Brief Cholesterol Review

Brief Cholesterol Review

1. General information

   • Cholesterol is classified as a sterol and also as an isoprenoid
   • Discovered by M. E. Chevreul, a French chemist, in 1815
     • The discovered sample was isolated from the gallstones
     • In 1932, Wieland and E. Dane, accurately described the chemical structure of cholesterol
       • Years later, the joint work of K. Bloch and collaborators, determined that in the biosynthesis of cholesterol there are more than thirty enzymatic reactions
   • The importance of cholesterol lies in the consequences that occur whenever the homeostasis of this molecule is not in balance
     • If cholesterol is found in excess in the body, the risk of patients suffering from various diseases is increased, and among the most important is cardiovascular disease
     • When serum cholesterol levels are deficient in the body, the incidence of some neurological diseases increases, including mental retardation, congenital malformations and death at an early age

2. Functions

   • Fundamental constituent of animal cell membranes; its importance lies in its ability to provide fluidity and permeability
     • Its presence is indispensable in the formation and stability of neuronal communication, specifically at the synapse
       • It is present in the formation of neurites, indicating its importance in neuronal differentiation
         • Other functions: ensure balance in embryogenesis, be a metabolic precursor in the biosynthesis of bile salts and fatty acids, can be transformed into steroid hormones and is important in cell differentiation and proliferation

3. Cholesterol Biosynthesis

   • This process is also called cholesterol genesis
     • It is necessary the presence of more than 30 enzymes, dispersed at the level of peroxisomes, endoplasmic reticulum and cytoplasm
       • Of the forms of regulation of cholesterol biosynthesis, the most important is retroregulation
   • Stages of biosynthesis
     • 1) Synthesis of mevalonate, where the enzyme HMG-CoA reductase catalyzes the conversion of 3β-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate
       • 2) Formation of isopentenyl 3-pirophosphate (IPP), it is important to note that this molecule is a potential substrate for the synthesis of isoprenoids, at this stage, squalene arises, which in turn forms lanosterol
         • 3) Lanosterol is the molecule previous to cholesterol, for its conversion there are two ways, the unsaturated (from Bloch) and the saturated (from Kandustch-Russell)

4. Reverse transport of cholesterol

   • Peripheral tissues do not have the capacity to metabolize cholesterol, the most reliable way to eliminate the excess of this molecule is to export it to the extracellular medium
     • The liver is capable of degrading a quantity of this lipid. Cholesterol residues in peripheral tissues are directed to the liver, the degradation product can be excreted in the bile or can be transformed into bile acids
       • The process of excretion of excess cholesterol by the liver is called reverse transport of cholesterol
   • First, the excess cholesterol in the peripheral tissues goes into the extracellular medium
     • By enzymatic action cholesterol is fused and changes from preβ-HDL to α-HDL
       • the action of ABCA1 and ABCG1 conveyors is key
       • the expression of the apo A-I is necessary
       • The second step is the output of the high density lipoprotein (HDL) complex from the interstitial space to the blood plasma
         • in this step it is important the HDL transcytosis that is mediated by SR-BI of the endothelium
         • The third step is the passage of cholesterol present in HDL to the liver
           • direct way: bonding of HDL with the CLA-1/SR-BI receptor, in this step the cholesterol is no longer in the HDL, but becomes part of the receptor, the cholesterol is free or esterified
           • indirect way: union of HDL with CETP, after union cholesterol is exchanged for triglycerides
           • third way: involves the ATP synthase chain β
           • Fourth step, the hepatocytes are responsible for detecting cholesterol esters
             • Finally, cholesterol can be converted to the corresponding bile acids or salts, or excreted into the intestinal or hepatobiliary spaces
               • the ABCG5/G8 conveyors are indispensable for the excretion
   • First, the excess cholesterol in the peripheral tissues goes into the extracellular medium
     • By enzymatic action cholesterol is fused and changes from preβ-HDL to α-HDL

5. Regulation of cholesterol homeostasis

   • Fundamental to maintaining good health
     • It involves the function of three families
       • 1)SREBP
         • factors linked to the endoplasmic reticulum membranes and activate more than 30 genes, whose function is to detect cholesterol and support its synthesis
           • -In mammals there are three isoforms of this factor, which are SREBP-1a, SREBP-1c and SREBP-2
             • have a transcription factor in the NH2-terminal and a regulatory factor in the COOH-terminal
             • functions of the three isoforms
               • SREBP-1a activates genes for cholesterol synthesis and lipogenesis
               • SREBP-1c transcribes the genes of the enzymes that are responsible for the conversion of Acetyl CoA to fatty acids, incorporates TGC and phospholipids into the fatty acids and assists in the production of NADPH
               • SREBP-2 promotes cholesterol synthesis and retention
       • 2) LXR
         • Include the LXRα and LXRβ
           • The connection of the corresponding ligands with the LXR, from this connection benefits
             • Favor the exchange of co-repressors to co-activators and the transcription of target genes; inhibit the transcription of pro-inflammatory cytokines
               • LXRs are also cholesterol sensors, so when cellular cholesterol levels increase disproportionately, the binding of LXRs to ligands helps transcribe genes that protect the cell from this excess cholesterol
                 • Other functions of the LXRs: cholesterol biosynthesis; cholesterol uptake, absorption and excretion in the liver; synthesis and excretion of bile acids and control of lipogenesis
       • 3) PPAR receivers
         • They are nuclear in nature
           • Three types are expressed
             • Agonists of these types reduce cholesterol synthesis
             • studies have observed that this group has a close relationship with the other families, thus complementing their regulation processes
             • α (NR1C1) which is expressed in the liver, heart, muscle and kidney
               • increase the expression of CLA-1/SR-BI in monocytes and macrophages, this expression has the ability to remove excess cholestero
                 • expression of CLA-1/SR-BI is related to inhibition or alteration of genes that prevent expression of atherogenesis disease
             • δ/β (NR1C2) which is expressed in the adipose tissue
             • γ (NR1C3) which is ubiquitous
               • The activation of PPARγ mediates the expression of CD36 by the macrophage, this causes the retention of LDL-Ox to increase; this is a detrimental effect, it accumulates the cellular cholesterol, however, the activation of PPARγ helps in the expression of the transporters ABCA1, ABCG1, apo E and LXR targets and, that favor the exit and export of the cholesterol towards the liver

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