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1) OBESITY & high plasma triglycerides Adipose cells, adipocytokines . . White fat cells store a large lipid droplet of triglycerides and cholesteryl ester.

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1 obesity high plasma triglycerides adipose cells adipocytokines l.jpg
1) OBESITY & high plasma triglyceridesAdipose cells, adipocytokines

.

  • White fat cells store a large lipid droplet of triglycerides and cholesteryl ester.

  • Synthesise and secrete leptin167(aminoacids), peptide hormone, binds to receptors in hypothalamic nuclei “satiety center” regulates energy). Leptin signals a decrease in appetite. Prooxidant like fructose.

  • Adiponectin (244aa) , most abundant protein in adipocyte, (similar structure to TNFα) & released into the blood. Higherin females. Antioxidant.

  • adipocyte oxidative stress (insulin activates NADPH oxidase (Nox4)

  • body weight , mitoch.fatty acid oxidation,gluconeogenesis, insulin resistance. Insulin causes lipogenesis and fatty acid release ( fatty liver) .

  • Plasma adiponectin decr. & leptin incr. in obesity (promotes breast cancer).

  • Brown fat (babies) mitochondria make heat.


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Adipocyte dysfunction & Metabolic disease

  • Obesity due to overnutrition (high fat or sugar diet ) & inactivity causes metabolic disease .

  • Insulin resistance & diabetes mellitus

  • Hypertension

  • Hyperlipidemia , nonalcoholic steatohepatitis (NASH), alcoholic liver disease, chronic hepatitis, liver cancer

  • Therapy: caloriesexercise,taurine,salicylate,thiazolidinediones,

  • Research : how to increase adiponectin levels

  • J.Gastroenterol(2008)43,811-822,Clinical Chemistry (2008)54,945-55


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Fatness increases cancer risk

  • Fatness cancer rate may exceed cancer from smoking soon.

  • Breast cancer, esophagus, colorectal, pancreas, ovary.

  • gall bladder,endometrium, liver (after cirrhosis) NASH.

  • NOT prostate,bladder, mouth, lung, skin, cervix, nasopharynx,skin cancer

  • Associated with energy-dense foods,fast food,sugary drinks,sedentary living,TV/computers.

  • 2007 WCRF/AICR report


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Adipocyte dysfunction & Metabolic disease

  • Obesity due to overnutrition (high fat or sugar diet ) & inactivity causes metabolic disease .

  • Cancer rate may exceed that from smoking in 10y!

  • Insulin resistance & diabetes mellitus

  • Hypertension

  • Hyperlipidemia , nonalcoholic steatohepatitis (NASH), alcoholic liver disease, chronic hepatitis, liver cancer

  • Therapy: caloriesexercise,taurine,salicylate,thiazolidinediones,

  • Research : how to increase adiponectin levels?

  • J.Gastroenterol(2008)43,811-822,Clinical Chemistry (2008)54,945-55


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Figure 1 Following chronic alcohol ingestion, endotoxin is released from certain intestinal bacteria. Endotoxin moves from the gut into the bloodstream and the liver where it activates Kupffer cells- a type of immune cell (resident liver macrophages) - by interacting with CD14 causing nuclear factor kappa B (NFκB) production.This generates superoxide radicals (O2) and various signaling molecules (the cytokine TNF–α) which injures hepatocytes. (Alcohol Res Health. 2003; 27(4):300-6.)


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2) High plasma cholesterol and atherosclerosis

Clinical chemistry

Fat Absorption

Liver cell synthesis of LDL and HDL

Cholesterol Synthesis

Drug Therapy

Fibroblasts and other extrahepatic tissues for membrane biosynthesis

Atherosclerosis

Genetic Disorders


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Lipoproteins, Cholesterol and Atherosclerosis

  • A) Clinical chemistry - Lipoproteins

  • Conjugated proteins in which the prosthetic group

  • are lipids

  • Responsible for the transport and distribution of

  • lipids:

  • - Lipid hormones

  • - Lipids absorbed by the intestine

  • - Fat-soluble vitamins


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Plasma cholesterol >6.2mM (change diet); 5.5-6.2mM (borderline); <5.5mM normal

Percent contribution of cholesterol and saturated fat from fats/oils,

meats, dairy products and eggs in the US diet.

Biochim. et Biophys. Acta 1529 (2000) 310-320


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A lipoprotein: (borderline); <5.5mM normal

Horton Fig 17-5


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B) Stage 1 - Fat Absorption (borderline); <5.5mM normal

  • Chylomicrons

  • Found in lymph draining the intestine not hepatic

  • portal systems

  • Largest ones are microscopically visible (diameter

  • 500 nm) (floats upon centrifugation)

  • Responsible for the lipemic (milky turbidity) of the

  • blood following food digestion and disappears at 5 hours

  • Contains 1% protein - formed by intestinal cell

  • triglycerides (apo AI and II, B)


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Dietary cholesterol (borderline); <5.5mM normal chylomicron & HDL formed in intestinal epithelial cell

 remnant  lymph vessel taken up by adipose cells & extrahepatic tissues

B48 M.W. = 300,000

(chylomicrons,

chylomicron remnants)


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C) (borderline); <5.5mM normalStage 2 : LDL activity and function

LDL(apoB100) synthesised by liver moves cholesterol to the tissues (taken up by the apoB100 receptor of tissues).

LDL carries 75% plasma cholesterol and HDL carries 25%.


