A triglyceride is a glycerol molecule joined with three fatty acid molecules. It stores more than twice as much energy as a pound of carbohydrate. Humans stock these long term food stores in adipose cells. A fatty acid is said to be “unstaturated” if it has a double bond in the carbon skeleton. A fatty acid is “saturated” is they contain the maximum number of H atoms, giving them a straight shape. Diets rich in saturated fats may contribute to cardiovascular disease by promoting atherosclerosis where lipid containing deposits called plaque build up along the inside walls of blood vessels, reducing blood flow and increasing risk of heart attacks and strokes. 

Steroids are lipids that are very different from fats in structure and function. All steroids have a C skeleton with four fused rings. Different steroids vary in the functional groups attached to this set of rings and these chemical variations affect their function. One common steroid is chlesterol which is a key components of the membranes that surround cells. It is also a “base steroid” form which the bondy produces other steroids, such as hormones estrogen and testosterone, which are responsible for the development of female and male sex characteristics. 

In addition to exogenous uptake of cholesterol, nearly all mammalian cells are able to synethesize cholesterol de novo. Cholesterol and triacylglycerols are transported in the body in the form of lipoproteins. Cholesterol esters or triacylglycerols are contained on the inside of such lipoproteins (no charge) and polar groups form the exterior of the lipoprotein. In cells of peripheral tissues, excess cholesterol needs to be removed and transported to the liver for reutilization and excretion. There are several types of lipoproteins, each of which has a particular apolipoprotein surface which serves as the ligand for a specific lipoprotein receptor.

Types of Lipoproteins

1. chylomicrons are the lowest density type of lipoprotein. Chylomicrons are produced in the intestinal mucosal cell and have the apolipoprotein B-48 which forms an amphiphathic shell round the fat globule. Apo-B is synthesized by the intestine and the liver in mammals, where it serves as the main structural component in the formation of chylmicrons and the synthesis of VLDL, LDL and IDL lipoproteins. The formation of chylomicrons by the intestine is very important for the absorption and transport dietary fats and fat-soluble vitamins. The chylomicrons travel to the lining of blood vessels in tissues that use fatty acids as fuels where the cylomicrons are hydrozlymed by lipoprotein lipases. Lipoprotein lipases are activated by the apolipoprotein C-II. Chylomicron remants then travel to the liver.

2. Low density lipoproteins (LDL “Bad” cholesterol): 

LDL or “bad cholesterol can lead to plaque buildup in arteries and result in heart disease or stroke. An optimal LDL level is about 100 mg/dL. 

LDL particles come in different sizes. The smaller sizes have been thought to be the most dangerous type. However, some studies have suggested that large LDL size may be associated with CHD. are divided into 3 groups (VLDL, IDL, and LDL) and all have the apolipoprotein B100 which is encoded by the same gene as the Apo B48 for chylomicrons but is larger because it has not been edited.

(a) VLDL (very low density lipoproteins) are formed in the liver (they are used to export the triacylglyerols in excess of the liver’s needs) and then travel to the lining of blood vessels where like chylmicrons, they are hydrolyzed by lipases. The resulting remnants are rich in cholesterol ester called IDL (intermediate density lipoproteins).

(b) IDL Half of the IDL are taken up by the liver whereas the other half is converted to LDL (low density lipoproteins) which are the major carrier of cholesterol in the blood.

(c) LDL Mammalian cells acquire exogenous cholesterol mainly from low-density lipoprotein (LDL) particles vial the LDL receptor pathway. The majority of LDL receptors expressed in mammals are on the surfaces of liver cells, although a certain level of LDL receptor expression also occurs in the peripheral tissue. LDLs travel to the lining of blood vessels where the apoliprotein 100 binds to specific LDL receptors. LDLs are internalized by endocytosis to form a vesicle which then fuses with lysosomes which have enzymes that hydrolyze the protein component of the LDL. The LDL receptor is then free to retun to the PM and the cholesterol is free for use for membrane biosynthesis or can be reesterified for storage inside the cell by ACAT (acyl CoA: cholesterol acyltransferase) discussed above. Defects in LDL receptors leads to a very dangerous condition called familial hpercholesterolemia (FH) which results in the accumulation of LDL in the plasma which can lead to atherogenesis. Oxydation of LDL and uptake by scavenger receptors are key events in atherogenesis (damaging of the endothelium tissues). Homozygotes for this disease have amost no LDL receptors whereas heterozygotes for the defficient gene have half the normal number.

