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Cholesterol metabolism

Color index : Main text IMPORTANT Extra Info Drs Notes RespiratoryCardiovascular Block Block - Biochemistry - Biochemistry Team Team Objectives:

Understand the structure and functions of cholesterol.

Discuss the regulation of cholesterol homeostasis in the body.

Comprehend the important steps of cholesterol synthesis pathway.

Identify different levels of regulation of cholesterol synthesis.

Discuss the association of hypercholesterolemia with abnormal cholesterol metabolism.

Understand the role of statins in the treatment of hypercholesterolemia. Cholesterol

Major sources of liver cholesterol

● It’s the most important animal . Dietary cholesterol Cholesterol synthesized because it is the structural component of all cell comes to liver in De novo in extrahepatic tissues membranes form of synthesis in comes to liver in form Chylomicron the liver of HDL(2) اﻟزاﺋد ﻋن ﺣﺎﺟﺗﮭﺎ ﺑﯾﻧﺗﻘل ﻟﻠـ remnants “lipoprotein” liver Functions:

Maintains membrane fluidity. Liver plays a 1 Liver central role in because at high temperatures, it stabilizes the membrane and raises its Cholesterol the regulation melting point, whereas at low temperatures it intercalates between the Pool of cholesterol phospholipids and prevents them from clustering together and stiffening. homeostasis 2 Insulating effect on nerve fibres. It's a component of the Myelin sheath “Low level of cholesterol lead to degradation of nerves “ Secretion of Conversion to Free cholesterol Cholesterol is the parent molecule for bile VLDL secreted in the bile bile acids/salts (Very low density lipoprotein ) 3 Excreted by stool ﯾﻧﺗﻘل ﻟﻛل اﻷورﻗﺎﻧز acids and bile salts We need them for digestion and absorption of dietary fat , Steroid hormones e.g cortisol , (1) Vitamin D3 Major routes by which cholesterol leaves the liver ﺑﺎﺧﺗﺻﺎر اﻟﻠﻲ ﯾﮭﻣﻛم ﺗﻌرﻓوﻧﮫ ھﻧﺎ ھو ان اﻟـ cholesterol ﻣﻣﻛن ﯾوﺻل ﻟﻠـ liver ﺑﺛﻼث طرق : ﻣن ﺧﻼل اﻻﻛل او ﻣﻣﻛن (1) cholesterol is not important only for Vit D3 but it’s important for all fat soluble vitamins. اﻟـ Extrahepatic tissues ﺗﺻﻧّﻌﮫ ﺑﻧﻔﺳﮭﺎ او اﺧر طرﯾﻘﮫ ان اﻟـ liver ﺗﺻﻧّﻌﮫ ﺑﻧﻔﺳﮭﺎ This is why we consider HDL a good cholesterol, because it brings all the excess cholesterol (2) from the body to the liver to be metabolized. ﺑﻌدھﺎ ﻟﻣﺎ ﯾوﺻل ﻟـ liver راح ﺗﺗﺧﻠص ﻣﻧﮫ ﺑرﺿو ﺑﺛﻼث طرق : ﯾﺎ اﻧﮭﺎ ﺗرﺳﻠﮫ ﻟﻸﻋﺿﺎء اﻟﺛﺎﻧﯾﺔ ﻋﻠﻰ ﺷﻛل VLDL أو ﺟزء ﻣﻧﮫ *extra info : keep in mind extrahepatic tissues means anything formed outside the liver tissue like راح ﯾُرﺳل ﻣﺑﺎﺷرة ﻓﻲ اﻟـ bile اﻣﺎ آﺧر طرﯾﻘﺔ أﻧﮭﺎ ﺗﺣوﻟﮫ ﻣﺑﺎﺷرة إﻟﻰ adipose tissue and muscles* bile Cholesterol structure “ tail”

Cholesterol is made of steroid nucleus that has 4 hydrocarbon fused rings and contain:

Hydroxyl group at Double bond Hydrocarbon “tail & 8-10 hydrocarbon C3. between C5 & C6.

