and release immunoglobins in response to current infection, and die soon after infection has cleared.

Natural Killer Cells

• Have a lot of T-cell characteristics
• Cytoxity by cell adhesion and antibody targetting.
• Still a topic of research, so comparatively little is known about them.

PLATELETS

• Major component in vascular clotting system.
• Platelets are fragments of cells rather than whole cells.
• Platelets release chemicals which initiate and control the clotting process.
• They form a temporary plug in the walls of damaged blood vessels - a platelet plug. This inhibits blood loss whilst repairs occur.
• Because platelets contain actin and myosin filaments commonly found in muscle tissue, they are capable of shrinking, thus repairing, the break within the vessel wall.
• Circulate for around ~12 days before being destroyed within the spleen.

BLOOD PLASMA

Consists of 92% water, 7% proteins, and 1% solutes like electrolytes and waste products like urea.

Proteins

• Coagulation and haemostatic (blood clotting) proteins
• Albumin for transportation of non-esterified fatty acids
• Growth factors and cytokines
• Proteins from cells of the immune system
• Lipoproteins such as VLDLs and chylomicrons (See notes on fat metabolism)

Haemostasis prevents excessive blood loss and stimulates the regrowth and repair of damaged tissue. Components and factors of haemostasis include coagulation proteins, platelets, the fibrinolytic system (prevents blood clots from growing and becoming a problem) and coagulation inhibitors.

The integumentary system is often overlooked as a body system but is absolutely vital as a first line of pathogenic defence, vitamin D synthesis for calcium metabolism, protection and insulation, thermoregulation, production of melanin which shields us from cancer-causing ultraviolet radiation, storage of lipids as an energy reserve, and detection of senses including touch, pressure, pain and temperature.

There are two distinct layers to human skin, and subsequent sublayers in each one. The two main types are the epidermis and the dermis. The hypodermis, found underneath the dermis, is not usually regarded as part of the skin but I will mention it in the dermis notes regardless.

Thin skin, which covers most of the body surface, has an epidermis around ~0.08mm thick. Thick skin, such as that on the palms or the soles of the feet, has an epidermal thickness of around ~0.5mm. This thickness rating only applies to the epidermis and not to the skin as a whole. If we take the dermis into account too, skin is generally 1-2mm thick, with exceptions being eyelids at 0.5mm and the skin between the shoulder blades which is 6mm thick. Skin accounts for about ~15% of your total body weight, depending on your obesity rating I imagine.

The epidermis

The epidermis (epi- upon, derm - skin) is, as the name suggests, the layer of skin we can see - the outside layer. There are four sublayers in thin skin and five in thick skin. The layers are, in backwards order, as follows:

