Why exactly is HDL-cholesterol good for us and LDL-cholesterol bad for us. It has been well-established that LDL-cholesterol is associated with atherosclerosis and that HDL-cholesterol helps remove excess LDL-cholesterol from the circulation. From a biochemical view, however, what is the difference between the molecules that causes this difference?
First of all, we should specify that there is no such thing as "HDL-cholesterols" and "LDL-cholesterols". On the same note there is no such thing as "good cholesterol" and "bad cholesterol": cholesterol is just one molecule, with this chemical structure
What blood tests generally report is HDL-C and LDL-C, that is the amount of cholesterol in HDL or LDL respectively (again, cholesterol is always the same molecule, whether in an HDL or in an LDL).
HDL (high density lipoprotein) and LDL (low density lipoprotein) are lipoproteins, aggregates of proteins and lipids that can carry, amongst other things cholesterol. There are 5 major types of lipoproteins, called chylomicrons, VLDL, IDL, LDL, and HDL and are distinguished by their size, density and the proteins they are composed of.
The main function of lipoproteins is that of carrying lipids (=fats) around the organism in the blood. The problem is that lipids are not soluble in water (try to pour some oil in a glass of water) and blood is mainly composed of water. Lipoproteins, on the other hand, have a hydrophilic (="water-loving") exterior and a lipophilic (="fat-loving") interior, like this:
In the picture, the "balls" represent proteins, called apoproteins, and the C represent cholesterol and T tryglicerids, which are both lipids. As you can see, all the fats are inside the lipoprotein, but the exterior, being soluble in water can be easily dissolved in the blood.
The biochemistry of lipoproteins is quite involved and I will not go into details here (but please leave a comment if you want further explanations) but, to simplify things:
- HDL bring lipids from the periphery back to the liver
- LDL bring lipids from the liver to the periphery
It is very important, at this point, to note that lipids are a physiologically important part of our organisms. All the cells in our body contain lipids: the membrane of each cell in the body is made up of lipids (called phospholipids) and also contain cholesterol. In fact, cholesterol is extremely important for the correct functioning of the body as, for instance, it is used as the base to make many hormones (the so-called steroid hormones, such as estrogen, progesterone, cortisol, testosterone etc).
However, too high levels of lipids, particularly cholesterol, are not beneficial, as high cholesterol levels have been in fact linked to many cardiovascular diseases, which we hear a lot about these days.
So, because HDL tend to remove the lipids from the circulation and bring them back to the liver they can be considered as some sort of "cleaners", that remove excess cholesterol from circulation.
Your question is about the molecular differences between LDL and HDL.
The way you formulate, asking about differences on the molecular level, draws the attention to the surprising fact that the molecular structure is not that different as the big differences in physiological function may make you assume. Your question is valid, as textbooks list different contents of cholesterol, triglycerides and proteins, but do not elaborate on differences in structure of - for instance - "molecular markers of LDL". Similar to different classes of antibodies (IgM, IgG, IgA...) there seems to be a very similar structure to all transporter lipoproteins.
Conversely, to illustrate, the word "chylomicrons" may mislead to thinking of those as "micelles" or being very distinct from those lipoproteins termed HDL, LDL,IDL and VLDL. However, they also belong to the class of lipoproteins the function of which is transport of lipids, and they are more similar in molecular structure as labeling suggests.
Interestingly, a similar question on Stackexchange Chemics has been refered to your question. That might illustrate the above: any relevant differences do not relate either to the load of the lipoproteins or to their differences in coating or core proteins (that exist), but any difference is in biology that,ironically, very much corresponds to "labeling": which lipoprotein in contrast to the other derives from which organ, which one addresses and unloads at which kind of target cells.
To sum up: differences are neither differences in load nor coat but are differences in send and receive signalling which are differences, as it turns out, of apolipoproteins.
Thus, the ligand on LDL to
is key difference "literally",
which is remarkably reflected by the fact that the LDL-ligand on LDL-molecules is the biggest protein known, called
Anwswering your question: it is expression of Apo B-100 protein, that distinguishes LDL from HDL on the molecular level in respect of pathogenicity.
