2018-01-21 11:10:45
Today, Jorge Laborda invites us to celebrate his 400th story of the “Quilo de Ciencia” podcast with a theme that features one of the molecules that most concern us in this troubled world: cholesterol.
Who is unaware today that high blood cholesterol levels are a clear risk factor for cardiovascular disease? Who who is not concerned about his health ignores his own cholesterol levels in his beloved blood plasma? However, I also believe that I am not mistaken in stating that most people are unaware of the important functions that cholesterol plays in the body. These functions are crucial for life, because cholesterol is the most important molecule for regulating the fluidity of cell membranes, which is essential for cells to communicate with each other and with the outside world, and for the passage of nutrients. and other molecules through them.
Cholesterol is so important to the life of cells that all of them are capable of synthesizing it from simpler molecules in a process of no less than thirty-seven chemical reactions, each one regulated by the activity of an enzyme. An average person synthesizes around one gram of cholesterol a day and contains thirty-five grams in his body. Cholesterol can also be ingested with food, although the amount ingested is usually not enough to cover needs, so its synthesis is the main source of this molecule. Statins, one of the most widely consumed classes of drugs these days, do not act on the absorption of cholesterol from food, but instead inhibit the activity of an enzyme important for its synthesis, which manages to lower its concentration in the blood.
However, despite the importance of this molecule, all the cellular processes that influence its regulation are not yet known. Recently, not one new mode of regulation of cholesterol synthesis has been discovered, but two.
The first mechanism discovered reveals that a molecule present in the internal membranes of the cell (in the organelle called the endoplasmic reticulum, to be precise) is capable of detecting cholesterol levels in these membranes. If these are excessive, this molecule, baptized with the strange name of Nrf1, binds to cholesterol, leaves the membrane and travels to the cell nucleus, where it activates genes that will activate a cholesterol elimination mechanism. When it returns to normal levels, the molecule leaves the nucleus and returns to the inner membranes. This mechanism contributes significantly to maintaining the amount of cellular cholesterol in an adequate range.
The second mechanism discovered concerns an enzyme called squalene monooxygenase (EMO), also important for the synthesis of cholesterol, although it is not affected by statins. Like Nrf1, this enzyme is found embedded in the membranes of the endoplasmic reticulum, where it interacts with the cholesterol present in them.
The discovery of these two new molecular mechanisms that combat excess cholesterol in cells could lead in the near future to the development of drugs that, just as statins already do with another important step in cholesterol synthesis, can modulate them.
Referencias: Widenmaier et al., NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis, Cell (2017), – Ngee Kiat Chua et al. A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis. J. Biol. Chem. (2017) 292(49) 19959-19973.
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