• Stratum basale: The deepest layer. Contains stem cells in columnar tissue which mature into keratinocytes. Very high rates of mitosis as keratinocytes are constantly being replaced. Forms epidermal ridges which interlock with dermal papillae (more on this later). Interlocking ridges provide a larger surface area for absorption of nutrients from the dermis. On the palms and soles, these ridges produce palm/sole lines which increase friction and allow us to have a strong grip. Cells produced here are pushed upwards through the five layers of the epidermis (hence why this list is in reverse order).
• Stratum spinulosum: 8 - 10 layers of keratinocytes, pushed up from the basale, which carry on dividing by mitosis and contribution to the thickness of the epidermis. This layer also contains dendritic cells - macrophages which provide protection from microorganisms that manage to penetrate the skin from the outside.
• Stratum granulosum: 3 - 5 layers of keratinocytes. Cells stop dividing here and start to produce large amounts of keratin and keratohylin. Keratin is a tough, water-resistant protein which becomes very important in the top layer of the epidermis. As keratin levels increase within the cell, they become thinner and flatter with thicker membranes. Keratohylin creates large cytoplasmic granules within the cells which cause cell dehydration and rapid disintegration of the organelles (apoptosis) as well as fulfilling a secondary role of keratin crosslinkage within the cell.
• Stratum lucidum: This layer is only found in thick skin, such as that on the palms or between the shoulder blades, otherwise it goes straight to the next layer from the granulosum. All keratinocytes in the lucidium are dead, but contain an intermediate protein called eleidin which enables further keratin production. Lips have more eleidin than keratin, and because the lucidium is a clear and glossy layer (‘lucid’), it shows the colour of the underlying erythrocytes - giving the lips their red colour. 
• Stratum corneum: The top layer of the epidermis, and the one we can easily see just by looking at ourselves. Stratified squamous epithelium. The corneum consists of 15-30 layers of dead, flat keratinocytes which have taken 7-10 days to leave the stratum basale to get to here. Corneum is around ~10-40μm thick. Keratinocytes generally stay here for around two weeks before being shed or washed away. Keratin makes our skin water-resistant (not waterproof) and robust. The corneum is also capable of absorbing water in the right situation: freshwater is hypotonic and causes an influx of water to move into the epidermis, whereas salt water is hypertonic and causes water to move out of the skin. It is therefore possible to dehydrate just by swimming in the sea (although it would take a very long time). The surface of our skin is usually dry and therefore unsuitable for the growth of many pathogenic organisms (though obviously we have a wide range of commensalistic bacteria living on us).

Part 2 (dermis, hypodermis) will be posted later today and part 3 (accessory structures, functions) tomorrow. Hope it helps.

Image from dreamstime.com

Complementation tests

Complementation tests are genetic tests to determine whether two organisms with the same mutant phenotype have the same genetic mutation on the same gene, or whether the two phenotypes exist on separate genes.

• You must use homozygous recessive mutant organisms. Using heterozygous organisms defeats the point of this test and will not yield accurate results.
• Cross the two organisms and examine the offspring’s phenotype.
• If the mutations of the parents are on different genes, a heterozygous wild type F1 offspring will be produced. Because there are two separate genes involved, this is said to be complementary.
• If the offspring is a mutant like its parents, however, it shows that the mutation is on the same gene. The F1 is homozygous recessive like its parents and is said to be non-complementary.

Drosophilia body colour is an effective example of the above. If one mutant black body parent fly had e/e, b+/b+ and the other had e+/e+, b/b  (E being ebony, B being black) you would expect the F1 to have e+/e, b+/b and have a wild type goldish-body colour. It has inherited one mutant allele from each parent, but one dominant wild type allele also. This F1 fly is a heterozygous wildtype drosphilia.

Lipoproteins 3/3

HDLs (high density lipoproteins) are the tiniest of all the molecules within this little family, and they have a different role to their siblings. Whereas chylomicrons, VLDL, IDL and LDL disperse their contents to somatic cells before returning to the liver, HDLs transport excess cholesterol from the peripheral tissues to the liver, where it is used to form bile. They originate in the liver, and although structurally similar to its siblings, it contains extremely few triglycerides and cholesterol esters. It is actually quite empty. This is because it needs room to pick up cholestrol to take back to the liver. The integral protein that expands the phospholipid monolayer is not a B-family one like the others, its apoA.

When it is released from the liver, it obtains an enzyme from the bloodstream called LCAT (lecithin-cholesterol acyltransferase). The HDL then travels to cells and the LCAT binds to the free cholesterol found in many phospholipid bilayers of somatic cells. LCAT binds to the exposed alcohol group on the cholesterol (-HO) and causes esterification, removing the alcohol group and replacing it with an ester group. Because cholesterol esters are extremely hydrophobic, they rise from the cell membrane and are absorbed into the HDL. This process repeats until the HDL is full to capacity, then it returns to the liver and binds to apoA receptors which take up the HDL via endocytosis. Inside the hepatocytes, the cholesterol is converted into bile salts and sent to the gall bladder for storage.

