CHOLESTEROL HOMEOSTASIS

CHOLESTEROL HOMEOSTASIS

1. Cholesterol is a 27-carbon steroid, is a major structural part of cellular membranes of vertebrates

   • is amphipathic, with a polar head group (the hydroxyl group at C-3) and a nonpolar hydrocarbon body (the steroid nucleus and the hydrocarbon side chain at C-17)
     • Synthesis
       • Factors affecting cholesterol synthesis
         • Cholesterol biosynthesis is regulated through a system of feedback inhibition where the intracellular cholesterol levels are sensed, resulting in the modulation of the expression of key proteins that control cholesterol homeostasis
         • Body weight
           • Weight gain increases synthesis rates
         • Endocrine factors
           • Major hormones: thyroid, insulin, glucocorticoids, estrogens (affect synthesis)
         • Circadian rhythm
           • Delaying meal times modulates synthetic rates
         • Genetics
           • Gene polymorphisms: HMGCR, SREBP1&2 (synthesis) & apoE, ABCG5&8, NPC1L1, ACAT2 (absorption)
             • Sterol regulatory binding protein (SREBP, mainly type 2) is the most important element in this process.
               • SREBP2 is usually located in the endoplasmic reticulum in the form of a complex with SREBP2 cleavage-activating protein (SCAP) under conditions when the cell cholesterol levels are high
                 • when cells are depleted of sterols, SCAP facilitates the transfer of SREBP2 from the endoplasmic reticulum to the Golgi apparatus
                   • At this stage, the complex is cleaved, resulting in the release of a part of the protein from the membrane. This enables SREBP2 to enter the nucleus and activate the transcription of multiple genes regulating cholesterol synthesis by binding to a sterol response element (SRE) in their enhancer/promoter regions.
         • Gut microbiome
           • Roles in SCFA production and composition of bile acid pool. Alters absorption and synthesis
         • Biliary and luminal factors
           • Biliary bile salt and phospholipid output regulates cholesterol absorption. Increased gastric emptying increases absorption
         • Early nutrition and epigenetics
           • Maternal nutrition, maternal-fetal cholesterol input, and metabolic state control fetal programming and cholesterol metabolism in offspring
         • Dietary factors
           • Dietary fat quality and quantity and dietary cholesterol affect synthesis and absorption. Plant sterols, dietary fibres, and phospholipids intake reduce absorption
         • Pharmacological factors
           • Statins (synthesis), ezetimibe (absorption)
         • Environmental pollutants
           • Endocrine disruption, modulation of LXR and synthesis
       • Synthesis takes place in four stages
         • Stage 1 Synthesis of Mevalonate from Acetate
           • Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)
             • Enzymes involved
               • acetyl-CoA acetyl transferase and HMG-CoA synthase
                 • The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isozyme that catalyzes HMG-CoA synthesis in ketone body formation
             • reduction of HMG-CoA to mevalonate, for which two molecules of NADPH each donate two electrons
               • HMG-CoA reductase, an integral membrane protein of the smooth ER, is the major point of regulation on the pathway to cholesterol.
         • Stage 2 Conversion of Mevalonate to Two Activated Isoprenes
           • three phosphate groups are transferred from three ATP molecules to mevalonate
           • The phosphate attached to the C-3 hydroxyl group of mevalonate in the intermediate 3-phospho-5- pyrophosphomevalonate
           • in the next step, both this phosphate and the nearby carboxyl group leave, producing a double bond in the five-carbon product, Δ 3 -isopentenyl pyrophosphate.
           • Isomerization of δ 3 -isopentenyl pyrophosphate yields the second activated isoprene, dimethylallyl pyrophosphate
         • Stage 3 Condensation of Six Activated Isoprene Units to Form Squalene
           • Isopentenyl pyrophosphate and dimethylallyl pyrophosphate now undergo a head-to-tail condensation, in which one pyrophosphate group is displaced and a 10-carbon chain, geranyl pyrophosphate, is formed
             • Geranyl pyrophosphate undergoes another head-to-tail condensation with isopentenyl pyrophosphate, yielding the 15-carbon intermediate farnesyl pyrophosphate
               • Finally, two molecules of farnesyl pyrophosphate join head to head, with the elimination of both pyrophosphate groups, to form squalene.
                 • Squalene has 30 carbons, 24 in the main chain and 6 in the form of methyl group branches.
         • Stage 4 Conversion of Squalene to the Four-Ring Steroid Nucleus
           • The action of squalene monooxygenase adds one oxygen atom from O2 to the end of the squalene chain, forming an epoxide. This enzyme is another mixedfunction oxidase; NADPH reduces the other oxygen atom of O2 to H2O. The double bonds of the product, squalene 2,3-epoxide
             • This cyclization results in the formation of lanosterol, which contains the four rings characteristic of the steroid nucleus
               • Lanosterol is finally converted to cholesterol in a series of about 20 reactions that include the migration of some methyl groups and the removal of others