Conversely, the apoA-I protein may be considered distinguishing feature of HDL (see, for instance, quote down below, Verghese et al.)
What's more, and may come to a surprise, is the fact that there is no one and the same HDL or LDL molecule, both terms denote classes of proteins; it seems that no single "LDL-cholsterol" is like any other "LDL-cholesterol". See, for instance, Kontush et al.,2014 Structure of HDL: Particle Subclasses and Molecular Components.
Relevant feature of those proteins are their receptor ligand proteins.
LDL-receptor downregulation is the key cause of atherosclerosis (No known other detrimental effects of cholesterol).
From Nobelprize.org "Brown and Goldstein have discovered that the underlying mechanism to the severe hereditary familial hypercholesterolemia is a complete, or partial, lack of functional LDL-receptors. In normal individuals the uptake of dietary cholesterol inhibits the cells own synthesis of cholesterol. As a consequence the number of LDL-receptors on the cell surface is reduced. This leads to increased levels of cholesterol in the blood which subsequently may accumulate in the wall of arteries causing atherosclerosis and eventually a heart attack or a stroke."
Note that hereditary disorder is not the only cause for LDL-R downregulation: "LDL receptors are downregulated by increased cellular cholesterol to prevent sterol engorgement, which is a characteristic of cells in atherosclerotic lesions." From: Biochemistry of Lipids, Lipoproteins and Membranes (Sixth Edition), 2016
The way you put your question draws attention to the fact that there is no corresponding downregulation of HDL-receptor.
Search on Wikipedia for "HDL-receptor" results in: "The page "HDL-receptor" does not exist." Presumably, no trivial knowledge that Nobel prize laureates Goldstein and Brown discovered a whole family of so called "scavenger receptors".
What would happen if the HDL-receptors was downregulated (to compare with LDL downregulation)?
The "molecular difference" seems surprisingly unclear then: both HDL and LDL do carry cholesterol (It is the very same molecule in both HDL and LDL). If too much LDL leads to depositon of cholesterol, same deposition might be made by ("too much") HDL - your question is valid in that respect. Downregulation of receptor distinguishes LDL from HDL.
There is one answer to a related question on Stackexchange that seems to exactly fit, in regard of the distinguishing role of Apo B100, quote: "Because LDL contains only the ApoB protein, it is less easily recognized. Thus, more LDL lingers in the blood.", with further reference about the pathological effects. If any (distinguishing) molecular mechanism other than Apo-protein-signalling presumably protecting transported lipids from oxidation or degradation existed, it would had been mentioned. Apo-B100 makes the difference.
The essential molecular feature of LDLs is the LDL-receptor-ligand Apo B-100 which binds to LDL-receptors (on cells of adipose tissue) in contrast to HDL-receptor-ligand to HDL-receptor (on liver cells, surprisingly, however, not only on liver cells) - the latter known as "scavenger receptor class B type I"
which is barely mentioned in Wikipedia (not having done intensive searching, admittingly: there should not be found in literature any discussion or even mentioning on downregulation causing common disease, cp.Rigotti et al., 1997, A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism: "(...) hepatic overexpression dramatically lowers plasma HDL." - wheras only the knock out experiment this paper is about is cause for downregulation. Presumably, there is no downregulation of HDL receptor that would correspond to LDL-receptor downregulation.
On Apo B-100 as distinctive molecular marker see, for instance, Encyclopedia Britannica:
"LDL contains a single apoprotein and is the principal carrier of cholesterol to the peripheral tissue as both the free sterol and esters. The discharge of the lipid contents of this complex requires the recognition of the LDL B-100 apoprotein by a receptor located on the surface of recipient cells. When the protein is bound to the receptor, the receptor-LDL complex is engulfed by the cell in a process known as endocytosis. The endocytosed LDL discharges its contents within the cell, and B-100 is degraded to free amino acids that are used to synthesize new proteins or are metabolized as an energy source. The elucidation of the process of cellular uptake of LDL by Michael Brown and Joseph Goldstein earned them the Nobel Prize for Physiology or Medicine in 1985."