Free long” at C17

★ Steroid cholesterol The total number of carbon is 27C. nucleus

cholesterol is a type of sterol . all sterols are , (but not all steroids are sterols)

Cholesterol Cholesteryl ester has similar structure to cholesterol, but added Fatty acid to the site of hydroxyl group (C3). Hydrocarbon “ tail”

Most plasma cholesterol is esterified with a fatty acid. CEs (cholesteryl esters) are not present in Fatty acid membranes Due to absence of the hydrophilic part Steroid (hydroxyl group)& what present in the membrane is free cholesterol ester nucleus

cholesteryl Present in small amounts in most cells.

More hydrophobic than cholesterol because a fatty acid group was added to it. Cholesteryl ester Cholesterol synthesis

Synthesized in all Major sites for synthesis: All carbon atoms Enzymes involved in tissues liver, adrenal cortex, are derived from biosynthesis are partly testes, ovaries and acetyl CoA located in ER and partly (1) intestine (has 2 carbons) in cytoplasm

We put the 3 pictures in case if they come as a SAQ , these 3 pictures explained in the next slides اﻟﺳﻼﯾدات اﻟﻠﻲ ﺑﻌدھﺎ ﻣرﯾﺣﮫ ﻟﻠﻌﯾن اﻛﺛر ﻟو ﺗﺑون ﺷرح ، ﺗﻘدرون ﺗرﺟﻌون ﻟﮭﺎﻟﺻور ﻋﺷﺎن ﺗﻌرﻓون byproducts ﻟﻠﻲ طﻠﻌت ودﺧﻠت زي NADPH … اﻟﺦ

(1)Even though the enzyme is present in the ER, synthesis only occurs in the cytoplasm, how? Because the catalytic domain of the enzyme that found in the cytoplasm. reversible A helpful video Cholesterol synthesis irreversible

2C 2C ★ Isomerase Acetyl coA Acetyl coA

Thiolase 5C DPP

coA Transferase IPP ★ HMG CoA synthase is present in both cytosol(cytoplasm) and Acetoacetyl coA Condensation to a 30C 4C 10C compound () mitochondria of liver: GPP ( which is an opened ring Acetyl coA • Mitochondrial - ketogenesis molecule ) HMG- CoA synthase IPP formation of ketone bodies coA Transferase • Cytosolic – cholesterol synthesis 3-Hydroxy-3-methylglutaryl-CoA 15C FPP • Rate limiting and key step(1) 6C ( HMG CoA ) ★ Squalene • Occurs in cytosol FPP HMG- CoA reductase coA synthase • HMG CoA reductase is an ER membrane enzyme with catalytic Mevalonic acid 30C Squalene unit hanging in the cytosol 6C The enzyme is present in ER but Cyclization of squalene to ★ Squalene the site of action ( catalytic Kinase 30C lanosterol(2) HMG CoA reductase monooxygenase unit ) hanging in cytosol. Lanosterol This step is not 5- Pyrophosphomevalonate 30C 6C (First sterol) Synthesis of 27-Carbon important cholesterol (defect in this leads to Smith-Lemli- decarboxylase Multiple steps Opitz Syndrome “SLOS” ) There is an enzyme that has Production of a 5-carbon unit Isopentenyl pyrophosphate to transfer the double bond patent sterol for all sterols, and the building between C7&C8 to C5&C6, if 27C Cholesterol block of cholesterol the enzyme is absent that 5C5C (IPP) lead to SLOS because the lanosterol didn’t not get (1) step that regulates the whole pathway, which is an irreversible and slow step, and is the target for inhibitors. converted to cholesterol. (2) to form a ring ( the first sterol that is made in the body ). 2 x Acetyl CoA Summary of the pathway In order for you to gain a better understanding