High levels of LDL-C in the bloodstream can cause heart attacks, strokes, and cardiovascular disease. Typically high LDL-C is treated using small molecules called statins. In some cases, however, statins have adverse side effects or cannot reduce a pateint’s LDL-C to a healthy level, requiring alternative treatment. One such alternative treatment is a PCSK9 inhiibtor. PCSK9 is a naturally occurring protein that binds to and causes the destruction of liver cell receptors (LDL receptors, or LDL-Rs) that are responsible for extracitng LDL-C from the bloodstream. Amgen has a drug called Repatha™ which using an active ingredient called “volocumab” which is a mAb that target PCSK9 to preevent it from destroying LDL-R proteins. The fDA approved Repatha in August 2015. Amgen has two patents US Patents Nos: 8,829,165 and 8,859,741 which cover the entire genus of antibodies that bind to specific aamino acid residues on PCSK9 and block PCSK9 from binding to LDL-Rs. The patents do not specifically cliam Repatha by amino acid sequence. Instead the claim recites “An isolated monocloanl antibody, wherein, when bound to PCSK9, the mAb binds to at least one of the following reisudes: S153, I154… and wherein the mAb blocks binding of PCSK9 to LDL-R”.  The Federal Court has held that these composition claims were invalid for lack of enalbement. The claims were defined not by structure, but by meeting functional limitations. and applicant did not enable preparation of the full scope of the function claims without undue experimentation.  see Amgen v. Sanofi (Fed. Cir. 2021). 

3. HDL (high density lipoproteins) 

HDL also known as “good”cholesterol because hihg levels of it can lower one’s risk of heart diease and stroke. 

In cells of peripheral tissues, excess cholesterol needs to be removed and transported to the liver for reuitlization and excretion. HDLs, which are sometimes referred to as “good cholesterol”, are involved in the reverse transport of cholesterol from the peripheral cells back to the liver cells. The cholesterol is transported out of the cells to HDL using ABC1 protein transporters. HDLs have a major role in removing excess cholesterol from extrahepatic cells, providing a protection against the development of atherosclerosis in the arterial wall. The major component of HDL particles is apolipoprotein A-I (ApoA-I). Lipid-free apoA-I is secreted predominantly by the liver and intestine and acquires phospholipids and cholesterol via cellular efflux from peripheral tissue cells and macrophages, giveng rise to nascent HDL. Once mature, HDL particles are transported to the liver, adrenal glands, and steroidogenic tissue where they are recognized by the HDL receptor, scavenger receptor type B class I, upon which the process of “selective lipid uptake” by the target cell is induced, which fundamentally differs from receptor-mediated endocytosis. During “selective lipid uptake,” cholesterol and phospholipids are effectively transferred to target cells, releasing extracellular, lipid-depleted HDL particles which can reenter circulation.

Low levels of high density lipoprotien (HDL) have long been associated with an increased risk of myocardial infarction. Alone with stroke, myocardia infarction is often a consequence of cardiovascular disease, and these two conditions share a common underlying etiology of atheroscerosis. Thus, therapeutic stratgies develope to promote atheroprotection –protecitng patients form cardiovascular diase and thereby reducing the risk of myocardial infarction have focuses on increasing a patient’s HDL levels. I

Apoliproportein A-1 (AOA1) is hte prcinicpal protein componetn of HDL. Introducing ApoA1 into the body can, thus be a mechanism for increasing HDL Howeer, ApoA1 has a relatively short half-life in the human body. The half-life can be improved by joining it to another protein such as the Fc fragment of an immunoglobulin. Sino Biological ApoA-1Fc fusion protein for example contains ApoA1 direclty bound to an Fc.