MyFatDog        

Enough jargon!

What do these things mean?

Angptl4 antibody.  Angptl4 is a protein that can inhibit lipase activit yin plasma and increase plasma triglyceride levels.   If you can lower the levels of this protein then, in theory, you should be able to lower triglyceride levels in plasma.  One way to lower Angptl4 is to make an antibody to it and clear it out of plasma just as your body would clear any bacteria that got into blood.   This treatment is in the early stages but should be interesting.

apoA-I mimetic.  Apolipoprotein A-I (abbreviated apoA-I) is a protein that is associated with HDL.  ApoA-I acts like a docking port that connects HDL to different parts of the body and allows excess cholesterol to transfer out so it can be taken to the liver.  Some scientists figured out that apoA-I has several different parts that have different functions.  They found that you could make small proteins that only have one of the functions of apoA-I.  These are called apoA-I mimetic peptides.  One company made a apoA-I mimetic peptide that is made up of the part that acts like a docking port and that this will allow more cholesterol to get transferred out of different parts of the body to HDL.  Another company made a very small peptide, called D4F, that seems to reduce inflammation when administered to humans. 

ApoB Antisense. Antisense is one way of achieving RNA interference.  ApoB is the main protein on VLDL and LDL.  If you block apoB from being made then you block VLDL and LDL from being made.  Antisense is a way to limit the amount of protein, in this case apoB, from being made.  The effect is to lower VLDL and LDL levels.

CETP Inhibitor.  CETP inhibitors work by blocking one of the pathways that cholesterol is transfered out of HDL.  As a result cholesterol accumulates in HDL and HDL cholesterol levels increase.  There is some debate among scientists about whether this is a good way to increase HDL cholesterol levels.  Studies in animals suggest that it is good.  One CETP inhibitor, called torcetrapib, that was tested in humans was discontinued because it also increased blood pressure.  Other CETP inhibiors that don't raise blood pressure are being tested to see if they can reduce the risk of heart disease.

Cholesterol absorption inhibitor.  These drugs include ezetimibe, which is one of the drugs in Vytorin, as well as plant sterols that are found in more and more as supplements that are supposed to lower cholesterol.  These work by blocking the protein that takes cholesterol out of your intestine.  Of these, ezetimibe is the most potent and the others, such as phytosterols, are less potent.  Since your body is taking in less cholesterol it pulls cholesterol out of the blood to make up for what is being lost in the gut.

Extended-release niacin.  Niacin is a vitamin (vitamin B3).  When given at very high doses (1-2 grams) it can activate a receptor in fat that is normally only activated during starvation.  This keeps fat from going to liver and making a lot a of VLDL.  The end result is that plasma triglcyeride levels decrease.  Another beneficial effect is that HDL levels increase although its not known how this happens.  Unfortunately niacin can also cause some unpleasnt side effects such as skin flushing and itching.   These side effects can be minimized if niacin is absorbed slowly using an extended-release formulation. 

Fibrate.  Fibrates are a group of drugs that include TriCor and Lopid.  These drugs make your body think that it has too much fat in the liver.  The body responds by speeding up fat metabolism in the liver and blood.  In response to this triglyceride and VLDL levels in blood are reduced and , in some people, HDL levels are increased. Fibrates doesn't cause weight loss but may improve a fatty liver in some people.

Fish oils. Fish oils are rich sources of the fatty acids eicosopentaenoic acid (EPA) and docosohexaenoic acid (DHA).  These fatty acids can have beneficial effects such as reducing inflammation, reducing clotting, reducing triglycerides and increasing HDL cholesterol.  These effects can be due to competion with other fatty acids in the body as well as direct effects of activating nuclear receptors such as PPAR alpha and PPAR gamma.

Laropiprant.  This is a drug that blocks the prostaglandin D2 receptor in skin.  It was found that by blocking this receptor that the unpleasnt side effects of niacin such as skin flushing and itching can be minimized.

LCAT activators. LCAT activators increase the activity of an enzyme in plasma named lecithin:cholesterol acyltransferase, abbreviated LCAT.  This enzyme takes the cholesterol that is on the outer layer of an HDL particle and converts it to cholesteryl ester.  The cholesteryl ester is stored in the middle of an HDL particle.  This frees up the outer layer so it can take up more cholesterol from cells.  Otherwise it would get saturated with cholesterol and wouldn't be able to take up any more.

Liposomes.  Liposomes are basically small sacks of phospholipid that are very simiar to HDL except that they lack the proteins that are on HDL.   If these are mixed with a natural or recombinnat form of apoA-I they can make a synthetic HDL particle that can be injected as a way of moving excess cholesterol out of the body.

Lp-PLA2 inhibitor. Lipoprotein -associated-phospholipase A2, abbreviated Lp-PLA2, is a protein that can eat away at the outside part of LDL creating a damaged LDL particle that can’t be cleared normally from plasma.  If a large amount of LDL gets damaged in this way then the white blood cells that clear them from blood can get overwhelmed and end up as part of a an atherosclerotic plaque which can eventually block your arteries and cause a heart attack. If you inhibit sPLA2 with a sPLA2 inhibitor then you can prevent the LDL damage and reduce the risk of developing atherosclerosis.  Some scientists have their doubts about how much this protein contributes to the development of atherosclerosis.  If sPLA2 doesn’t make much of a contribution to atherosclerosis then a sPLA2 inhibitor will have little effect on the risk of developing atherosclerosis.