Thiolase CoA

ﻓﻲ اﻟﺑداﯾﺔ ﺑﻧﺣﺗﺎج ﯾﻛون ﻋﻧدﻧﺎ اﺛﻧﯾن Acetyl coA ﯾﻧدﻣﺟون ﻣﻊ ﺑﻌض ﺑﻌدﯾن ﻧﺣذف CoA ﻣن وﺣدة ﻣﻧﮭم ﺑﻣﺳﺎﻋدة إﻧزاﯾم اﺳﻣﮫ (Thiolase) ﻓﺑﺳﺑب اﻧدﻣﺎﺟﮭم ﺑﯾﺗﻛون ﻋﻧدﻧﺎ ﻣرﻛب ﺟدﯾد اﺳﻣﮫ Acetoacetyl coA ﺑﻌدھﺎ ﺑرﺿو ﺑﻧﺿﯾف Acetyl coA ﺛﺎﻟث وﺑﻧﺣذف ﻣﻧﮫ اﻟـ CoA ﺑﻣﺳﺎﻋدة إﻧزاﯾم اﺳﻣﮫ HMG-COA (HMG-coA synthase) وﺑﯾﺗﻛون ﻋﻧدﻧﺎ ﻣرﻛب ﻣﮭم ﺟدًا اﺳﻣﮫ HMG coA ﺑﻌدھﺎ ﺑﯾﺟﯾﻧﺎ إﻧزاﯾم اﺳﻣﮫ (HMG-coA reductase) ﻣﺎ راح ﯾﺿﯾف synthase

Will be explained in ﺷﻲء ﻣﺛل اﻹﻧزاﯾﻣز اﻟﻠﻲ ﻗﺑﻠﮫ ﻷن وظﯾﻔﺗﮫ ﻓﻘط ﯾﻐﯾر اﻟﻣﺟﻣوﻋﺔ اﻟوظﯾﻔﯾﺔ وﯾﺣذف coA وﺑﯾﻛون ﻋﻧدﻧﺎ ﻣرﻛب اﺳﻣﮫ (the next slides .. (Mevalonic acid

ﺣﺎﻟﯾًﺎ ﺻﺎر ﻋﻧدﻧﺎ اﻷﺳﯾد ھذا اﻟﻠﻲ ﻋدد اﻟﻛرﺑون ﻓﯾﮫ 6 ﺑﯾﺻﯾر ﻟﮫ ﻛم ﺧطوه ﻋﻠﻰ اﻷﻏﻠب ﻣﺎ ﯾﮭﻣﻛم ﺗﻌرﻓوﻧﮭﺎ ( راح ﯾﻧﺿﺎف ﻓوﺳﻔﺎت وﯾﺻﯾراﺳﻣﮫ

Pyrophosphomevalonate ﻋن طرﯾق اﻧزاﯾم kinase وﺑﻌدھﺎ ﺑﻧﺷﯾل ﻣﻧﮫ CO2 ﻋن طرﯾق اﻧزاﯾم decarboxylase) اﻟﻠﻲ ﯾﮭﻣﻛم ﺗﻌرﻓوﻧﮫ أﻧﮫ ﺑﯾﺗﻛون ﻋﻧدﻧﺎ

ﻣرﻛب ﺟدﯾد ﻋدد اﻟﻛرﺑون ﻓﯾﮫ 5 واﺳﻣﮫ (IPP) ﺑﻌدھﺎ ﻣن ﺧﻼل Isomerase راح ﯾﺗﺣول إﻟﻰ (DPP) ﻋدد اﻟﻛرﺑون ﻣﺎ ﺗﻐﯾر ﻟﻠﺣﯾن 5 ﻷن اﻷﯾزوﻣﯾرﯾز ﻓﻘط ﻏﯾر HMG-COA ﺷﻛﻠﮫ ﻣﺎ أﺿﺎف ﻟﮫ ﺷﻲء. reductase