It goes without saying that when HDL concentration is low, cholesterol concentration in the body rises in the endothilia and other tissues and organs. Interestingly, and perhaps a little obviously, I read a few days ago that cardiovascular exercise (such as running, gymnastics, etc) increases the levels of HDL synthesis within the liver which then serves to lower your whole body free cholesterol levels.

Notes

• Although I haven’t really covered NEFAs, they circulate the bloodstream attached to proteins called albumins. This complex dissociates in tissues so that the NEFAs can be used for ATP via ß-oxidation (more on this in the future).
• Once triglycerides have been hydrolysed into individual fatty acids and glycerol and incorporated into adipocytes through VLDL and IDLs, they are reassembled into triglycerides for storage purposes. Adipocytes are cells that contain huge amounts of fat - so much so that the amount of fat causes the nucleus to be squashed right up against the cell membrane.
• TAG breakdown is regulated by hormones. Insulin inhibits the release of NEFA and glycerol wheras adrenaline and noradrenaline increase the release.

Lipoproteins 2/3

The liver itself releases fat for storage and anabolic purposes around the body in molecules called VLDLs - very low density lipoproteins. The density in question is the protein density: VLDLs have around a ~10% protein content, compared to the 1% of chylomicrons. They also contain around 8% free cholesterol within the phospholipid monolayer membrane and around 15% cholesterol esters combined in the centre with around 56% triglycerides. Essentially they still contain high levels of triglycerides (but substantially less than chylomicrons) but also have increased levels of cholesterols. The integral protein in a VLDL is also different to chylomicrons. Remember how chylomicrons have apoB48? VLDLs have apoB100. Just like B48 defines a chylomicron, B100 defines a VLDL.

VLDLs are released into the bloodstream using where they, like chylomicrons, obtain apoC2 and apoE from HDLs (more about them in part three). They then travel to adipose or muscle tissue to hand over their triglyceride stores. apoC2 binds to the lipoprotein lipase (LPL) enzyme on the surface of the adipocyte and its triglyceride stores are cleaved into free fatty acids and glycerol. When it gets to around 50% of its original fat level, it leaves the adipocyte and one of two things can now happen.

1. It can travel back to the liver, where it is taken in by endocytosis upon binding its apoE protein to an LDL receptor on the hepatocytes. Inside, its stock of triglycerides is replenished and it is sent out again.
2. It can attach to another adipocyte and continue to have its stock of triglycerides depleted.

If the second option occurs, once it gets to around ~30% of its original triglyceride stock, it becomes an IDL - an intermediate density lipoprotein. It now has the same options as before, and if it ‘decides’ to give up more of its triglycerides it becomes a LDL - a low density protein. Low density proteins only contain around 10% of their original triglyceride stores, and the apoC2 and apoE proteins dissociate from their monolayer membrane, leaving just apoB100 behind. LDLs contain very few lipoproteins, but vast amounts of cholesterol esters - making them the body’s most abundant source of cholesterol for cells. They are taken into cells and their cholesterol is absorbed before being returned to the bloodstream for return to the liver.

However, attachment to the hepatocytes is much harder now that the apoE protein has been lost. apoB100 still binds to the LDL receptors on hepatocytes, but at a much lower affinity. This means that LDL is present in the bloodstream for a longer amount of time than any of its intermediates. Medically speaking, this is extremely dangerous over time.

Let’s say the LDL receptor on the hepatocyte is faulty in some way, that it either isn’t expressed at all or does not bind the LDLs. This creates a build-up of cholesterol in the blood and also stimulates the liver to create more VLDLs (effectively a precursor to LDLs) because it thinks there is a cholesterol shortage within the tissues. This tragic misunderstanding then causes masses and masses of cholesterol to build up within the arteries of the circulatory system. Free radicals oxidise LDLs and they bind to the arterial endothelium, causing atherosclerosis - a hardening of the blood vessels. It also causes blockages within the lumen which restricts how much blood can get through. These are prime causes of cardiovascular diseases and strokes.

