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The good, the ugly and the bad: the three faces of the same “coinesterol”

The amount of remnant particle cholesterol in the blood, the so-called ugly cholesterol, is much higher than previously believed. This is shown in new research from the University of Copenhagen. The discovery may have implications for future prevention and treatment of cardiovascular disease. Three quarters of the Danish population have moderately elevated levels of cholesterol. If cholesterol levels are too high, risk of cardiovascular disease is increased. Often, LDL cholesterol, the so-called bad cholesterol, is considered the culprit. However, new research from the Faculty of Health and Medical Sciences at the University of Copenhagen and Copenhagen University Hospital shows that a completely different type of cholesterol may be more responsible than previously assumed. What we are talking about is remnant cholesterol – also known as ugly cholesterol. To their surprise, the researchers have discovered that the amount of remnant cholesterol in the blood of adult Danes is much higher than previously believed.

From the age of 20 until the age of 60, the amount in the blood is constantly increasing, and for many people it remains at a high level for the rest of their lives.  The results are based on data from people from the Copenhagen General Population Study. A total of 9,000 individuals had cholesterol in their fat particles in the blood measured by means of new advanced measuring equipment, known as ‘metabolomics’. The measurements show that total cholesterol in the blood consists of equal parts of “ugly”, “bad” and “good” cholesterol. The Copenhagen General Population Study is a Danish population survey with a total of 140,000 participants who received a free health check. All these Danes thus contribute personally to better knowledge about prevention and treatment of major widespread diseases such as cardiovascular disease, cancer, COPD, asthma, diabetes, depression, rheumatic diseases, etc. Previous studies from the Copenhagen General Population Study show that overweight and obesity are the main cause of the very high amount of remnant cholesterol in the blood of adult Danes.

In addition, diabetes, genes and lack of exercise play a part. In 2018, a large international, controlled clinical trial was published that clearly showed that when triglycerides and thus remnant cholesterol were reduced by the help of medication in people with elevated levels in the blood, the risk of cardiovascular disease was reduced by 25%. According to the scientists, their findings point to the fact that prevention of myocardial infarction and stroke should not just focus on reducing the bad LDL cholesterol, but also on reducing remnant cholesterol and triglycerides. So far, both cardiologists and general practicers have focused mostly on reducing LDL cholesterol, but in the future, the focus will also be on reducing triglycerides and remnant cholesterol. Besides, there are already proofs that high HDL cholesterol may not provide top cardiovascular protection, as demonstrated by swedish teams.

People with familial chylomicronemia syndrome are born with a genetic mutation that means they can’t produce an enzyme called lipoprotein lipase. Without the enzyme, their bodies can’t break down dietary-derived fat in the blood. Instead, fat-carrying molecules called chylomicrons build up in the blood, causing many life-threatening symptoms, most notably pancreatitis. People living with this condition must follow a strict low-fat diet, but there is no treatment. Chylomicrons carry dietary triglycerides from the gut into the blood, where they are normally broken down by the enzyme lipoprotein lipase. Without that enzyme, chylomicrons accumulate and thicken the blood of people with familial chylomicronemia syndrome. Triglyceride levels are regulated by a molecule called apolipoprotein C-III, which is made in the liver, and then secreted into the blood. Reducing apolipoprotein C-III in the blood in turn reduces triglyceride levels.

Joseph Witztum, PhD, professor of Medicine at University of California San Diego School of Medicine, recently helped lead a global research team that tested how well the drug volanesorsen reduces fat accumulation in the blood (triglycerides) of participants with familial chylomicronemia syndrome. Volanesorsen, an antisense drug developed by Ionis Pharmaceuticals, is designed to block the mRNA in the liver that encodes apolipoprotein C-III. In a randomized, double-blind Phase III clinical trial, 33 participants received the drug and 33 received a placebo. Triglyceride levels were dropped by an average of 77%; in contrast, for participants who received a placebo, triglyceride levels increased by an average of 18%. Volanesorsen was recently approved for clinical use in Europe, as an adjunct to diet in adult patients who have genetically confirmed familial chylomicronemia syndrome and are at high risk for pancreatitis, and who haven’t responded to diet and triglyceride-lowering therapy. The team is now waiting for FDA approval to market the drug in the United States. These results have just been published in the New England Journal of Medicine.

Trial participants began by receiving 300 milligrams of volanesorsen under the skin once a week. The most common side effects were skin reactions at the injection site (20 of 33 participants who received volanesorsen vs. none in the placebo group) and thrombocytopenia (15 of 33 participants who received volanesorsen vs. none in the placebo group). Thrombocytopenia, or low levels of blood cells known as platelets, can limit the body’s ability to form blood clots. Later in the trial, the doses were reduced to once every other week to reduce these side effects. The trial lasted for one year. Participants were aged 20 to 75 years old, 80% were white and 55% were female. According to Witztum, this clinical trial also helped unravel some of the basic biology underlying dietary fat processing. Researchers had previously thought that lipoprotein lipase was a necessary intermediate that allowed apolipoprotein C-III to raise triglycerides levels. This trial revealed that that’s not always the case — apolipoprotein C-III has a second role independent of lipoprotein lipase, in which it inhibits the liver from taking up triglyceride-carrying particles.

These data still underscore the lack of complete information about the real metabolism of cholesterol and the subtle yet pivotal informations about it to be applied in the clinical practice.

edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references<

Balling M et al. Atherosclerosis 2019; 286:97-104.

Benn M et al. J Am Coll Cardiol. 2019; 73(24):3102-114.

Verbeek R et al. Eur Heart J. 2018; 39(27):2589-2596.

van Capelleveen JC et al. J Clin Lipidol. 2018; 12(6):1493.

Hegele RA et al. J Clin Lipidol. 2018; 12(4):920-927.

Pechlaner R et al. J Am Coll Cardiol. 2017; 69(7):789-800.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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