Sterols are crucial components of cell membranes in animals and plants. Therefore, we all get them in our diet whether we are omnivorous or vegan though vegetarians tend to get higher amounts. Rich sources of these sterols are plant oils, nuts, cereals, seeds, fruits, and vegetables. Non-cholesterol sterols are sterol & phytosterol precursors to cholesterol.
Cholesterol, as I’ve stated many times, is absolutely essential for life and virtually every cell in our body is capable of synthesizing it from fatty acid derivatives, acetate, and acetoacetyl-CoA. We also absorb it from our diet. For those of you that believe that decreasing dietary intake will impact your overall cholesterol, think again. Ancel Keys (the father of the ‘Lipid Hypothesis’) has stated that dietary cholesterol has no impact on your blood cholesterol. If you decrease your dietary cholesterol you will simply increase your production of cholesterol in your body. Conversely, if you increase your dietary cholesterol you will generally decrease the amount of cholesterol that you produce.
These sterols and stanols are very similar structurally to cholesterol and only differ by a small change such as a methyl or ethyl group in their side chains or in the number of double bonds in the molecule. That may be more biochemistry than you’ll ever care to know but understand that it helps us assess your physiology. Phytosterols do not serve a physiologic purpose in the human body, they don’t get easily absorbed in the gut, and they can’t be synthesized easily inside our body. We know of over 200 phytosterols and the most common are sitosterol, campesterol, and stigmasterol. The different side chains of these molecules affect the amount of absorption of these molecules.
Many people believe that lowering cholesterol in the body reduces cardiovascular disease. Your body can absorb cholesterol in the diet and it can produce it from scratch. Some people tend to be better absorbers and some are higher producers. The most efficient method of cholesterol lowering is specific for the patient based on which they do more efficiently: absorb or produce. We can use these sterols and stanols to help us understand each patient’s unique physiology.
The National Cholesterol Education Program’s (NCEP) Adult Treatment Panel III (ATP III) recommends 2 grams per day of plant stanols & sterols as consumption of these substances has been shown to reduce circulating levels of total cholesterol (TC) & LDL. Interestingly, there have been no studies showing that increasing intake of plant stanols & sterols reduces cardiovascular disease events. This further solidifies the idea that elevated cholesterol alone is NOT the cause of cardiovascular disease.
Non-cholesterol sterols inhibit the absorption of cholesterol by competing for position in mixed micelles in the gastrointestinal tract.
**Warning – Excessive biochemistry follows!** But for those who are interested… read on!
Sterols are also known as steroid alcohols which are a sub-group of steroids which have a hydroxyl group at the number 3 carbon of the A-ring. Thus, they are given the name structure of 3-hydroxycholesterol. The major differences in these molecules are in the ‘R’ tail attached to the number 17 carbon. Plant sterols have an extra methyl (campesterol) or ethyl (sitosterol) group at the C-24 position and different levels of desaturation. Higher levels of carbon atoms and desaturation results in decreased absorption in the intestine.
5α-stanols are a group of sterols that are produced by saturation of the C5-6 double bond by hepatic enzymes. Thus, stanols are simply saturated sterols. They are found in tree bark (yum!) or can be commercially produced (scary!). Cholestanol is stanol form of cholesterol and sitostanol is the stanol form of sitosterol. Phytostanols are absorbed at an even lower rate than phytosterols (about 10x less).
Systemic entry of phytosterols is controlled by powerful mechanisms that increase intestinal and biliary excretion. A limited amount of these phytosterols are retained, <1%, which is reflective of the limited absorption in the small intestine as well as the high cholesterol production ability in the human body. Measuring serum cholesterol doesn’t help us understand if it were absorbed or produced in the body but we can use these sterols to clarify the picture since these phytosterols are not endogenously produced, are not readily absorbed (or involved in chylomicron synthesis), but taken up with cholesterol, and under normal physiologic circumstances do not enter the circulation. The are a valuable marker of cholesterol absorption. We generally look at sitosterol, campesterol, or cholestanol as markers of sterol absorption.