However, it should be pointed out that cholesterol does have a completely undeserved bad name for itself and in fact you need it for so many different hormones and membrane components. It is just this mass build-up that is dangerous. HDLs, which I will cover next, provide a solution (of sorts) to build-up within cells and tissues.

Lipoproteins (1/3)

Lipoproteins are transporters of fat and cholesterol, taking them through the bloodstream to peripheral tissues. This is the first of three sets of notes I will post tonight. I hope they help someone!

Chylomicrons are produced in the small intestine - the duodenum to be precise. Once chyme has left the stomach and has entered the duodenum, the presence of fat causes a release of CCK (cholecystokinin - chole, ‘bile’, cysto, ‘bag or sac’, kinin, ‘move’ - bile bag movement) which forces the gall bladder to contract and release bile along the bile duct into the duodenum. Remember I said bile was a detergent? Well the mixture of bile and chyme creates an emulsion which effectively shrinks the fat molecules to make it easier to transport them.

Enterocytes, cells lining the intestinal epithelium, then take up these fats and package them together with phospholipids, protein, cholesterol and cholesterol esters to form a nascent chylomicron. A chylomicron is the largest of the fat transport molecules, and the only one that is not produced directly by the liver. This compound of fats and protein is called an apolipoprotein.

Chylomicrons have very high proportions of triglycerides inside, with very little cholesterol and cholesterol esters. The phospholipids form a phospholipid monolayer around the triglycerides with (very little) cholesterol scattered throughout. Transcending the length of the phospholipid monolayer is a single protein that is utterly essential in the production of chylomicrons - apoB48. If there is a defect within the gene that produces this protein, chylomicrons cannot transport fats out of the enterocytes and thus enterocytes hold onto the fat. I’m not sure if this is a medical condition or not but I think it is safe to say it most likely causes abdominal obesity and probably leads to death without some sort of drug intervention, but don’t take my word on that.

Once nascent chylomicron synthesis is complete, the apolipoprotein is expelled from the enterocyte and enters a lymphatic structure called a lacteal. A lacteal is essentially a specialised vessel purely for shuttling chylomicrons to the bloodstream. The chylomicrons travel along the lacteals, through the lymphatic system, and are expelled out of the thoracic duct (in your chest - almost at the shoulder) and into the bloodstream.

Whilst in the bloodstream, they acquire two new proteins donated from HDL (high-density lipoprotein - I’ll cover these later) called apoC2 and apoE. The chylomicron now loses the nascent tag and becomes a mature chylomicron. So now we have a fat-protein complex with a high level of triglycerides inside a phospholipid monolayer, with three types of protein attached: apoB48 which defines a chylomicron, and apoC2 and apoE. There are now three routes it can take: it can go to your liver, go to your adipose tissue, or go to your muscles. For the sake of simplicity I’m just going to concentrate on the first two.

If it goes to the liver, the apoE protein binds to an LDL receptor on the surface of hepatocytes (liver cells) and is taken inside the liver where the triglycerides and cholesterol can be utilised.

If it goes to adipose tissue, it is a bit more complex. Adipocytes have a membrane-surface enzyme called LPL - lipoprotein lipase. This enzyme binds to the apoC2 protein on the surface of the chylomicron and it starts to hydrolyse the contents and absorbing them; triglycerides and broken down into individual fatty acids and glycerol and the adipocyte takes them in by endocytosis. When around 80% of its total triglyceride storage has been depleted, the apoC2 molecule detaches from the chylomicron and adipocyte absorption stops. apoB48 and apoE are still present, however. The chylomicron is now a shadow of its former self, broken and weak, and loses the mature tag in its name to become a chylomicron remnant. It then leaves the tissue and travels to the liver, one protein and 80% fat less, and its  binds to CRR (Chylomicron remnant receptor) on the hepatocytes where the liver takes the remnant up to utilise its remaining triglycerides. 

image from aimeeblack.com

Here’s another mnemomic I was taught to remember the various parts of the small intestine in order:

Don’t Jump In

• Duodenum
• Jejunum
• Ileum

There are three types of lipids:

• Tricylglycerols (TAGs) - primarily used for energy storage.
• Phospholipids - primarily used as as cellular membrane component.
• Steroids - primarily use in hormone synthesis.