2. some important cholesterol metabolites

   • Bile acids
     • are polar derivatives of cholesterol that act as detergents in the intestine, emulsifying dietary fats to make them more readily accessible to digestive lipases
   • steroid hormones
     • are potent biological signals that regulate gene expression
   • oxysterols

3. Whole body cholesterol is regulated by the interaction of three factors: absorption, synthesis excretion or conversion of cholesterol into bile acids

4. Cholesterol absorption process

   • Factors affecting cholesterol absorption
     • Biliary Factors
       • Decreased size of the biliary bile salt pool and output and biliary phospholipid output reduces the proportion of cholesterol absorbed
       • factors such as increased cholesterol content of bile, hydrophilic-hydrophobic index of bile salt pool, and biliary cholesterol output suppress absorption
     • Luminal Factors
       • increased gastric emptying and small intestinal transit times are known to increase absorption
       • Reduced mucin production, especially Mucin1, has been identified to reduce absorption
     • Dietary factors
       • Dietary fibres
         • ability to sequester bile acids affecting the enterohepatic bile acid cycle
         • could directly affect cholesterol synthesis is by lowering postprandial glucose levels, resulting in a decline in insulin levels and consequently suppressing hepatic cholesterol synthesis by inhibition of HMGCR
       • Phospholipids
         • The normal dietary intake of phospholipids is 2–8 g/day from foods such as eggs, organ and lean meats, fish, shellfish, cereal grains, and oilseeds
         • Higher amounts of dietary phospholipids lead to decreased cholesterol absorption
       • Plant Sterols
         • Campesterol and sitosterol are the mostabundant plant sterols
           • Plant sterols significantly inhibit intestinal cholesterol absorption with an efficacy of 5–15 % from dietary and biliary sources
           • induce a compensatory rise in cholesterol synthesis
     • Therapeutic Factors
       • Ezetimibe (SCH 58235), a pharmaceutical drug developed to reduce cholesterol absorption
         • exerts its action by interfering with the function of the NPC1L1 transporter
         • A dose of 10 mg/day of ezetimibe is found to lower TC up to 15 % and LDL-C up to 20 %
     • Genetic Factors
       • Polymorphisms in apolipoprotein E (apoE)
         • carriers of the apoE2 allele are known to have lower rates of cholesterol absorption and higher rates of cholesterol synthesis compared to carriers of the apoE3/E4 allele
       • variant in the promoter region ( 204 A>C) of the cholesterol 7α-hydroxylase gene (CYP7A1) is shown to be associated with enhanced CYP7A1 activity
       • Mutations in the NPC1L1 gene have been reported in individuals displaying low cholesterol absorption and an associated lower level of plasma LDL-C
       • gene locus of PARK2 (parkin RBR E3 ubiquitin protein ligase), rs9364628
         • PARK2 variant was found to be associated with dietary fat quality and serum LDL-C concentrations
     • Epigenetic Factors
       • Methylation of the promoter region of the NPC1L1 gene regulate its expression in the gastrointestinal tract, in particular resulting in a low colonic expression
         • 5AZA (decitabine or 5-aza2′-deoxycytidine) treatment resulted in the release of this suppression in NPC1L1 expression in the colon
     • Gut Microbiome
       • bile acid metabolism is affected by the gut microbiome
         • microbiome not only controls the composition of the bile pool but also affects the expression of genes controlled by FXR ( Farnesoid X receptor)
       • In the small intestine, bile salt hydrolase active bacteria in the gut microbiota perform bile acid deconjugation and aid in the maintenance of normal levels of circulating deconjugated bile acids and cholesterol
   • Is derived from three main sources
     • Diet
       • Depends on food intake
         • Dietary cholesterol is partly esterified (<15 %)
     • Bile
       • contributes about 800–1200 mg/day
         • biliary cholesterol is predominantly unesterified
     • Intestinal epithelial sloughing
       • Intestinal mucosal epithelium turnover provides nearly 300 mg/day
   • The duodenum and proximal jejunum are the major sites of absorption
   • In healthy humans, approximately 50 % of intestinal cholesterol is absorbed
   • enzymes that mainly control the intestinal uptake and transport process of sterols
     • acetyl-CoA acetyltransferase (ACAT2)
       • facilitates intracellular cholesterol esterification
     • microsomal triglyceride transfer protein (MTTP)
       • Involved in intestinal chylomicron assembly