There is one more aspect to your question in the context of this answer.
The term "scavenger" (for HDL, not LDL) hints to the fact that another difference between HDL and LDL lies in LDL being degraded in lysosomes after uptake (by adipose tissue cells), whereas HDL is being recycled after "touch down" on HDL-receptor, i.e. not even uptaken by liver cells. Please let me add this tentative thought: Thus, as there seems to be no "feedback" loop for LDL; the liver producing LDL (which start as so called VLDL, by the way) might not downregulate LDL-synthesis if target tissue downregulates LDL-receptors.
You may skip the following further tentative thoughts of mine:
According to Voet et al, Biochemistry, the receiving of LDL via LDL-receptor by adipocytes leads to those "shedding" cholesterol (which seems to be picked up by "scavenging" HDL). See, for instance, Verghese et al., 2007
"In the presence of HDL, composed of human apoA-I and phosphatidylcholine, adipocytes release cholesterol in a lipoprotein-dose and time dependent fashion." This might be considered recycling of cholesterol (brought from liver to storing tissue by LDL and back again to liver on HDL, as delivery of fatty acids to storing tissue allows those to release cholesterol). In an evolutionary tentative concept, cholesterol as a molecule in itself might once have been the very transport vehicle to transport lipids and fats from and to cells (see above: HDL is not even endocytosed, in very contrast to LDL-receptor-uptake, when it returns to liver cells, still cholesterol enters the liver cells. HDL leaves the receiving "scavenging receptor" as it is; it is some taxi; my analogy is to cholesterol). This idea leads to considering the sheer quantity of loaded cholesterol as presumably distinctive: any quantity surmounting a level defined as upper limit for "taxi function" might be unloaded (or oxidized in scavenging funtion). This seems coherent with the existence of "remnants": there are LDL or VLDL-remnants and chylomicron remnants which the liver receives cholesterol by. On a molecular level, there might be a difference in relative or absolute quantity of cholesterol, between LDL and HDL, reflecting that HDL as such "is" a remnant in the sense that it recyles cholesterol in "remnant quantity/thus quality". (There do exist LDL and chylomicron remnants, however, there is no such term or thing as HDL remnant, to verify). By the way, counterintuitively, cholesterol is arguably considered "amphophilic", cp. source cited in comment to question and quote Encyclopedia Britannica above that mentions "sterols and esthers" as vehicles of cholesterol transport. Moreover, uptake of free fatty acids by adipose or muscle cells (that is the form derived from VLDL after lipase took on) seems not very well established in its mechanism. Cholesterol, then, is known to be the distinguishing feature of animal cell walls in contrast to plant and procaryote cell walls. Cholesterol in cell walls might - by "softening" - enable heterotrophic cells to absorb free fatty acid (derived form autotrophic (plant cells, unsaturated fats)) without use of any - yet unknown - membrane transport canal or receptor mechanism. Please let me add one more argument that seems surprising: target cells of adipose tissue are made to "shed" cholesterol by LDL-receptor signalling. "On the other side" these target cells of LDL "take on in" - and keep - cholesterol and lipids (from degration of LDL). There might be some feedback loop of receiving lipids and shedding free cholesterol that is - in evolution - still independent of APO-B100-LDL-receptor signalling, and downregulating the LDL-receptor solely might interconnect both levels or regulating free "chole-sterols" in blood, or, if cholesterol is a former instrument of uptake as proposed, in interstitial fluid. Thank you for having allowed this tentative thinking.
To sum up:
Lipoproteins resemble each other in molecular structure and transported forms of fat/cholesterol more than the acronymes HDL/LDL may suggest.
The relevant difference lies in their ligands, which address different target cells: ligand to "LDL-receptor" (which HDL does not seem to have or has to a much lesser extent) is decisive in pathogenicity as there is "LDL receptor downregulation"; there is no physiological (in vivo) HDL downregulation.
Distinguishing molecular feature thus appears to be Apo-B100 molecule, which is the largest protein of the body.