TAGs are most abundant in the body. They are stored in various anatomical locations and inside specialised fat-holding cells called adipocytes. A TAG is essentially three single fatty acids attached to a single molecule of glycerol, a simple three carbon sugar (you may recall that glycerol can be turned into glycogen about half-way through the path of gluconeogenesis. Isn’t it nice when all these different pathways cross over a bit?) . A fatty acid is essentially a carboxylic acid with a very long aliphatic tail coming off the end. Depending on the type of fatty acid, this tail can vary from six carbons long to more than 22 carbons long.

Linkage forms between the glycerol and fatty acids by simple esterification - the condensation of an alcohol (-OH) and an acid (eg: carboxylic acid, -COO). I’m terrible at explaining things like this, so here’s a god-awful Paint interpretation of what I just said:

(NB: Hahahaha. My writing is not that bad in reality, I assure you.)

So what you should be able to see here is the loss of the OH group on the right side of the glycerol when fatty acids are adhered to it. I should also point out that there are essentially three types of fatty acid:

1. MUFAs: Monounsaturated fatty acids
2. PUFAs: Polyunsaturated fatty acids
3. SAFs: Saturated fatty acids

• MUFAs are characterised by a single double bond somewhere along the chain, which causes the molecule to kink and bend.

• PUFAs are characterised by multiple double bonds along the chain, causing multiple kinks along the molecule. In both MUFAs and PUFAs, there are two subtypes which are characterised by the structure of the double bond/s: cis bonds are bent and trans bonds are straight.

• SAFs are characterised by single bonds throughout the molecule which results in a straight chain. 

So each gram of fat stored in the body is essentially worth ~7.7kcal/g. So a person of 70kg has around 100,000 kcal stored away as TAGs. This is roughly around ~12kg of fat. In contrast, to store the same amount of kcal as glycogen, that 70kg person would shoot up to 125kg.

Phospholipids are membrane components. There are three primary types: phosphotidylcholine, phosphotidylserine, and phosphotidylethanolamine. I know these are ridiculously long words but if you remember the prefix phosphotidyl (I like to think of it as “phosphate is tidy”) then you can just learn the suffixes individually. And to be honest, if you know what acetylcholine, serine and ethanol is then you’re 3/4 of the way there. I won’t go into immense detail on this type of lipid as it is hard to explain without the use of graphs, but essentially you need a phospholipid membrane to consist of both saturated and monounsaturated phospholipids to have a fluid phospholipid bilayer.

The most frequently used steroid in the body is cholesterol. It forms a synthesising backbone for the production of bile salts, progesterones, androgens and oestrogens (Sexy hormones) and also glucocorticoids and mineralocorticoids as well as vitamin D. These steroid hormones bind to receptor molecules that serve as transcription factors. A slight change in structure of these molecules allows extremely diverse interaction. I suggest you look up steroid hormones for yourself to see just how many different types there are. Cholesterol is also found within cell membranes where it acts as a fluidity regulator.

So, a major source of lipids comes from the diet. Advice from my home country, England, recommends 100 grams of fat per day for adults: 94% of these being TAGs, 5% being phospholipids and 1% being cholesterol. Of course, whether people adhere to this 100g rule is another thing entirely. TAG structure and properties dominate how the fat is processed in the body.

To enable the body to process it, the fat needs to be emulsified before it can be absorbed. This is facilitated by detergents. Think about it - what does the detergent in your washing up liquid do? You can’t really wash dishes effectively without washing up liquid because you’d be left with greasy plates and a lot of elbow work would go into scrubbing the fat off. Detergents break-up fats because fat does not dissolve in water. Washing up liquid is a detergent, and natural body detergents have the same job - to break down fats. The stomach liquidises all the food you eat and churns its contents into a course emulsion called chyme. Chyme is a creamy substance consisting of mostly-digested food mixed with digestive enzymes and gastric juices. The pyloric sphincter at the base of the stomach opens momentarily to allow chyme to pass into the duodenum where emulsification continues. This whole process decreases surface tension.