MTP inhibitor.  MTP is an abbreviation for microsomal triglyceride transfer protein.  This protein loads triglyceride and cholesterol onto chylomicrons in the intestine and onto VLDL in the liver.  If you prevent MTP from working then you can block chylomicrons and VLDL from being secreted into the blood from the intestine and liver whic lowers triglyceride levels in blood.  Since LDL is made from VLDL then this has the effect of lowering LDL levels too.  People that have taken MTP inhibitor tend to lose weight, probably because they absorb less fat but also because the intestine, which gets full of fat since it can't secrete it on chylomicrons, sends a signal to the brain saying that its full and that you don't need to eat.  This sounds great except that if your body can't absorb a lot of fat then it stays in the intestine and can cause diarrhea and other intestinal problems.  These can be minimized if you eat a diet very low in fat.

Niacin receptor activator.  The niacin receptor is a newly identified protein, found mainly in fat cells, that binds niacin.  When niacin binds the fat cell releases hormones that make the body think that its starving and so it tries to pull triglyceride out of the blood and increase HDL.

Orphan approval.  Development of drugs for certain diseases may not be pursued because the disease only affects a small number of patients so its not profitable for comapnies to develop drugs to treat them.  An Orphan Drug act in the US lets companies develop these drugs and market them at a profit, despite the small number of patients.  For mipopersen, the disease is homozygous Familial Hypercholesterolemia which affects about 1 in 1 million people.

pan PPAR alpha/gamma/delta agonist.  PPARs are proteins that sense how much of specific types of fat is inside your cells.  If there is too much of this fat then PPARs become activated and takes steps to reduce the amount of fat in cells.  PPAR alpha works mainly in liver, PPAR gamma works mainly infat, and PPAR delta works mainly in muscle.  Activation of PPARs make cells clear more fat from plasma and burn more fat.  Drugs that bind to PPARs make the body think that it has too much fat inside cells.  The overall effect of this is lower plasma triglyceride levels and increase HDL cholesterol levels. 

PCSK9 antisense/PCSK9 RNAi.  Antisense and RNAi are ways of achieving RNA interference (RNAi). PCSK9 is a protein that was recently discovered that can block the receptor that pulls LDL out of your blood.  It was found that people that can't make PCSK9 have very low levels of LDL and also have a reduced risk of developing heart disease.  Several companies are working on ways to reduce the amount of PCSK9 that is made.  Two ways are antisense and RNAi  both of which block the amount of protein that is made. This should result in low levels of LDL and a low risk of heart diesease.  So far the most effective way of delivering these is by injection which limits their use on a wide scale.

PPAR alpha activator. PPAR alpha is a protein that senses how much of specific types of fat is inside your cells.  If there is too much of this fat then PPAR alpha becomes activated and takes steps to reduce the amount of fat in cells, particularly the liver, by making the cell burn more fat and by making the body clear fat much more quickly from blood so that it doesn't come back to the liver.  Some drugs can bind to PPAR alpha and make the body think that it has too much fat inside cells.  The overall effect of this is lower plasma triglyceride levels and increase HDL cholesterol levels.  There is some evidence that activating PPAR alpha can also reduce the amount of fat in a fatty liver.

Recombinant HDL.  Recombinant HDL is HDL that is made in the laboratory using a lot of the components that make up HDL that’s found in blood.  A while ago when scientists found out that lipoproteins were just a mixture of lipids and proteins they tried to re-create them in ht lab to see how they functioned.  VLDL and LDL were pretty difficult to recreate, but HDL was easier.  Someone had the idea that if you could make HDL in the lab and inject it into people it could help to transfer excess cholesterol from different parts of the body to the liver.  

RNA interference.  Also known as RNAi, is a technique that targets RNA, the template that is used to make a protein.  If you interfere with RNA in certain ways the cell will destry the RNA and this will decrease the amount of the target protein being made. 

siRNA delivery.  siRNA is a method of achieving RNA interference (RNAi).  siRNA stands for small interfering RNA.  This is a natural way that the body regulates the amount of some proteins that are made.  Scientists have found a way to trick the body into using this to reduce the amount of some proteins that are made.  So far the most effective way of delivering these is by injection which limits their use on a wide scale.

sPLA2 inhibitor.  sPLA2 is an inhibitor of an enzyme in plasma called secretory phospholipase A2.  sPlA2 can break down phospholipids that form the outer layer of some lipoproteins like LDL and HDL.  This is thought by some to result in damage of LDL and possibly HDL so that they don't function normally.  This could result in an increased binding of LDL to artery walls and lead to the formation of atherosclerotic plaque.  By inhibiting this enzyme this damage should be prevented and LDL and HDL should function normally.

Squalene synthase inhibitor. These drugs also reduce the amount of cholesterol being made by the liver in a way that is different from the statins.  In response to this the liver pulls LDL cholesterol out of plasma resulting in lower LDL levels.

Statin.  Statins are a group of drugs that include Lipitor and Zocor.  These drugs reduce the amount of cholesterol being made by the liver.  In response to this the liver pulls LDL cholesterol out of plasma resulting in lower LDL levels.

Thyroid receptor beta activator. These are drugs that activate the thyroid hormone receptor.  Thyroid hormone is a substance that your body makes to control its metabolism.  Thyroid hormone can speed up metabolism.  People who don’t make enough thyroid hormone are called hypothyroid and can have slow metabolism that causes them to be tired, to gain weight and to have high LDL cholesterol levels.  These people are treated with a synthetic thyroid hormone that speeds up metabolism.  If you give thyroid hormone to someone to someone with normal metabolism you can get unwanted side effects, including a racing heart. Scientists have found ways to stimulate some of the effects of thyroid hormone so that it can lower LDL cholesterol level without having side effects.