However, some stanols, such as cholestanol, can be produced within the body. Cholestanol intake, absorption, synthesis, and biliary cholestanol secretion are some of the factors that regulate the amount of cholestanol in the body. Cholestanol concentration in the blood is a valuable marker for cholesterol absorption efficiency since stanols can interfere with cholesterol absorption.
Intermediate sterols such as lathosterol (aka cholestenol) and desmosterol are frequent and useful markers to evaluate the extent to which we are making cholesterol in our body. Elevated levels of these two sterols indicate elevated cholesterol synthesis. If these levels are low then this is yet another reason why statins may not be the best thing for a specific patient.
So, we ingest cholesterol in two different forms: esterified and unesterified. Generally, only unesterified cholesterol is absorbed into enterocytes. Cholesterol is de-esterified by esterolases & lipases in the intestine. However, most of this unesterified cholesterol is of hepatobiliary origin meaning that it is what is excreted in the bile into the intestine and is then reabsorbed.
Lecithin then emulsifies the lipids (cholesterols, sterols, fatty acids, phospholipids, monoglycerides, etc) and packages them into micelles which are simply lipid taxi cabs. The micelles then ‘ferry’ the fatty acids and sterols to the intestinal brush border where all of the microvilli live. These lipids are then absorbed passively or transported by transport proteins. The NPC1L1 transporter is the one that internalizes the sterols.
Most people are able to absorb about 50% of ingested sterols from the gut but some can absorb higher amounts (60-80%) are considered ‘hyperabsorbers’. Others only absorb about 20-30% and are ‘hypoabsorbers’.
These noncholesterols sterols do not have a physiologic purpose in the human body so we try to keep them out. Thus, some of the cholesterol and nearly all of the noncholesterol sterols are send back out into the gut lumen by G5 & G8 which are ATP binding cassette transporters.
The cholesterol that is absorbed is either packaged into chylomicrons or excreted back into the gut lumen depending on the body’s need for cholesterol. If someone has a deficiency of either the G5 or G8 transporter protein mentioned above then none of this stuff is sent back out of the enterocyte and into the gut lumen. This means that everything that gets absorbed stays absorbed and you don’t eliminate it resulting in higher serum levels of this stuff. This is a rare condition that used to be called sitosterolemia but, since other sterols besides sitosterol are involved, it is called phytosterolemia and can lead to up to 100 fold increases in serum phytosterol levels. It is considered one form of Familial Hyperlipidemia (FH). This condition has been associated with xanthomas in childhood as well as premature atherosclerosis. Because of this finding, there is question of plant sterols can be a risk factor of atherogenesis.
Patients who are heterozygous, meaning that they have 1 normal and 1 abnormal gene of the ABCG5 or ABCG8 transporter protein, are able to eliminate some but not all of the sterols mentioned above. They often have moderately increased serum plant sterols (10-20x less than homozygotes). 2-3 grams of sterol intake in these patients increases serum sitsosterol and campesterol by 50 & 125% respectively whereas the same intake increases them by 30 & 70% in normal patients. This suggests that one normal G5/G8 allele is enough for nearly normal function. Polymorphisms do exist and can alter the function of these proteins even more.
All of these sterols that are not secreted back into the lumen are available for chylomicron packaging or incorporated into the HDL molecule. There is suggestion that HDL transport is the preferred method. Absorbed cholesterol can be esterified by acyl-cholesterol acyltransferase (ACAT), an endoplasmic reticulum enzyme. This cholesterol ester is then packaged along with triglycerides, phospholipids, and ApoB to form chylomicrons which are then absorbed.
Any cholesterol that is unesterified can be effluxed from enterocytes into cholesterol-acceptor proteins such as ApoA-1, pre-beta HDLs, or ApoE. So, cholesterol can enter circulation via chylomicrons and/or HDL. HDL elevation has been noted in patients with cholesterol hyperabsorption via this mechanism. In fact, up to 30% of HDL may be of this enterocyte absorption origin.
