The lengths our bodies go to to make cholesterol
For decades we were urged to consume less of foods high in cholesterol (such as eggs), despite it being known since the 1950s that there was no relationship between cholesterol in our diet and cholesterol in our blood. Our bodies make cholesterol whether we eat it or not, we just make less of it if we eat more of it. Cholesterol is a crucial molecule for our biology, and an adequate supply is essential for us to be healthy. More recently, dietary guidelines have watered down their negative cholesterol advice, although they have only whispered this reversal to the public.
Our production of cholesterol
All cells in our body (other than red blood cells) make cholesterol, and the first steps in this process are shared by all members of the animal, plant and fungi Kingdoms, indicating these processes were being formed with the very beginning of life on Earth.
A graphical depiction of the processes to be described:
The pathway starts with a two-carbon molecule, acetate (indicated in yellow). Our cells can make acetate out of any macronutrient — glucose (from carbohydrate), amino acids (from proteins), fatty acids (from fats), ketones (from fatty acids) or ethanol (from alcohol). Acetate can be used for energy production, or it can be used to synthesise other molecules such as glucose, fatty acids, triglycerides or, as with the present case, cholesterol.
It takes only a few steps to convert acetate to HMGCoA (I will just use acronyms). However, the crucial step is the subsequent conversion of HMGCoA to mevalonate, catalysed by the enzyme HMGR (indicated in red). This is the rate-limiting step for cholesterol production because it is irreversible and, once mevalonate is formed, the synthesis of cholesterol is inevitable provided the substrates are available.
Our cells use HMGR to regulate cholesterol synthesis, by raising or lowering the availability of HMGR based on four different feedback loops, the main one being the level of cholesterol already in the cell (e.g. from cholesterol synthesis or uptake from circulating low-density lipoproteins). Statins also act at this level, out-competing HMGR to block downstream cholesterol production and the byproducts of cholesterol synthesis.
Seven more steps lead to the production of squalene. Along the way, a number of biologically-important byproducts are generated, including coenzyme Q10 and haem(a), both of which have crucial roles in the production of cellular energy, and isoprenoids that are involved in protein-protein and lipid-protein binding.
Cells from animals, plants, fungi and bacteria have this mevalonate pathway in common, starting with acetate and ending with squalene. This is an ancient pathway.
The bacterial branch
While bacteria do not synthesise sterols, they can go on to synthesise another class of compounds (hopanoids) from squalene, which gives bacterial membranes some similar properties to our cholesterol-containing membranes.
Oxygen
Up to this point, the biochemical reactions have not involved oxygen, and these reactions likely pre-date the oxygenation of the Earth’s atmosphere (~2 billion years ago). However, the new availability of oxygen may have removed squalene as an evolutionary bottleneck and allowed for the formation of newer molecules with more useful properties. It is at this point that animals, plants and fungi diverge, each evolving their own versions of sterols. The structural molecular diagrams in the top-right of the diagram indicate how subtle the differences are in these sterols across Kingdoms.
The plant branch point (phytosterols)
The oxidation of squalene to oxidosqualine is the first branch-point that, through a multi-step process (not indicated, but requiring 10 oxygen molecules per sterol), leads to plant phytosterols such as sistosterol. While animals and fungi have evolved only the one sterol (each), plants have a number.
The fungi/animal branch point
One further step from oxidosqualine to lanosterol, gives us the earliest common ancestor sterol for fungi and animals that then go their separate ways to ultimately produce ergosterol or cholesterol respectively.
Cholesterol synthesis pathways
For animals, an additional ~18 steps after lanosterol, requiring 10 oxygen molecules and 15 enzymes, are needed before one molecule of cholesterol is formed.
Furthermore, animal cells do not rely on just one pathway to go from lanosterol to cholesterol, they run two in parallel — the Bloch Pathway and the Kandutsch-Russell Pathway. These pathways share enzymes at various steps that enable them to regulate each other. Cells are taking no chance with the synthesis of cholesterol, ensuring that there is more than one way to get there. A third pathway (not shown) called the Shunt Pathway, regulates the balance between the two primary cholesterol pathways.
The last step in the Kandutch-Russell Pathway, before cholesterol is finally formed, branches to the synthesis of vitamin D in skin cells (in the presence of UVB radiation). Finally, cholesterol itself can undergo further transformations to produce oxysterols, bile and all the steroid hormones, or be used in cell membranes for its various structural properties or configurations.
Concluding perspective
I invite you to contemplate that graphic for a moment.
It is not only a depiction of the complexity of cholesterol (and other sterol) synthesis, remarkable enough as those processes are.
It also represents a cross-sectional snapshot of a few billion years of the painstaking evolution of life on Earth.