اﻟﻣراﺣل اﻟﺟﺎﯾﺔ ﻛﻠﮭﺎ ﻋﺑﺎرة ﻋن إﻧدﻣﺎج ﻣرﻛﺑﺎت ﻣﻊ ﺑﻌض ﻋﺷﺎن ﯾﻧﺗﺞ ﻟﻧﺎ اﻟﻛوﻟﯾﺳﺗرول ﻓﻲ اﻟﻧﮭﺎﯾﺔ، اﺣﻔظوھم ﻛذا ﻛﺄﻧﮭم ﻣﻌﺎدﻻت:

DPP(C5) + IPP (C5) = GPP(C10).. The enzyme: Transferase

Isomerase GPP (C10) + IPP(C5) = FPP(C15).. The enzyme: Transferase

FPP (C15) + FPP (C15) = Squalene (C30).. The enzyme is: Squalene synthase Dimethylallyl pyrophosphate Then Dimethylallyl pyrophosphate + isopentenyl pyrophosphate ﻟﻛن ﻓﻲ ھﺎﻟﺣﺎﻟﺔ اﻟـ Squalene ﺑﯾﻛون linar وأﺣﻧﺎ ﻧﺣﺗﺎﺟﮫ ﯾﻛون rings ﻓﺑﻧﺳوي ﻟﮫ Cyclization ﻣن ﺧﻼل إﻧزاﯾم اﺳﻣﮫ Transferase Squalane monoxygenase وﺑﺗﻐﯾر اﺳم اﻟﻣرﻛب وﺑﯾﺻﯾر Lanosterol وھذا ﯾﻌﺗﺑر أول ﺳﺗﯾرول ﯾﺗﻛون ﻟﻛن ﻣو ھو اﻟطﺑﯾﻌﻲ اﻟﻠﻲ

ﻧﺣﺗﺎﺟﮫ ﻷن ﻋدد اﻟﻛرﺑون ﻓﯾﮫ 30 وﻟو ﺑﻘﻰ ھذا ﺑﺟﺳﻣﻧﺎ وﻣﺎ ﺗﺣول إﻟﻰ ﻛوﻟﯾﺳﺗرول ﻓراح ﯾﺳﺑب ﻟﻧﺎ ﻣرض اﺳﻣﮫ (SLOS) ﻓﻌﺷﺎن ﻛذا ﺿروري ﯾﺗﺣول Geranyl pyrophosphate

Then ﻟﻛن ﺣﻧﺎ ﻣﺎ ﯾﮭﻣﻧﺎ ﻧﻌرف ﺧطوات اﻟﺗﺣول اﻟﻣﮭم ﺑﺎﻷﺧﯾر ﺑﯾﺗﻛون ﻋﻧدﻧﺎ اﻟﻛوﻟﺳﺗرول اﻟطﺑﯾﻌﻲ اﻟﻠﻲ ﻋدد اﻟﻛرﺑون ﻓﯾﮫ 27 Geranyl pyrophosphate + isopentenyl pyrophosphate

اﻟﺧطوات اﻻوﻟﻰ ﻟﯾن ال pyrophosphomevalonate ﻋﻠﯾﻛم ﺗﺣﻔظوﻧﮭﺎ ﺑس ﻋﺷﺎن ﺗﺣﻔظون ال sequence of products ﺑﻌدھﺎ ﻋﻧدﻛم ھﺎﻟـ mnemonics Transferase ”I Don't Get it why Fatimah Stole Lama's Coat or I Do Get Frightened Stealing Luxurious“

I = isopentenyl pyrophosphate Farnesyl pyrophosphate D = Dimethylallyl pyrophosphate

Then 2 x Farnesyl pyrophosphate G = Geranyl pyrophosphate F = Farnesyl pyrophosphate Squalene S = Squalene synthase Squalane Squalene monoxygenase Lanosterol Cholesterol L = Lanosterol Multistep Finally we arrived  C = Cholesterol ★ extra explanation Summary of the pathway In order for you to gain a better understanding In tables

