Cholesterol, Metabolic Pathways and Correlations

Cholesterol is one of the subjects I am personally interested because despite of my lifestyle and the way I eat, it keeps on average normally high, especially the LDL compound.

As much as I am acknowledged and understand as biologist, I have learned from books and articles, talked about in previous blogs, and aware of the benefits and function, I am honestly, at this time concerned about, especially in regard of the LDL compound, and this is why I have been researching more and looked at a molecular and biochemical level trying to understand where this cholesterol comes from, and/or which pathways are involved and connected, as much as  always more persuaded of the genetic origins and overproduction by liver.

I still cannot get the complete picture of what does happen inside the incredible microscopic environment of our body and our cells and systems, so interconnected and complex, especially when we start to look at the metabolic pathways.

The questions remain for me a little bit, and this is the reason why I am brainstorming and assembling fractions of these biochemical steps and descriptions partially rearranged to simplify the original content and clarified.

Cholesterol is a sterol, present in animal tissue, in large concentration in liver and brain. It is the structural component of all cell membranes, regulates fluidity and confers stability, and has an important role in brain synapsis and the immune system.

It is also the precursors of bile acids, steroid hormones, and vitamin D.

Hydrophobic compound made of four fused hydrocarbon rings, A, B, C and D called steroid nucleus, and with 8 carbon branched hydrocarbon chain (CH) attached to C17 of D-ring. Ring-A has a hydroxyl group (OH) at C3, ring-B a double bond between C5 and C6.

Cholesterol is an extremely important biological molecule that has roles in membrane structure as well as a precursor for the synthesis of the steroid hormones, bile acids, and vitamin D. Both dietary cholesterol, and that synthesized “de novo”, are transported through the circulation in lipoprotein particles. The same is true of cholesteryl esters, the form in which cholesterol is stored in cells. Due to its important role in membrane function, all cells express the enzymes of cholesterol biosynthesis.

The synthesis and utilization of cholesterol must be tightly regulated to prevent over-accumulation and abnormal deposition within the body. Of clinical importance is the abnormal deposition of cholesterol and cholesterol-rich lipoprotein in the coronary arteries, leading cause of atherosclerosis, and coronary arteries diseases.

Cholesterol Biosynthesis

Cholesterol is synthesized by all tissues in human, an essential molecule in many animals, including human but is not required in diet as all cells can synthesize it from simple precursors. It is made of 27 carbon compounds. All the carbon atoms in the cholesterol are provided by acetate. NADPH provides the reducing equivalents.

The biosynthesis pathway of cholesterol is endergonic and so requires ATP. To produce 1 mole of cholesterol are necessary 18 moles of Acetyl coA, 36 moles of ATP and 16 moles of NADPH.

In the first step in cholesterol biosynthesis, step I, two molecules of acetylcoA condenses to form AcetoacetylcoA. The reaction is catalyzed by enzyme thiolase.

AcetoacetylcoA condenses with another molecule of acetylcoA to form β-hydroxyl-β-methyl-glutaryl-coA (HMG).

-An elementary observation, acetyl-coA is a molecule of the Krebs cycle, the major step of the general metabolism where glucose in presence of oxygen is metabolized and decomposed in water and carbon dioxide through a number of reactions catalyzed by different enzymes and with ox-reduction processes that allow flow of electrons and release of energy. The cholesterol biosynthesis therefore steels substrates for the Krebs cycle, generating increase demand for glucose and so of carbohydrates and that is why also the carbs relate to the cholesterol production-

In step II, reduction of HMG-coA to Mevalonate is catalyzed by HMG-coA reductase enzyme and happens in in cytosol, in this reaction 2 NADPH are used for donation of 2 electrons. This reaction is the key step in regulation of cholesterol biosynthesis.

In step III, three phosphate groups are transferred from three ATP molecules to Mevalonate to generate Isoprene units.

During step IV, six activated units of isoprene condense with elimination of both pyrophosphate group to form Squalene.

In step V Squalene is converted in Lanosterol, which contains four rings steroid nucleus, through hydroxylation and cyclization utilizing NADHP.

Finally in Step VI happens the conversion of Lanosterol into Cholesterol where Lanosterol undergoes a series of about 20 reactions to finally convert into cholesterol.

