Regulation of Lipoprotein Metabolism

Another post on lipids and the cardiovascular system! This post, like the last one, also has a lot of ground to cover, but hopefully you will find it interesting.

Clinical Lipidology: Methods of studying lipoprotein metabolism

Clinical lipidology is, to my understanding, using our knowledge of lipids to aid in the diagnosis of different kinds of dyslipidemia. Having too much of a particular lipid could be due to increased production or decreased clearance, and having too little could be due to decreased production or increased clearance, but this can't be discerned by simply measuring lipid concentrations.

Tracer studies are a common way of finding answers to this question. In tracer studies, the relative concentrations of a tracee and a tracer are measured over time. The tracee is the endogenous molecule that you're interested in, for example glycerol, whereas the tracer is the same molecule but with a label of some description. In the past, molecules were often labelled using radioisotopes, but this raised safety concerns, so nowadays stable isotopes such as deuterium (essentially hydrogen with an extra neuron) are used instead. For example, a tracer for glycerol might be ²H₅-glycerol.

The tracer is first given to the patient by an intravenous bolus or by primed constant infusions (i.e. a constant infusion given immediately after a priming dose). After this is done, the body can begin to incorporate the labelled lipid, amino acid etc. into other molecules. The fraction of molecules that have the newly-introduced tracer as opposed to those that just have the naturally-occuring tracee can be measured by gas chromatography-mass spectometry (GCMS) and given as a tracer/tracee ratio, or TTR. TTR curves can then be drawn to give an indication of the production and clearance of molecules with the tracer. (Or at least that's my understanding of how it works. Correct me if I'm wrong.)

(Note: I've emailed my lecturer asking for clarification on this part, but he hasn't responded yet. Watch this space.)

Lifestyle interventions, lipid changes and metabolic changes

Lifestyle interventions for dyslipidemia include the general "healthy dietary changes" that I've mentioned in BIOC3004: reduce your intake of saturated fat and balance your caloric intake with your caloric expenditure. Additionally, plant stanols/sterols and viscous (soluble) fibre may also help with lowering LDL. I'm not too sure about how fibres achieve this, but stanols/sterols can compete with and bind to cholesterol in order to achieve their effects. Aside from dietary changes, increased physical activity and general weight reduction can also help in the prevention and treatment of dyslipidemia.

n-3 polyunsaturated fatty acids (or n-3 PUFAs for short) may also have a protective effect against CVD and dyslipidemia, though to my understanding there's still some room for debate on this one. n-3 PUFAs include eicosapentanoic acid and docosahexanoic acid, which cannot be synthesised by the body, but can be derived from fish and plants.

Lipid-lowering drugs: Statin therapies

Statins, which primarily lower LDL cholesterol, work by targeting HMG CoA reductase. This enzyme, as I mentioned all the way back in first-year, is the rate-limiting step in cholesterol synthesis. Some statins may also help with raising HDL and lowering triglycerides (rosuvastatin currently being the most effective at both).

Aside from blocking the synthesis of cholesterol, statins also help hepatocytes to take up more LDL from the blood. You see, when the synthesis of cholesterol is blocked, hepatocytes upregulate LDL receptors in order to try and make up for the cholesterol that they're no longer sythesising. A study done on rosuvastatin found that while production of VLDL, IDL and LDL did not change when on the drug, the catabolic rate increased significantly. This is consistent with an increased number of LDL receptors that allow these lipoproteins to be removed from the blood more efficiently.

Statins have been shown to reduce the rates of cardiovascular disease morbidity and mortality. They may even have an anti-inflammatory effect: studies done on statins show reduced concentrations of C-reactive protein (an acute phase inflammatory protein). However, just like every other drug, statins are also associated with a range of adverse effects. Possibly one of the more well-known side effects is muscle pain (myalgia), or even rhabdomyolosis (breakdown of muscle fibres). Other adverse effects include liver damage, gastrointestinal problems and rashes. The jury is also out over whether or not statins may increase the risk of type 2 diabetes or neurological side effects. Just like everything else on this blog, though, don't change or stop your medicine based on what some random blogger is saying: talk to your doctor about it first.