Since the noncholesterol sterols are not readily esterified by ACAT the plasma levels of these plant sterols are typically only about 0.5% of cholesterol. We have to esterify these noncholesterol sterols in order to package them into chylomicrons. Plant stanol levels are only about 0.05% that of cholesterol.
If these noncholesterol sterols do make it into the liver cells (hepatocytes) via HDL or chylomicrons they will be eliminated back into the gut via G5/G8 transporters in the bile canaliculi. Since some patients don’t have optimal G5/G8 function some of these sterols can make it into VLDL and LDL and gain systemic entry in these patients and they will, therefore, have elevated levels of cholestanol, sitosterol, or campesterol. Patients with hyperabsorption often have a family history of CAD, postmenopausal women, diabetes (type 2), and have used higher doses of statins. It is interesting to note that diabetic patients who have CAD are often hyperabsorbers but those with diabetes or metabolic syndrome that do not have CAD are often hypersynthesizers. Therefore, shifts in cholesterol balance may predispose a patient to CAD.
ApoE genotype can also affect plant sterol levels so increasing dietary plant sterols & stanols may not have the effect on LDL that one may expect. ApoE4 may be more of a cholesterol hyperabsorption and so statins may be less effective in these patients.
Cholesterol levels are controlled within the body and cholesterol deficient states result in upregulation of NPC1L1 (increases absorption) and downregulation of G5/G8 (increases elimination) as well as increased synthesis in the body. Conversely, cholesterol excess states result in the opposite reactions. NPC1L1 will be downregulated, G5/G8 will be upregulated, and synthesis will be decreased. This will be evident by low lathosterol & desmosterol levels as well as high levels of sitosterol, campesterol, or cholestanol.
Since we are able to measure these components we can have a much better understanding of overall cholesterol status, cholesterol synthesis, and cholesterol absorption. If therapy to lower cholesterol is indicated the understanding each of these components can optimize therapy to each patient.
Any of these components, cholesterol & phytosterols, can contribute to atherogenesis if they gain entry into the arterial wall. The unesterified sterols are potentially more atherogenic if they are able to get into the arterial wall macrophages. They are more prone to oxidation and these oxyphyotsterols are very atherogenic. The Prospective Cardiovascular Munster Study (PROCAM) has shown that elevated levels of noncholesterol sterols are markers for increased CAD risk. Other studies that have shown that elevated plan sterols are not a risk factor for CAD.
I mentioned this topic previously but it is worth looking at again in a different light. Cholesterol status in the body is controlled. If a patient is treated with a statin to decrease cholesterol they may upregulate NPC1L1 and increase cholesterol absorption. The total cholesterol lowering effect of the statin could potentially be completely offset by the absorptive capacity in the gut.
Ezetimibe (Zetia) is a drug that is designed to block the absorption of sterols. It does this by binding to the NPC1L1/AP2-clathrin complex in the gut lining which prevents micelle absorption. It has approximately a 50% reduction in the absorption of sterols. When used alone, ezetimibe can cause an increase in the amount of cholesterol synthesis due to the overall control of total body loads of cholesterol. Labs will often reflect this with lower levels of sitosterol, campesterol, & cholestanol but increased levels of desmosterol & lathosterol.
Two trials (ENHANCE & EXPLORER) have demonstrated lowered cholesterol levels with combination therapy. The EXPLORER trial was only 6 weeks in duration and the ENHANCE trial did not show difference in atherosclerosis so the clinical effect remains to be seen. This seems to be further evidence that lower levels of cholesterol are not more beneficial as the effects seem to be limited to statin use independent of lipid lowering effects.
As mentioned previously, ATP III recommend >2 grams per day of plant stanols & sterols as part of a comprehensive plan to decrease cholesterol. However, it seems by these labs that some patients may benefit from this approach but some patients clearly will not. Comprehensive lab assessment can help properly identify these patients.