Metabolics and Cholesterol and Bile

Cholesterol and Bile

Cholesterol is a fatty substance which supports cell membrane fluidity, bile acid production, and synthesis of sex steroid hormones, CoQ10 (coenzyme Q10) and vitamin D.

Most (approximately 80%) cholesterol is synthesised in the liver, and the remainder is obtained from the diet. Dietary sources include red meat, eggs, liver, kidney, shellfish and butter. Excess fat and sugar intake promote cholesterol synthesis.

As described in the Fats Section, cholesterol is packaged with triglycerides into lipoproteins. There are several types of lipoproteins but the two most common are LDL (low-density lipoprotein) – considered to be 'bad' cholesterol – and HDL (high-density lipoprotein) – often called 'good' cholesterol.

Cholesterol is regulated by negative feedback. When cholesterol is too high, synthesis is suppressed and liver uptake is reduced (by inhibiting LDL receptors). This causes LDL to accumulate in the blood, which can initiate atherosclerosis. Cholesterol-lowering drugs, such as statins, also exploit the feedback system by blocking cholesterol synthesis, but conversely increase the activity of LDLRs (LDL receptors).

Cholesterol Synthesis

Acetyl-coA is converted to cholesterol via the mevalonate pathway. This series of reactions (30+ steps) is primarily regulated by HMGCR (HMG-CoA reductase) which converts HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) into mevalonate.

HMGCR is upregulated in obesity and high glucose and is inhibited by statins. A SNP on this gene decreases its expression, lowers circulating LDL and increases LDLR sensitivity, mimicking the mechanism of statins. This reduces the risk of coronary heart disease.

However, this SNP is associated with lower plasma phosphatidylcholine and sphingomyelin levels (which are important for cell membranes), as well as GLUT4 (glucose transporter 4) inhibition which increases BMI, body fat and risk of type 2 diabetes. Lower HMGCR activity can also lead to reduced CoQ10 and vitamin D production, needed for metabolic, antioxidant and mitochondrial functions. Therefore, for carriers of this SNP, it may be preferable to lower cholesterol naturally, through dietary changes such as increasing fibre and limiting saturated and trans fats, as an alternative to statins.

SREBF1 (sterol regulatory element-binding factor 1) facilitates storage of fatty acids as triglycerides by inducing lipogenesis, and promotes cholesterol synthesis by inducing HMGCR activity. A SNP on SREBF1 increases its expression, is associated with higher LDL and total cholesterol, and increased risk of type 2 diabetes and non-alcoholic fatty liver disease. Insulin (via mTOR) increases SREBF1 activity while PUFAs (polyunsaturated fatty acids) – such as oily fish, nuts and vegetable oils – decrease it.

Cholesterol Uptake and Metabolism

LDL receptors enable uptake of cholesterol by the liver, which removes about 70% of LDL from the bloodstream. LDLRs therefore have an essential role in LDL regulation. Some rare mutations in LDLR and other genes can cause a form of high cholesterol called familial hypercholesterolemia. Common SNPs that decrease LDLR sensitivity can lead to higher total cholesterol and LDL levels, increased risk of coronary heart disease and Alzheimer's disease (especially in men). Red grape juice (polyphenols), berberine and omega-3 fatty acids can increase LDLR sensitivity. Conversely, high fructose intake can increase the risk of glycation which negatively impacts LDLR.

Finally, cholesterol is converted to bile acids via CYP7A1 (cholesterol 7 alpha-hydroxylase 1). Bile acids are needed to absorb and digest fats in the small intestine. This is also the primary mechanism for removing cholesterol from the body. A SNP on CYP7A1 lowers its activity, leading to a slower conversion to bile acids, and therefore, higher cholesterol levels. Oats, taurine and green tea can support CYP7A1 activity and help remove cholesterol.

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