cholesterol from edu. blog

7/30/2019 cholesterol from edu. blog

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Cholesterol

1. Present in tissues as eitherfree cholesterol orcholesterol ester.

2. Synthesized in many tissues from acetyl CoA.

(a) 75% of the cholesterol in the body is synthesized, only 25% comes from the diet

(b) major sites of synthesis are liver, intestine, skin and endocrine glands

Synthesis of Mevalonate from Acetyl CoA: Acetyl CoA is produced primarily from -

oxidation of fatty acids.


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HMG-CoA Reductase is induced by low cholesterol and regulates the entire pathway.

Synthesis of Squalene from Mevalonate:


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Synthesis of Cholesterol from Squalene:

Cholesterol

1. Present in tissues as eitherfree cholesterol orcholesterol ester.

2. Synthesized in many tissues from acetyl CoA.

(a) 75% of the cholesterol in the body is synthesized, only 25% comes from the diet

(b) major sites of synthesis are liver, intestine, skin and endocrine glands

Synthesis of Mevalonate from Acetyl CoA: Acetyl CoA is produced primarily from -

oxidation of fatty acids.


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HMG-CoA Reductase is induced by low cholesterol and regulates the entire pathway.

Synthesis of Squalene from Mevalonate:


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Synthesis of Cholesterol from Squalene:


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Note: The enzyme that catalyzes "Esterification" of cholesterol is ACAT. 7-Hydroxylase is

activatedby XS Cholesterol and inhibitedby XS Bile Acid.

3. Ultimately eliminated from the body as cholesterol in bile acids.

4. Cholesterol is the precursor ofALL other steroids in the body, i.e. corticosteroids, sex

hormones, vitamin D, bile acids.

5. Occurs in foods ofanimal origin, i.e. egg yolk, meat and liver.


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6. Cholesterol is an amphiphilic lipid ----> essential structural component of membranes.

7. Lipoproteins transport cholesterol esters in their hydrophobic core.

Low Density Lipoprotein (LDL) mediates cholesterol up-take into tissues. (BAD chol.)

High Density Lipoprotein (HDL) removes cholesterol from the tissues to the liver where it is

transformed to bile acids and eliminated. (GOOD Chol.)

8. Cholesterol is the major contributor to atherosclerosis (blocking and hardening of the

arteries) caused by deposits of LDL (cholesterol) on artery walls.

Coronary atherosclerosis correlates with a high plasma LDL:HDL cholesterol ratio.

9. CholesterolBalance in Tissues: Steps 1, 2, 3, 4, 5 addto the cholesterol "pool"; a, b, and c

remove cholesterol.

When the Body Needs to Increase in Cholesterol

(a)up-take ofcholesterolcontaining lipoproteins by receptors, i.e. LDL receptor.

(b)up-take ofcholesterolcontaining lipoproteins by a non-receptor mediated pathway.

(c)up-take offreecholesterolfrom cholesterol rich lipoproteins to the cell membrane.


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(d)cholesterolsynthesis.

Via HMG-CoA Reductase and LDL Receptor Induction:

(e)hydrolysis ofcholesterol esters.

When the Body Needs to Decrease in Cholesterol:

(a)efflux ofcholesterolto HDL, promoted by LCAT.

(b)HDL's cleared by the liver as bile acids.

(c)esterification ofcholesterolfor storage by ACAT.

(d)utilization ofcholesterolfor synthesis of othersteroids such as hormones.

Dietary Measures:

Low cholesterol.

High mono- and polyunsaturated fats (sunflower, canola, corn, soybean, olive).

Low saturated fats (butter, beef, palm).

Cholesterol Lowering Drugs:

Drug Indications Primary Effect

CholestyramineHigh LDLBinds bile acids (Bile Acid

Sequestrant)

Lovastatin High LDLCompetitive Inhibition of HMG-

CoA Reductase


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Mevastatin

Clofibrate Low HDLDiverts free fatty acids from

esterification

Gemfibrozil High LDLDecreases the secretion of

choles. cont. LDL

ProbucolFamilial

Hypercholesterolemia

Decreases accumulation of LDL

in arteries

Niacin Low HDL and High LDL

Decreases flux of free fatty acids

for-oxidation

Decreases the secretion of

choles. cont. LDL

Summary of Cholesterol Metabolism:

Dr. Noel Sturm 2013


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Note: The enzyme that catalyzes "Esterification" of cholesterol is ACAT. 7-Hydroxylase is

activatedby XS Cholesterol and inhibitedby XS Bile Acid.