Reaction 1 ★ Reaction 2 ★ Reaction 3

Reactant 2 Acetyl coA Reactant Acetoacetyl coA + Reactant HMG CoA Acetyl coA

Product Acetoacetyl coA Product Mevalonic acid Product HMG CoA

Enzyme Thiolase Enzyme HMG- CoA reductase Enzyme HMG- CoA synthase

Action Join 2 Acetyl coA Action Join them together and together and remove Action Join them together and remove CoA CoA remove CoA

Byproduct Use 2NADPH + 2H+ and Byproduct COA Byproduct COA produce NADP+

Reaction 4 ★ Reaction 5 Reaction 6

Reactant IPP Reactant Mevalonic acid Reactant 5- Pyrophosphomevalonate

Product Dimethylallyl Product 5- Pyrophosphomevalonate Product Isopentenyl pyrophosphate (DPP) pyrophosphate (IPP)

Enzyme Kinase Enzyme Isomerase Enzyme decarboxylase

Action Add 2 phosphate groups Action Change the structure of to it the molecule

Action Remove CO2 group Consume 2 ATP Byproduct - Consume 1 ATP ★ extra explanation Summary of the pathway In order for you to gain a better understanding In tables … contd

Reaction 7 Reaction 8 ★ Reaction 9

Reactant DPP + IPP Reactant GPP + IPP Reactant 2 FPP

Product Squalene Product Geranyl pyrophosphate Product Farnesyl pyrophosphate ( GPP ) ( FPP ) Enzyme Squalene synthase Enzyme Transferase Enzyme Transferase Action Join the two molecules together Action Join the two molecules Action Join the two molecules together together Byproduct 2 phosphate groups + Use NADPH + H+ and produce Byproduct 2 phosphate groups Byproduct 2 phosphate groups NADP+

★ Reaction 10 Reaction 11

Reactant Squalene Reactant Lanosterol

Product Lanosterol Product Cholesterol

Enzyme Squalene Enzyme ( multiple steps not only monooxygenase one step )

Action Cyclization of squalene Action Synthesis of 27-Carbon ( close the rings ) cholesterol

Byproduct H2O + Use NADPH + H+ and produce NADP+ Byproduct - A helpful video HMG CoA Reductase Regulation

It’s cholesterol independent regulation and It’s cholesterol dependent regulation and means the more depends on which type of hormones are sterol ( cholesterol ) you have the faster degradation present that stimulate or inhibit the synthesis Sterol-accelerated enzyme degradation. Hormonal regulation.

A B C D

Sterol-dependent regulation of gene Sterol-independent expression. phosphorylation and dephosphorylation. the amount of cholesterol in your body will determine the expression of the genes related to cholesterol synthesis A) Sterol-dependent regulation of gene expression of HMG CoA

The goal of this regulation is to regulate transcription, how ? By transcription factors. These factors bind before the gene, and either activate or inhibit its transcription When sufficient cholesterol is present, transcription is suppressed and vice versa. Sterol Regulatory Element (SRE) is a recognition sequence in the DNA. “ the area that binds with the transcription factor “ “ﻧﻘدر ﻧﻘول ﻣﻛﺎن ﻣوﺟود ﻓﻲ DNA ﻋﺷﺎن ﯾﺧﻠﻲ ال SREBP اﻟﻠﻲ ھو transcription factor ﯾﻧﺗﺑﮫ اذا ﺟﺎ ال nucleus ان ﻣن ھﻧﺎ ﯾﺑدا ال transcription” SREBP(SRE binding protein) binding to SRE (Sterol Regulatory Element) is essential for transcription of this gene. “وﻋﺷﺎﻧﮫ ﻣوﺟود ب ER ﻻزم ﯾروح ﻟل nucleus ﻋﺷﺎن ﯾﺑدا ال SREBP is the transcription factor that present in the ER. "transcription of the gene SREBP cleavage-activating protein (SCAP) is an intracellular cholesterol sensor. so when the levels of cholesterol decrease, SCAP will take SREBP to the golgi bodies then in the Golgi bodies there are some enzyme that will cleave SCAP ( remove it from SREBP ) why ? Because SREBP wants to be free and able to bind with SRE in the DNA to synthesize more colesterol, and if cholesterol levels increase the cleavage will be stopped.

