The relationship between cholesterol and magnesium

The relationship between cholesterol and magnesium

Magnesium deficiency can have a very strong impact on lipid metabolism and spoil the mood when you see blood cholesterol tests. Why?

Magnesium regulates the activity of the main enzyme in the cholesterol production pathway (HMG-CoA reductase) and without it, this enzyme "can't stop" producing cholesterol.

The human body obtains cholesterol from two sources: from food or from its own production. The essential enzyme for our body to synthesize cholesterol is HMG-CoA reductase (HR). If this enzyme is turned off (eg by statins (a class of cholesterol-lowering drugs)), cholesterol production is significantly reduced. The human body itself is able to regulate HR activity and, accordingly, the amounts of cholesterol and other substances produced by enzymes in this pathway (eg, coenzyme Q 10 ). How is it going?

Regulation of HR activity is a very complex process that depends on many factors and includes slow and fast mechanisms of regulation of the activity of this enzyme. Slow control involves feedback inhibition by both cholesterol and mevolonate (in other words, in the presence of sufficient cholesterol or mevolonate, HR activity is inhibited) and other, more complex mechanisms. Short-term or rapid control of HR occurs by attaching or detaching a phosphorus molecule from this enzyme (phosphorylation and dephosphorylation). When the phosphor is attached, HR is turned off (it no longer produces cholesterol precursors), and when it is removed, it is turned on. [1,2] In order for phosphorylation to take place successfully, the Mg-ATP complex is required (this complex acts as a phosphorus donor), so in the absence of

magnesium or ATP this process cannot occur, HR cannot be switched off and it remains active. [1]

Some of the enzymes that activate HR also require Mg, but it can be replaced by other metals such as manganese. [3] Thus, if magnesium is deficient, HR, the key enzyme in the cholesterol-making pathway, cannot be turned off "fast-tracked," but can be turned on.

Magnesium activates an enzyme (LCAT) that compactly "packages" cholesterol and helps transport it to the liver.

Another very important enzyme for lipid metabolism, which is also activated by Mg, is lecithin cholesterol acyltransferase (LCAT). This enzyme esterifies cholesterol (cholesterol esterification is a universal mechanism for storing and transporting large amounts of cholesterol between organs and tissues and avoiding cellular toxicity of excess cholesterol [4]), thereby allowing more cholesterol to bind to HDL. [5] HDL, or good cholesterol, picks up cholesterol from tissues and carries it to the liver for processing. Gueaux et al. found that LCAT activity is reduced by more than 50% in magnesium-deficient mice. and significant increases in blood serum cholesterol and triglycerides

quantity. [6] A Japanese double-blind placebo-controlled clinical trial

confirmed that magnesium significantly increased LCAT activity and, accordingly, HDL levels and reduced LDL (bad cholesterol) levels. [7]

Magnesium is important for the activity of the enzyme (LPL), which breaks down triglycerides and prevents them from accumulating on the walls of blood vessels.

Another enzyme related to cholesterol metabolism for which Mg is important is lipoprotein lipase (LPL). Lipoprotein lipase (LPL) plays an important role in lipid metabolism. Impaired LDL activity leads to plasma accumulation of chylomicrons (particles that transport digested fat from the intestine to other tissues) and very low-density lipoproteins (LDL, "bad cholesterol"). [8] Experimental data suggest that Mg may be an important factor in increasing LPL enzyme activity [9] and promoting LPL expression (production). [10] By increasing the amount and activity of this enzyme, blood vessel walls are protected from dangerous triglyceride accumulations.

Although at first glance, magnesium and cholesterol seem to be completely unrelated, in fact, cholesterol metabolism is very strongly dependent on the amount of magnesium in our body. Therefore, when facing challenges in regulating the level of cholesterol and other lipids in the blood, it is necessary to pay attention to the amount of magnesium consumed. Maybe sometimes its lack is the cause of the problems?

And finally, a very interesting and very old (1957) study on the relationship between cholesterol and magnesium in rabbits. More than half a century ago, these scientists observed that rabbits fed a cholesterol-rich diet showed signs of magnesium deficiency compared to rabbits fed their normal diet, which disappeared when the amount of magnesium in the diet was increased 4- to 8-fold. The researchers concluded that a cholesterol-rich diet somehow depletes magnesium, and this is not related to poorer magnesium absorption.

Another particularly interesting thing that this study found was that early atherosclerosis lesions caused by a cholesterol-rich diet were reduced or appeared later by increasing magnesium intake, even though blood cholesterol levels did not change. [11]

Food for thought, right?

  1. Rosanoff, Andrea, and Mildred S. Seelig. "Comparison of mechanisms and functional effects of magnesium and statin pharmaceuticals." Journal of the American College of Nutrition 23.5 (2004): 501S-505S. 
  2. Feingold KR, Wiley MH, Moser AH, Lear SR, Siperstein MD. Activation of HMG-CoA reductase by microsomal phosphatase. J Lipid Res. 1983 Mar;24(3):290-6. PMID: 6302189
  3. Gil, Gregorio, et al. "Inactivation and reactivation of rat liver 3-hydroxy-3-methylglutaryl-CoA reductase phosphatases: effect of phosphate, pyrophosphate and divalent cations." (1982): 1217-1224. 4. Gonen, Ayelet, and Yury I. Miller. "From inert storage to biological activity—in search of identity for oxidized cholesteryl esters." Frontiers in Endocrinology 11 (2020): 602252. 5. Rousset X, Shamburek R, Vaisman B, Amar M, Remaley AT. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor? Curr Atheroscler Rep. 2011 Jun;13(3):249-56. doi: 10.1007/ s11883-011-0171-6. PMID: 21331766; PMCID: PMC3794709. 
  4. Gueux, Elyett, et al. "Reduction of plasma lecithin—cholesterol acyltransferase activity by acute magnesium deficiency in the rat." The Journal of nutrition 114.8 (1984): 1479-1483.
  5. Itoh K, Kawasaka T, Nakamura M. The effects of high oral magnesium supplementation on blood pressure, serum lipids and related variables in apparently healthy Japanese subjects. Br J Nutr. 1997 Nov;78(5):737-50. doi: 10.1079/bjn19970191. PMID: 9389897.
  6. Kumari A, Kristensen KK, Ploug M, Winther AL. The Importance of Lipoprotein Lipase Regulation in Atherosclerosis. Biomedicines. 2021 Jul 6;9(7):782. doi: 10.3390/ b iomedicines9070782. PMID: 34356847; PMCID: PMC8301479.
  7. Rayssiguier Y, Noé L, Etienne J, Gueux E, Cardot P, Mazur A. Effect of magnesium deficiency on post -heparin lipase activity and tissue lipoprotein lipase in the rat. Lipids. 1991 Mar;26(3):182-6. doi: 10.1007/BF02543968. PMID: 2046484. 
  8. Chen, Shiyan, et al. "Magnesium supplementation stimulates autophagy to reduce lipid accumulation in hepatocytes via the AMPK/mTOR pathway." Biological Trace Element Research 201.7 (2023): 3311-3322. 
  9. Vitale, JJ, et al. "Interrelationships between experimental hypercholesteremia, magnesium requirement, and experimental atherosclerosis." The Journal of Experimental Medicine 106.5 (1957): 757-766.