3. Ultimately eliminated from the body as cholesterol in bile acids.

4. Cholesterol is the precursor ofALL other steroids in the body, i.e. corticosteroids, sex

hormones, vitamin D, bile acids.

5. Occurs in foods ofanimal origin, i.e. egg yolk, meat and liver.


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6. Cholesterol is an amphiphilic lipid ----> essential structural component of membranes.

7. Lipoproteins transport cholesterol esters in their hydrophobic core.

Low Density Lipoprotein (LDL) mediates cholesterol up-take into tissues. (BAD chol.)

High Density Lipoprotein (HDL) removes cholesterol from the tissues to the liver where it is

transformed to bile acids and eliminated. (GOOD Chol.)

8. Cholesterol is the major contributor to atherosclerosis (blocking and hardening of the

arteries) caused by deposits of LDL (cholesterol) on artery walls.

Coronary atherosclerosis correlates with a high plasma LDL:HDL cholesterol ratio.

9. CholesterolBalance in Tissues: Steps 1, 2, 3, 4, 5 addto the cholesterol "pool"; a, b, and c

remove cholesterol.

When the Body Needs to Increase in Cholesterol

(a)up-take ofcholesterolcontaining lipoproteins by receptors, i.e. LDL receptor.

(b)up-take ofcholesterolcontaining lipoproteins by a non-receptor mediated pathway.

(c)up-take offreecholesterolfrom cholesterol rich lipoproteins to the cell membrane.


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(d)cholesterolsynthesis.

Via HMG-CoA Reductase and LDL Receptor Induction:

(e)hydrolysis ofcholesterol esters.

When the Body Needs to Decrease in Cholesterol:

(a)efflux ofcholesterolto HDL, promoted by LCAT.

(b)HDL's cleared by the liver as bile acids.

(c)esterification ofcholesterolfor storage by ACAT.

(d)utilization ofcholesterolfor synthesis of othersteroids such as hormones.

Dietary Measures:

Low cholesterol.

High mono- and polyunsaturated fats (sunflower, canola, corn, soybean, olive).

Low saturated fats (butter, beef, palm).

Cholesterol Lowering Drugs:

Drug Indications Primary Effect

CholestyramineHigh LDLBinds bile acids (Bile Acid

Sequestrant)

Lovastatin High LDLCompetitive Inhibition of HMG-

CoA Reductase


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Mevastatin

Clofibrate Low HDLDiverts free fatty acids from

esterification

Gemfibrozil High LDLDecreases the secretion of

choles. cont. LDL

ProbucolFamilial

Hypercholesterolemia

Decreases accumulation of LDL

in arteries

Niacin Low HDL and High LDL

Decreases flux of free fatty acids

for-oxidation

Decreases the secretion of

choles. cont. LDL

Summary of Cholesterol Metabolism:

Dr. Noel Sturm 2013


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Cholesterol Serum Influx/Efflux

Cholesterol Transport

Gianpiero Pescarmona2007-09-29

Description

Plasma cholesterol is derived from two sources:

1. exogenous (dietary and biliary excretion)2. endogenous (liver and peripheral tissues)

Exogenous

Dietary and biliary cholesterol are absorbed in the intestine by a saturable transport

mechanism.

Roughly 2/3 of intestinal cholesterol is from bile and 1/3 from diet.

Diet cholesterol absorption (percentage of the intake) is very different from people to people

and it has a Gaussian distribution, ranging from almost null to 100% on a genetic base whith

an average intake (around 400 mg/d).

Roughly 50% f intestinal cholesterol is absorbed and recycled while the remaining part is

eliminated with feces.
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Importantly, individual variability exists with regard to the proportion of cholesterol that is

absorbed or synthesized, depending on sensitivity of HMG-CoA reductase to inhibition by

exogenous cholesterol. (Physiological and therapeutic factors affecting cholesterol

metabolism: does a reciprocal relationship between cholesterol absorption and synthesis

really exist?)

Evaluation of the relative role of cholesterol absorption or synthesis in determining its serum

level is difficult even using radioactive tracer. Therefore in most studies the ratio between

cholestanol/cholesterol and fitosterols/cholesterol is used as indirect marker of these fluxes.