SCAP ( which already bound with SERBP ) will 01 SCAP-SREBP moves to Golgi bodies. 01 sense the raise in cholesterol and will bind to INSIG Cholesterol protein ( insulin induced protein ) in ER membrane. SCAP is removed from SREBP because Cholesterol level Inside the golgi bodies, there are enzymes 02 02 SCAP-SREBP is retained in the ER because INSG level that remove SCAP and release SREBP. prevents them from leaving to the golgi body. SREBP goes the the nucleus and binds to 03 Down regulation of cholesterol synthesis in SRE in DNA and then HMG CoA gene 03 other word the transcription of HMG CoA reductase is activated. enzyme will be inhibited. B ) Sterol-“ dependent” accelerated enzyme degradation “Dr : it’s a missing slide , you can find it in the reference “. The reductase itself is a sterol sensing integral protein of the Smooth ER membrane( SER ). When sterol levels in the Smooth ER are high, the enzyme binds to INSIG (insulin-induced protein) ➔ Binding leads to cytosolic transfer ubiquitination and proteasomal degradation of the reductase. To make it clear the HMG CoA reductase enzyme has the ability to sense the levels of cholesterol in the cell if the cholesterol level is high in the SER the HMG CoA reductase enzyme will bind to insig and when the HMG CoA reductase enzyme binds to insig , the enzyme will go under degradation why ? To stop the synthesis of cholesterol since the HMG CoA reductase enzyme step is the rate limiting step that regulates the whole pathway Absence of HMG CoA reductase enzyme = low levels of cholesterol

اﯾش ھو upiquitin ؟ ھو small protein ﻟﻣﺎ ﯾرﺗﺑط ﻣﻊ ﺑروﺗﯾن اﺧر راح ﯾﺻﯾر ﻋﻧدي Ubiquitination ﻣﻌﻧﺎه ان اﻟﺑروﺗﯾن اﻻﺧر ﻣﻌد ﯾﺷﺗﻐل ﺑﺳﺑب ارﺗﺑﺎط upiquitin ﻓﯾﮫ وﻧﺗﯾﺟﮫ ﻟﮭذا اﻻرﺗﺑﺎط راح ﯾﺻﯾر degradation ﻟﻼﻧزاﯾم via the proteasome واﺧر ﺷﻲ اﯾش ھو اﻟـ proteasome ؟  ھو protein complex ﻣﺳؤول اﻧﮫ ﯾﺳوي degradation ﻻﻧزاﯾﻣز ﻣﺎ ﻧﺣﺗﺎﺟﮭﺎ ( ﻻ ﻧﻧﺳﻰ ان اﻻﻧزاﯾم ھو ﺑﺎﺻﻠﮫ ﺑروﺗﯾن ﯾﻌﻧﻲ ﺑﯾﻛﺳر ﺑروﺗﯾﻧﺎت ﻣﺎ ﻧﺣﺗﺎﺟﮭﺎ ) to sum up : reductase+ INSIG → activitie the binding of upiquitin to them → this will active proteasome (to start degradation)→ finally leads to the degradation

C) Sterol-independent phosphorylation and dephosphorylation

This regulation depend on the amount of energy presented in the cell “ no enough ATP = no synthesis”.