5. Regulation of cholesterol biosynthesis

   • genetic diseases caused by disturbed cholesterol homeostasis
     • Schnyder corneal dystrophy
       • Enhanced cholesterol production due to HMGCR stabilization
       • Symptoms
         • Cholesterol accumulation in the cornea; corneal opacification
       • Mutation in UBIAD1 gene
     • Smith–Lemli–Opitz syndrome
       • 7-Dehydrocholesterol accumulation and cholesterol deficiency
       • Symptoms
         • Mental and growth retardation; cleft palate; malformations of heart, kidney and genitals (males); polydactyly or syndactyly
       • Mutation in DHCR7 gene
     • Familial hypercholesterolaemia
       • Impaired LDLR- mediated LDL uptake
       • Symptoms
         • Markedly elevated plasma levels of cholesterol containing LDLs; premature coronary heart disease
       • Mutation in LDLR, APOB a, PCSK9 b , ARH genes
     • Tangier disease
       • Impaired ABCA1-mediated cholesterol efflux
       • Symptoms
         • Extremely low HDL and apoA- I; massive deposition of cholesteryl esters in macrophage- rich tissues; increased risk of coronary artery disease
       • Mutation in ABCA1 gene
     • Sitosterolaemia
       • Impaired ABCG5 and ABCG8-mediated cholesterol efflux
       • Symptoms
         • Elevated plasma and tissue levels of plant sterols and cholesterol; xanthomas; premature cardiovascular disease
       • Mutation in ABCG5, ABCG8 genes
     • Niemann–Pick type C disease
       • Cholesterol accumulation within lysosome
       • Symptoms
         • Neurodegeneration; enlarged liver and spleen
       • Mutation in NPC1, NPC2 genes
   • Homeostatic regulation of cholesterol metabolism by sterols
     • Signals
       • Lanosterol, oxysterols, geranylgeraniol
         • HMGCR degradation
       • Cholesterol
         • squalene monooxygenase degradation
         • Biosynthesis decrease
       • Cholesterol
         • SREBP pathway inactivation
           • Cholesterologenic genes downregulation
             • Biosynthesis decrease
           • LDLR downregulation
             • Uptake decrease
           • NPC1L1 downregulation
             • uptake decrease
           • miR-33 ↓ and thus ABCA1 upregulation
             • Efflux increase
         • Biosynthesis decrease
       • Cholesterol
         • NRF1 retention in the ER and thus derepression of the LXR pathway
         • Efflux increase
       • Cholesterol, oxysterols
         • ACAT2 stabilization
           • Esterification increase
         • ACAT1 and ACAT2 allosteric activation
           • Esterification increase
       • Associated changes in cholesterol metabolic pathways that ensure maintenance of cholesterol homeostasis in the presence of sterols
         • Biosynthesis decrease

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