This kind of measurements is affected by large incertainities and therefore appliable only to

very large samples.

New insights into the regulation of HDL metabolism and reverse cholesterol transport.2005

Cholestanol: A serum marker to guide LDL cholesterol-lowering therapy

The interaction of cholesterol absorption and cholesterol synthesis in man

Effects of dietary cholesterol on the regulation of total body cholesterol in man

The number of receptors involved in intestinal cholesterol uptake explains the

variability and umpredictability of the process
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Endogenous

Daily synthesis in healthy man is around 750/1000 mg cholesterol (ca 2/3 of daily

requirement), with an intake of around 250/400 mg. But increased dietary intake canreduce the net synthesis

Cholesterol synthesis takes place in both liver (around 20%) and other peripheral tissues

(mainly gut) and it strongly dependent on intestinal uptake as de novo cholesterol synthesis is

inhibited at the level of HMG-CoA reductase by exogenous cholesterol. (Diurnal and dietary-

induced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA

reductase)

Circadian rythm of cholesterol synthesis
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Evidence for diurnal periodicity in human cholesterol synthesis

Cholesterol efflux from the cell

The cholesterol efflux from the cell is mediated by a carrier calledABCA1belonging to the

family ofABC transporter
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Cholesterol transport

LuXuRies of Lipid Homeostasis: The Unity of Nuclear Hormone Receptors, TranscriptionRegulation, and Cholesterol Sensing 2009

Regulation of ABC1 activity

The ABC1 belongs to the family of theABC-transporterincluding also theMDR1/pgp

Cerebral vascular dysfunction during hypercholesterolemia.

Metabolic and Hormonal regulation of Cholesterol Metabolism

The stringent regulation of the different metabolic pathways is achieved through a set of

interactions including nutrients concentration, hormones and Nuclear Factors, leading to a

tight dependence from any environmental change (diet, fasting, etc).

* * *
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Transcriptional Regulation of Metabolism 2006 FullText

See Cartoon

Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in

mice: gender and age effects. 2006

Glucose and Insulin release

Insulin effects
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Regulation of cholesterol metabolism by Nuclear Factors

Sterol response element binding protein (SREBP)-2 and SREBP-1c at the branching

point of cholesterol and fatty acid metabolism

The coordinated action of FXR, LXR, and SREBP-2 in the cholesterol metabolism


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The major source of cholesterol is the diet, while de novo synthesis of cholesterol is

stimulated by SREBP-2 if supplies are too low. If cholesterol is in excess, its efflux from the

cells and its conversion into bile acids for excretion in the feces are favored by the activation

of liver X receptor (LXR). High bile acid production in turn activates farnesol X receptor

(FXR), which limits the toxic accumulation of these metabolites in the liver, by increasing

their cell efflux and limiting their production. The plain blue arrows correspond to the action

of these transcription factors on the genes acting in the cholesterol metabolic pathway. Thegray arrows correspond to the action of these gene products. Some bile acid and cholesterol

metabolites are ligands for FXR and LXR, respectively (blue dotted line), while high

cholesterol levels directly inhibit SREBP-2.

Metabolic adjustment of glucose metabolism upon fasting.


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Summary of the network established by the transcription factors involved in metabolic

regulation

Summary of the network established by the transcription factors involved in metabolic

regulation. Each of the transcription factors mentioned in this figure participates in the

regulation of at least one aspect of metabolism, often by sensing metabolite levels and

adapting the cell response through transcriptional regulation of enzymes belonging to

different pathways. In addition, each of them may influence the activity of the others,

creating a regulatory network

by which homeostasis is achieved.

Thyroid hormones and cholesterol

Hypothyroidism is associated with hypercholesterolemia and hyperthyroidism with

hypocholesterolemia


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Thyroid hormone has a stimulatory effect on HMGCoA-reductase increasing de novo

cholesterol synthesis, but has an inhibitory effect on cholesterol absorption

Which is the molecular mechanism?

Shin DJ et al propose that the decreased LDL receptor and increased serum cholesterolassociated with hypothyroidism are secondary to the thyroid hormone effects on SREBP-2.