High AMP = Low ATP which means the cell HMG CoA Reductase is in need of energy. Cholesterol synthesis ↓ATP or ↑AMP ↑ATP or ↓AMP needs energy AMP- activated protein Phosphoprotein (anabolic reaction) kinase (AMPK) phosphatase and therefore when P the cell is running low on energy it inhibits P Phosphorylated form of Dephosphorylated form is the synthesis of Cholesterol through enzyme is Inactive Active AMPK cholesterol synthesis(1) cholesterol synthesis(2)

(1) When there’s high AMP, AMP kinase is activated and then the AMPK will phosphorylate the enzyme and make it inactive and the cholesterol synthesis will decrease. (2) When there’s high ATP another enzyme which is called phosphoprotein phosphatase will remove a phosphate group to make the enzyme active and the cholesterol synthesis will increase . D ) Hormonal Regulation HMG CoA Reductase Regulation “independent“

gene Insulin and thyroxine increase At the level of genes upregulation of enzyme expression. Cholesterol They increase enzyme concentration, thus increase cholesterol synthesis, because insulin Transcription has a major role in lipogenesis

Translation Glucagon and cortisol have opposite ( decease it ). effect HMG CoA

Reductase At the level of enzymes

HMG CoA Insulin Cholesterol concentration itself Thyroxine controlling the gene, while hormones Glucagon are controlling the enzymes Cortisones Statins

It also affects the phosphorylation and dephosphorylation of the Cholesterol enzymes Excretion of cholesterol

Normally most of the molecules (protein/carbohydrates) are broken down completely to CO2 and H2O , but cholesterol can not be broken down completely because it has a big ring structure ) so the body will convert it to other molecules that can be easily excreted from the body.

By conversion into bile acids and bile salts excreted in the feces. it’s the only way for cholesterol excretion • Direct secretion of cholesterol in bile. • Transported to intestine for elimination.

In the intestine, some cholesterol is converted by bacteria into coprostanol and cholestanol (which is reduced derivative of cholesterol) before excretion.

Normally 5% of bile acids/salts that synthesized from cholesterol are excreted, so If we wanna remove the excess cholesterol we use bile acids binding resin that excrete more bile acids/sats “ more than 5% of cholesterol is excreted “. Check the pharmacology team for more details ( Antihyperlipidemic drugs lecture )

High concentration of cholesterol in blood that Hypercholesterolemia leads to atherosclerosis or shock due to the loss of regulation of cholesterol synthesis

Hyper : high emia : in the blood statin drugs are used as a β-Sitosterols/phytosterols* Treatment of are clinically useful in the hypercholesterolemia dietary treatment of 2- (2) because2- they decrease hypercholesterolemia plasma cholesterol levels *β-Sitosterol Is a type of several phytosterols that’s why we sayTitle β-Sitosterol is used in the treatment of TitleCheck the pharmacology team for more details hypercholesterolemia not phytosterols ( Antihyperlipidemic drugs lecture )

What are the β-Sitosterols ? What are statin drugs ? -They’re plant sterols like in -Statins are structural analogs of avocados which are ( structurally similar to ) HMG CoA poorly absorbed by humans. reductase enzyme What is the M.O.A of β-Sitosterols ? What is the M.O.A of statins drugs ? -They Block the absorption of -inhibit enzyme activity by dietary cholesterol. competitive inhibition(1)

(1) group of drugs that are structurally similar to HMG coA reductase enzyme that decrease the level of the cholesterol as a result competition will occur between them. (2) substances similar to cholesterol found in the plants , poorly absorbed in in the intestine that’s why they prevent the absorption of the cholesterol . Take Home Messages

Cholesterol is important various body functions .

Liver plays a major role in the cholesterol homeostasis in the body.

