On Reverse Cholesterol Transport Solutions to Atherosclerosis

Atherosclerosis, the condition that kills upwards of a quarter of humanity at the present time, is a failure of cholesterol transport. Cholesterol is made in the liver and transported out into the body in the bloodstream, attached to LDL particles. All cells need cholesterol. Some of this LDL-cholesterol ends up stuck in blood vessel walls in too large an amount, or oxidized into toxic forms, aggravating the blood vessel tissues. Macrophage cells ingest this excess cholesterol and then attach it to HDL particles that return the cholesterol to the liver for excretion. The latter part of this complicated system is called reverse cholesterol transport, and works well in youth.

The point of failure that emerges with advancing age is that macrophages become less able to perform reverse cholesterol transport, allowing blood vessel walls to reach a tipping point of excess or altered cholesterol deposition. These regions become too much for macrophages to handle, but they keep on trying - arriving, becoming inflammatory, and dying while drawing in more cells to try to help. It is a feedback loop in which diseased region of blood vessel wall becomes a toxic cell graveyard, growing to form fatty lesions that narrow and weaken blood vessels. Eventually something ruptures, leading to a stroke or heart attack.

Finding ways to enhance the operation of reverse cholesterol transport has been the subject of research programs for some decades. Increased expression of proteins in macrophages involved in cholesterol ingestion, or transfer to HDL particles, or creation of HDL particles have all been tried, as well as the introduction of more HDL particles directly. All of this works at least modestly well to reverse the progression of atherosclerosis in mice, but the few of these approaches tried in humans have failed. It seems that the balance of factors determining the tipping point of fatty lesion growth versus reversal is quite different in the two species.

HDL, cholesterol efflux, and ABCA1: Free from good and evil dualism

Loss-of-function mutations in ABCA1 cause Tangier disease. The phenotype of their markedly reduced or loss of blood high-density lipoprotein (HDL) cholesterol, as well as examination of ATP-binding cassette transporter A1 (ABCA1)-deficient mice, proved that ABCA1 is a key player in HDL production. The ABCA1-mediated cholesterol efflux is the first step in the reverse cholesterol transport system and understanding the regulation of its expression was expected to lead to the development of anti-atherosclerotic drugs. However, from the viewpoint of intracellular cholesterol homeostasis, it is difficult to say that simple activation of ABCA1 or promotion of cholesterol efflux is a good strategy.

This review discusses the possibilities and limitations of strategies to increase HDL, activate cholesterol efflux, and enhance ABCA1 expression, centered on the strict regulatory mechanisms of intracellular cholesterol. Since the benefits of increasing blood levels of HDL-C, once called "good cholesterol," have been doubted, attention has turned to cholesterol efflux enhancement and ABCA1 activation as the next "good" thing. However, there is no evidence that HDL-increasing drugs by enhancing ABCA1 expression prevent atherosclerotic cardiovascular disease in humans.

Essentially, HDL, cholesterol efflux, and ABCA1, may be systems for transporting lipophilic "poisons" including cholesterol to the liver which is the main detoxification organ. In particular, ABCA1 has been reported to not only excrete cholesterol and phospholipids, but also to temporarily reserve the outer leaflet of the plasma membrane and to flop excess cholesterol from the inner to the outer leaflet of the plasma membrane. As these findings show, the organism has a very sophisticated system, so a rough treatment that simply increases blood HDL-C levels, cholesterol efflux, or ABCA1 expression is not likely to be successful. On the other hand, in situations where intracellular cholesterol homeostasis is disrupted by inflammation, aging, or metabolic abnormalities, a strategy that restores reduced ABCA1 expression and cholesterol efflux in a timely and localized manner may be useful.



I hope you cholesterol degradation platform will be available soon enough for me. At least, I hope, i have a few years before starting antistatins.

Posted by: Cuberat at September 13th, 2022 4:22 PM

"Mulberry leaves Deoxynojirimycin (MLD) treatment improved antioxidant and anti-inflammatory properties and serum lipid profile in heart disease patients. MLD reduce carotid intima-media thickness (IMT) and serum levels of DNJ (the main ingredient of mulberry leaf) had a strong relationship with IMT values."

"Mulberry leaf attenuates atherosclerotic lesions in patients with coronary heart disease possibly via 1-Deoxynojirimycin: A placebo-controlled, double-blind clinical trial"


Posted by: Lee at September 14th, 2022 6:30 AM

Probably better to take pterostilbene- from the leaves or berries of the mulberry/ bilberry bush, doesn't matter which - as capsules with one's morning porridge


Posted by: JLH at September 14th, 2022 1:11 PM
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