These results suggest that hypercholesterolemia associated with hypothyroidism can be

reversed by agents that directly increase SREBP-2. Additionally, these results indicate that

mutations or drugs that lower nuclear SREBP-2 would cause hypercholesterolemia. (Thyroid

hormone regulation and cholesterol metabolism are connected through Sterol Regulatory

Element-Binding Protein-2 (SREBP-2).)

The association between TSH within the reference range and serum lipid concentrations in a

population-based study. The HUNT Study. 2007

Pathways

Cholesterol Transport Private Il colesterolo

Items

Tangier DiseaseMeSH

Cholesterol

Comments 2010-04-26 17:48:42.366484 -Gianpiero Pescarmona

PgP and efflux
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Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol

homeostasis. 2006

may PgP be involved in loading of Chol on HDL?

TH and lipoproteins

Beneficial effects of a novel thyromimetic on lipoprotein metabolism. 1997

THYROMIMETIC LIPOPROTEIN

Thyroid hormones and thyroid hormone receptors: effects of thyromimetics on reverse

cholesterol transport.2010Fulltext

World J Gastroenterol. 2010 Dec 21;16(47):5958-64.

Pedrelli M, Pramfalk C, Parini P.

Fig. 1

Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from

peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid

hormones (THs) affect growth, development, and metabolism in almost all tissues. THs exert

their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of

TRs, TR and TR, and several isoforms (e.g. TR1, TR2, TR1, and TR2). Activation of

TR1 affects heart rate, whereas activation of TR1 has positive effects on lipid and

lipoprotein metabolism. Consequently, particular interest has been focused on the

development of thyromimetic compounds targeting TR1, not only because of their ability to

lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical

models. In this review we focus on THs, TRs, and on the effects of TR1-modulating

thyromimetics on RCT in various animal models and in humans.
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full figure

Figure 1: HDL-C mediated reverse cholesterol transport. Reverse cholesterol transport (RCT)

can be divided into four phases. 1) transfer of free cholesterol (FC) to pre-b HDL via

ABCA1, 2) esterification of surface-associated FC by the enzyme Lecithin:acyl CoA

Transferase (LCAT), 3) transfer of FC and triglycerides (TG) between HDL-C and Apo B-containing lipoproteins mediated by the enzyme cholesteryl ester transfer protein (CETP),
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and 4) uptake by the scavenger receptor B1 (SR-B1) and catabolism of mature HDL-C into

bile or small HDL-C particles by hepatic lipase (HL). Apo B-containing lipoproteins can be

acquired by the LDL-receptor (LDLr) for hepatic catabolism.

High density lipoprotein cholesterol: an evolving target of therapy in the management of

cardiovascular disease

Fig. 1: Postprandial lipoprotein metabolism in diabetes. Insulin resistance plays a central role

in the development of diabetic dyslipidemia. Under normal physiologic conditions, insulin

suppresses lipolysis from adipose tissue and hepatic very low density lipoprotein (VLDL)

production. However, hyperinsulinemia in the postprandial state and insulin resistance in type

2 diabetes initiates a dyslipidemic triad of high triglyceride, low high-density lipoprotein

(HDL) cholesterol and high small, dense low-density lipoprotein (LDL) levels. Prolonged

residence of triglyceride-rich lipoproteins (TRLs) in the circulation promotes the transfer of

HDL or LDL cholesteryl esters for triglyceride, mediated by cholesteryl ester transfer protein

(CETP). LDL can undergo hydrolysis by hepatic lipase (HL) or lipoprotein lipase (LPL),

which hydrolyzes triglycerides from the core of LDL, resulting in production of smaller,

denser particles. Moreover, triglyceride-enriched HDL particles become smaller, denser(HDL 3b and 3c) and are more rapidly catabolized, contributing to low plasma HDL in
http://www.pubmedcentral.nih.gov/picrender.fcgi?blobtype=pdf&artid=2464766http://www.pubmedcentral.nih.gov/picrender.fcgi?blobtype=pdf&artid=2464766http://www.pubmedcentral.nih.gov/picrender.fcgi?blobtype=pdf&artid=2464766http://www.pubmedcentral.nih.gov/picrender.fcgi?blobtype=pdf&artid=2464766http://www.pubmedcentral.nih.gov/picrender.fcgi?blobtype=pdf&artid=2464766


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insulin resistance and type 2 diabetes. apo apolipoprotein; CM chylomicron; FFA free fatty

acid; RLP remnant lipoprotein

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