Taurocholate and glycocholate are natural detergents (bile salts) that are produced in the liver but stored in the gall bladder. They are modifications of cholic acid, which is itself produced from cholesterol. We produce around 400 - 800ml of bile per day. Bile is amphipathic - meaning it has both hydrophilic and hydrophobic qualities. The bile molecules attach themselves to lipid molecules with their hydrophobic side on the inside and hydrophilic side on the outside, with the fat molecule in the middle. This is called a micelle (more on these in my next lipid post).

Gastric and pancreatic lipase (GL and PL) catalyse TAGs to catabolise them into their individual components.

TAG—-> DAG + NEFA ——> MAG + NEFA —-> Glycerol + NEFA

• Dag = diacylglyceride with two fatty acids attached

• Mag = monoacylglyeride with one single fatty acid attached

• NEFA = non-esterified fatty acid (a fatty acid that is not attached to glycerol)

As the name suggest, GL is produced in the stomach and PL is produced in the panceas. GL is very acid-stable with an optimum pH that is very low - perfect for working effectively in the high acid environment of the belly. GL is responsible for around 10 - 30% of TAG digestion. PL is facilitated by another enzyme, co-lipase. Co-lipase attaches PL to an emulsified TAG, allowing PL to avoid denaturation and liberating NEFAs.

I will do another post on the actual metabolism of lipid in my next set of notes. This was just to give a bit of an overview on what happens through intake and digestion, as well as introducing the structure of the molecules and the enzymes needed to rip them apart.

Now I am going to eat Chinese food and talk to the boyfriend for a while :D

Essential amino acids

• Arginine
• Histidine
• Isoleucine
• Leucine
• Lysine
• Methionine
• Phenyloanine
• Threonine
• Tryptophan
• Valine

Non-essential amino acids

• Alanine
• Asparagine
• Aspartic acid
• Cysteine
• Glutamic acid
• Glutamine
• Glycine
• Proline
• Serine
• Tyrosine

Essential amino acids are amino acids that your body cannot synthesise and you must acquire through your diet. Non-essential amino acids are readily synthesised in the body.

The synthesis of amino acids occurs through five families of mechanism

1) a-Ketoglutarate family:

This mechanism creates glutamic acid, glutamine, proline, arginine and lysine*.They are formed by enzymatic alterations, including both oxidation and reduction, to ketoglutarate (a carbohydrate).

2) Aspartate family

This mechanism creates aspartic acid, asparagine, methionine*, threonine*, isoleucine* and lysine* again. Aspartate is formed in the TCA cycle by transamination of oxaloacetate taking the amine group of glutamate. The others are formed through enzymatic hydrolysation of this aspartate precursor.

3) Pyruvate family

This mechanism creates alanine, valine* and leucine through transamination and decarboxylation of pyruvate.

4) 3-Phosphoglycerate family

This creates serine, glycine and cysteine from a serine precursor, itself formed from oxidation and transamination of 3-phosphoglycerate, an intermediate of glycolysis.

5) Phosphoenol pyruvate and erythrose-4-phosphate family

This creates phenylalanine*, tyrosine, tryptophan* and histidine* (all aromatic amino acids) from a metabolic intermediate called chorismic acid.

* indicates this amino acid is not synthesised in humans, but is often synthesised in organisms like fungi, bacteria, some plants, etc.

I dunno if this is just a British thing or not but we have a biochemical mnemonic here to recall the functions of oxidation and reduction. It’s probably popular everywhere but I’m sure some people won’t have heard it.

OIL RIG:

Oxiation Is Loss, Reduction Is Gain.