HMG CoA reductase is a rate-limiting enzyme for cholesterol synthesis. Numbering based on the cholesterol synthesis steps Summary

Cholesterols

HMG CoA reductase Structure Function Synthesis regulation:

1- sterol dependent Sterol: 4 ring with •most important animal steroid. Location Cholesterol synthesis regulation of HMG CoA hydrocarbon tail and a •maintains membrane fluidity. gene expression hydroxyl group . •insulating nerve fibers . • parent molecule for bile acids, Cholesteryl ester: have bile salt,steroid hormones, fatty acid tail vitamin D3. 2- sterol accelerated In all tissues mainly in liver, enzyme degradation intestines, adrenal cortex, testes , ovaries.

3-sterol independent phosphorylation/dephos phoryltion

3- hormonal regulation

1-HMG CoA 2-Mevalonic 5- condensation to 6- cyclization of 7-synthesis of 3-Synthesis IPP 4-synthesis FPP synthesis acid synthesis squalene squalene 27c cholesterol

Reactant: 2x farnesyl Reactant: squalene Reactant: Acetoacetyle Reactant: HMG CoA Reactant: Reactant: isopentenyl pyrophosphate Multiple steps & CoA ( from acetyl coA ) 5-Pyrophosphomevalonate pyrophosphate + Product: lanosterol defect on these steps Product: Mevalonic acid ( which comes from Geranyl pyrophosphate Product: Squalene lead to Smith Lemli Opitz Product: HMG CoA Mevalonic acid ) Enzyme : Squalane Syndrome Location: cytosol Product: farnesyl Enzyme: squalene monoxygenase Location: cytosol Product: pyrophosphate synthase Enzyme: HMG CoA Isopentenyl pyrophosphate

Enzyme : HMG-CoA reductase Enzyme : Transferase synthase Enzyme: decarboxylase Quiz

Q1 : One of major routes by which cholesterol leaves the liver is : SAQs :

A ) Secretion of VLDL B ) Secretion of LDL C ) Secretion of HDL D ) Secretion of Q1: Enumerate the major sites for Cholymicron cholesterol synthesis :

Q2 : converting of HMG CoA to mevalonic acid done by : Q2: Name the syndrome that result from defect in 27 carbon cholesterol synthesis A ) HMG CoA Reductase B ) HMG CoA dismutase C ) HMG CoA dismutase D ) HMG CoA Reductase in cytosol enzyme in cytosol enzyme in ER in ER Q3: Which drug can you give to a patient Q3 : When SCAP binds to INSIG protein that lead to …. ? with Hypercholesterolemia ? & mention the MOA of it A ) SCAP-SREBP moves to B ) SCAP-SREBP is C ) SCAP is removed from D ) SREBP binds to SRE in golgi bodies retained in ER SREBP DNA ★ MCQs Answer key:

Q4 : Cholesterol synthesis increases when …… ? 1) A 2) A 3) B 4) A 5) B 6) B

★ A ) ATP is high B ) ATP is low C ) AMP is high D ) B&C SAQs Answer key: 1) Liver , adrenal cortex , ovaries , testes Q5 : Upregulation of enzyme expression of cholesterol increases by : and intestine

A ) Glucagon B ) Insulin C ) Cortisol D ) None of them 2) Smith-Lemli- Opitz Syndrome “SLOS”

Q6 Which of one of the following is true when the cholesterol levels are high ? 3) statin drugs ,it’s structural analogs of HMG CoA reductase enzyme and they A ) SREBP binds to SRE B ) SREBP - SCAP binds to C ) SREBP is free D) go to the 3 choices inhibit the enzyme activity by INSIG and choose one ! competitive inhibition Girls team: Boys team: just wash your hands

Manal Altwaim Omar Alsuliman Duaa Alhumoudi Abdullaziz Alomar Rania Almutiri Hamad Almousa Alia Zawawi Homoud Algadheb Noura Alshathri Abdullah Alanzan Reem Alamri Abdullah Almazro Renad Alhomaidi Ahmad Alkhayatt Fatimah Alhelal Abdullaziz Alrabiah

Revised by Made by

Shatha Aldhohair Abdulaziz Alsalem

[email protected] @Biochemistry439