The effect of thyroid status on serum cholesterol levels has been known since the ’30s. The publication of Ancel Keys’ cardiovascular lipid hypothesis in the ’50s marked a turning point in how scientists and clinicians view cholesterol. The association between cardiovascular disease and hypothyroidism increased the urgency of cholesterol research and led to thousands of studies elaborating the link between the two.
The biosynthesis of cholesterol involves many steps and requires many different enzymes. The 2-carbon substrate, acetate, is what ultimately is used to form the 27-carbon cholesterol in incremental additions. With the help of coenzyme A and enzymes, the two 2-carbon acetate units fuse to form a 4-carbon unit which iterates again with acetate forming a 6-carbon unit called melavonate. One carbon is lost as CO? from this and the carbon skeleton is reduced forming isoprene units, 5-carbon alkenes which are used to construct long repeating carbon chains in the body. Six of these isoprene units combine to form a branched 30-carbon chain called squalene which condenates upon itself to form a 4-ringed sterol called lanosterol. ?¹? The removal of three methyl groups finally forms cholesterol. The small 2-carbon units which comprise cholesterol come from either sugar molecules or fatty acids. Hence, cholesterol is made from food regardless of whether you consume animal products (pre-formed cholesterol).
It has been demonstrated repeatedly decades ago that thyroid hormones effect the rate of cholesterol synthesis. There is no ambiguity to this phenomenon, as chemists gave radioactive acetate (¹?C) to both hyperthyroid and hypothyroid rabbits. The use of a scintillation (Geiger) counter was able to measure the rate of radioactive cholesterol formed by hyper- and hypothyroid rabbits. ?²? It has been shown many times that thyroid hormones increase the rate of cholesterol synthesis, and ablation of the thyroid decreases the rate of cholesterol synthesis (low T?).
One would be tempted to think then that hyperthyroid individuals would have higher plasma cholesterol levels because they synthesize more, but this is certainly not the case. The converse it actually true. It has been shown in clinic studies where subjects were kept for months on standardized diets that the hypothyroid subjects almost invariably had higher plasma cholesterol levels. When hypothyroid individuals were given thyroxine (T?), a very strong trend towards a reduction in plasma cholesterol levels was observed. When hyperthyroid individuals had their thyroids suppressed, the plasma total cholesterol levels were found to increase. This trend is strong and unambiguous. ?³????
The apparent paradox is explained by other mechanisms. It has been found by cholesterol balance studies (intake ± elimination) that thyroid hormone actually increases the rate of cholesterol excretion over the rate of production. The modern consensus view of how this works is that thyroid hormone increases the production of thyroid receptor beta (TR?), which acts in the liver to capture serum lipoproteins. Also, the enzyme cholesterol 7?-hydroxylase was found to increase as well. This enzyme hydroxylates cholesterol making it more hydrophillic and priming it for elimination as a bile salt. ???
Larger sample sizes improve confidence in results. A 2002 analysis examined data from 2,799 people and calculated the average serum cholesterol levels as a function of thyroid status. The results show a clear correlation: ???
Subclinical Hypothyroid: 204.8
Subclinical Hyperthyroid: 199.0
Whatever the precise biological mechanism may be for this, it cannot be argued that thyroid status and serum cholesterol levels are highly correlated. This has become so well known that drugs are being developed to mimic thyroid hormone to decrease serum cholesterol levels. Drug developers are trying to improve specificity by creating analogues which bind only to the thyroid beta receptor (TR?) since the thyroid alpha receptor (TR?) is thought to be responsible for the cardiac effects of thyroid hormone. Regardless, natural thyroid hormone has been shown to decrease total serum cholesterol. These are powerful hormones, and those should be scaled gradually to achieve the metabolic balance desired for each person.
* in millimoles per liter