Cholesterol Synthesis Pathway - YouTube

-These are instead some and more common molecules involved in the pathways, the steps are endless and too complex to report each of them, I have tried to summarize in a way –

Cytochrome P450 enzymes are involved in a diverse array of biological processes that includes lipid, cholesterol, and steroid metabolism. The common nomenclature for P450 enzymes is CYP. There are at least 57 CYP enzymes in human tissues, eight of these are involved in cholesterol biosynthesis and metabolism, which includes conversion of cholesterol to bile acids. CYP metabolism of cholesterol generates several oxysterols that function as biologically active molecules such as in the activation of liver receptors.

Coenzyme Q, or ubiquinone is a red-ox active molecule that is composed of a benzoquinone ring conjugated to a polyisoprenoid tail that is of variable length in different species and organisms. In humans the polyisoprenoid tail consists of 10 isoprenoid units which impart the common name for the molecule as CoQ10. In undergoing reduction and oxidation reactions the electrons are accepted and donated from benzoquinone ring. The polyisoprenoid tail of ubiquinone serves to anchor the molecule in the membrane.

-Here is why the importance of taking CoQ10 during therapy with Statins, as we can see CoQ10 is an important molecule in the cholesterol metabolism-

Heme A is an essential component of the oxidative phosphorylation pathway by serving as the prosthetic group for cytochrome c oxidase of complex IV. Cytochrome c is so-called due to the presence of two distinct heme a prosthetic group with heme a being the direct electron donor in the complex IV catalyzed reduction of O2 to H2O.

Regulation of Cholesterol

A relatively constant level of cholesterol in the blood (150–200 mg/dL) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol.

-In regard of this assertion I just want to mention some that I read from a nutrition book, and that made me wonder, the book was stating that “more fat we eat, less cholesterol is produced from the body” Is this the reason why they were emphasizing the importance of eating fats and of ketogenic diet? To me sounds still controversial-

Cholesterol from both diet and synthesis is utilized in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis.

The cellular supply of cholesterol is maintained at a steady level by three distinct mechanisms:

  1. Regulation of HMGR activity and levels.
  2. Regulation of excess intracellular free cholesterol through the activity of sterol O-acyltransferases, SOAT1 and SOAT2 which is the predominant activity in liver.
  3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDL-mediated reverse transport.

Regulation of HMGR activity is the primary means for controlling the level of cholesterol biosynthesis. The enzyme is controlled by four distinct mechanisms: feed-back inhibition, control of gene expression, rate of enzyme degradation and phosphorylation-dephosphorylation.

The Utilization of Cholesterol

Cholesterol is transported in the plasma predominantly as cholesteryl ester associated with lipoproteins. Dietary cholesterol is transported from the small intestine to the liver within chylomicrons. Cholesterol synthesized by the liver, as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum within LDL. The liver synthesizes VLDL, and these are converted to LDL through the action of endothelial cell-associated lipoprotein lipase. Cholesterol found in plasma membranes can be extracted by HDL and esterified by the HDL-associated enzyme lecithin-cholesterol acyltransferase, LCAT. The cholesterol acquired from peripheral tissues by HDL can then be transferred to VLDL and LDL via the action of cholesteryl ester transfer protein (CETP) which is associated with HDL.

Reverse cholesterol transport allows peripheral cholesterol to be returned to the liver in LDL. Ultimately, cholesterol is excreted in the bile as free cholesterol or as bile salts following conversion to bile acids in the liver.

-To make simple the role of HDL is to absorb cholesterol from the body and to carry to the liver from where then will be flushed out from the excretory systems, while LDL delivers fat molecules to the cells and is involved in atherosclerosis, a process where LDL is oxidized within the arterial walls and responsible of plaques production and so of blood flow blockage and cardiovascular consequences-

As we can see the steps and regulation are endless, and utilization differs based on the lipoproteins of transport and site of production, for this reason the subject must be separated in more steps.

To be continued

Thanks For Reading

Mariarosaria M.

Sources:

Pubchem.ncbi.nih.gov/pathway/wikipathways

themedicalbiochemistrypage.org

Onlinebiologynotes.com

Picture by youtube.com

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