*Geek Box: Lipoproteins and Cholesterol Pathways

*Geek Box: Lipoproteins & Pathways of Cholesterol Regulation

There are a number of relevant measures for blood lipids which are useful in the overall risk equation. The most important historically is LDL-C, as this is the lipoprotein which is causal in the initiation of atherosclerosis and the most abundant atherogenic lipoprotein in circulation. However, LDL-C is not the only lipoprotein class that has atherogenic potential. In fact, all lipoproteins of <70-nanometers in diameter are capable of penetrating into the arteries: this includes smaller VLDL, IDL, and Lp(a) in addition to LDL-C.

Previously, the best way of accounting for all circulating atherogenic lipoproteins in circulation was the calculate ‘non-HDL-C’, which was a crude measure derived from subtracting the measured level for HDL from the total cholesterol value. This remains useful, particularly for prospective cohort studies where it provides an inexpensive means of calculating a score which may be more predictive than LDL-C alone. However, each atherogenic lipoprotein particle contains one molecule of Apolipoprotein-B; consequently, measuring ApoB provides a direct measure of the exact number of atherogenic lipoproteins in circulation. From 2019, the European Atherosclerosis Society have recommended a direct measure of ApoB to assess cardiovascular risk, where circumstances allow for it.

So each of these measures is valuable, it depends on the context as to which may be more informative for risk assessment [individual vs. population, etc.]. Now, circulating cholesterol is influenced by a number of relevant gene pathways. The most important of these is the LDL-receptor, the discovery of which won Joseph Goldstein and Michael Brown the Nobel Prize in 1985. The LDLR is the main receptor which provides cells with cholesterol, which it uptakes from lipoproteins like LDL transporting cholesterol to body tissues. Thus, the LDLR is responsible for clearing cholesterol from the circulation. All of the effective drugs for reducing cardiovascular disease – statins, ezetimibe, and PCSK9-inhibitors – act by ultimately upregulating the LDLR expression and activity, clearing and reducing cholesterol levels.

The PCSK9 gene is critical in this process, as PCSK9 negatively regulates circulating LDL levels by mediating the degradation of the LDLR. In simple terms, high PCSK9 activity reduces expression of the LDLR, inhibiting the uptake of cholesterol and resulting in elevated cholesterol levels. PCSK9-inhibitor drugs act by doing exactly that: inhibiting PCSK9 expression, resulting in upregulated LDLR activity and cholesterol clearance.

Finally, the SREBP gene pathway influences cholesterol metabolism by sensing the levels of cholesterol within cells, and SREBP proteins regulate multiple pathways that influence cholesterol metabolism: the HmG-CoA-reductase enzyme [which statins inhibit], the LDLR, and also HDL-receptors. Decreasing cholesterol within cells results in increased cholesterol uptake, mediated by SREBP. There are, however, limits to this because cells will prevent accumulating excess cholesterol, meaning that an overproduction of cholesterol from diet may not be compensated by just increasing cellular uptake.

In fact, the most well-established dietary regulator of blood cholesterol levels – the ratio of saturated to polyunsaturated fats – is due to oppositional effects, i.e., polyunsaturated fats positively influence cholesterol clearance, while saturated fats inhibit cholesterol uptake.