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Liver cell synthesis of LDL,VLDL and HDL (borderline); <5.5mM normal

B-100

A,C,E

i.e. LDL, VLDL, HDL


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Electron micrograph of a (borderline); <5.5mM normal

part of a liver cell actively

engaged in the synthesis

and secretion of very low

density lipoprotein

(VLDL). The arrow points

to a vesicle that is releasing

its content of VLDL

particles.

Liver mitochondrial fatty acid oxidation inhibited by some drugs causing FATTY LIVER

10


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F) Stage 3- Fibroblasts and other extrahepatic tissues - cholesterol taken up

for membrane biosynthesis

Extrahepatic tissues obtain cholesterol from plasma LDL & NOT by synthesis

STEPS:

a) ApoB100 protein of LDL binds to receptor in coated

pits

b) Receptor-LDL complex is internalised by endocytosis

c) Vesicles containing LDL fuse with lysosomes (proteases, esterases)

proteases

LDL Protein amino acids

LDL Cholesterol esters cholesterol + fatty acid

LINOLEATE

esterases

LDL receptor returns to plasma membrane

(10min. - turnover ever 24 hours)


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Steps (cont’d) cholesterol taken up

d) Free cholesterol in the cell is used or stored

Cholesterol

Membrane biosynthesis

+ Linoleate

Cholesterol ester

i.e., store for cholesterol

Acyl-CoA: cholesterol acyl transferase

Regulation:

When excess, the synthesis of new LDL receptors is stopped, therefore LDL not taken up by cells


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The LDL receptor cholesterol taken up

The LDL receptor consists

of five domains with

different functions: an

LDL-binding domain, 292

residues; a domain bearing

N-linked sugars, 350

residues; a domain bearing

O-linked sugars, 58

residues; a membrane-

spanning domain, 22

residues; and a cytosolic

domain, 50 residues.

Membrane

spanning

domain


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Mutations affecting LDL receptors cholesterol taken up

1) no receptor is synthesised

2) receptors are synthesised but lack signals for transport

 don’t reach plasma membrane

3) receptors reach cell surface but don’t bind LDL

normally

4) receptors don’t cluster in coated pits


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Genetic disorders cholesterol taken up

e.g. Familial hypercholesterolemia (Type II)

- Autosomal dominant trait 1:500

- Cholesterol 680 mg/100 mL instead of 175 mg/100 mL

- Die of heart disease before 20 years (homozygous)

- Die of heart disease before 40 years (heterozygous– inherit one defective

and one normal gene)

1.LDL receptor is unable to bind to coated pitsrandomly distributed

in membrane LDL binds but can’t be absorbed by endocytosis

2. Faulty LDL receptor formed which can’t bind LDL


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Extrahepatic tissues take up cholesterol via LDL receptors cholesterol taken up

e.g. fibroblasts and stored as cholesterol esters in lysosomes

Voet et al., Fig 19-37


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Cholesterol Ester Synthesis cholesterol taken up

Endoplasmic reticulum


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LYSOSOMES cholesterol taken up

Autophagic vacuole

Aged proteins,

Nucleic acids,

lipids

NADH

FAD

Acid proteases (cathepsins)

Cholesterol ester esterase

Nucleases

Acid phospholipases

Require acid pH

ROS

Cyt b5

Amino acids

Cholesterol

Nucleotides

Fatty acids

CoQ

H+

ACID pH

Stores dietary CoQ

CoQ reduction maintains acid pH

Arch Biochem Biophys. 375, 347-54, (2000).


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G) Atherosclerosis - metabolic biochemistry cholesterol taken up

An atherosclerotic plaque

(marked by the arrow)

blocks most of the lumen of

this blood cell. The plaque

is rich in cholesterol.



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D) Stage 4 HDL : Reverse cholesterol transport and function cholesterol taken up

1. HDL is synthesised and secreted from the liver and the intestine. HDL contains 65% protein + free fatty acids, cholesterol, triacylglyceride and phospholipids.

2 Function:

HDL picks up cholesterol released into the plasma from dying cells

and from membranes undergoing turnover and returns it to the liver

3. HDL contains cholesterol, cholesterol ester, phospholipid and Lecithin:Cholesterol Acyl Transferase (LCAT) - synthesised in the liver that catalyses :

LECITHIN + CHOLESTEROL

 LYSOLECITHIN + CHOLESTEROL ESTER

LCAT is activated by apo-A1 and deficiency in LCAT means that HDL can’t take up cholesterol from tissue, therefore  cholesterol and lecithin in tissue


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Raising HDL to decrease tissue cholesterol cholesterol taken up

  • Niacin best

  • Fibrate drugs

  • bile acid binding resins

  • Exercise , -3 fatty acids,red wine,orange juice,beans, soy,oat bran

  • Not trans fatty acids, high carbohydrates


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E) Cholesterol synthesis cholesterol taken up

Step 1 Mitochondria

Biochim. et Biophys. Acta. 1529 (2000) 89-102.


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Step 2 cholesterol taken up

Synthesis of isopentenyl

pyrophosphate from

Mevalonate occurs in the cytosol

Stryer Fig 27-12

J Biol Chem. 271, 1784-8 (1996)


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Step 3 cholesterol taken up

Synthesis of squalene occurs in the cytosol

then the e.r.

peroxisome

peroxisome

e.r.

Squalene synthase DIMERIZATION

CoQ

dolichol

J Biol Chem. 271, 1784-8 (1996)


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Step 4 cholesterol taken up

Squalene

Synthesis of cholesterol occurs in the ER

P450, O2, NADPH

Squalene epoxide

cyclase

Lanosterol

diet

sunlight

Dehydrocholesterol

Vitamin D3

NADPH

P450 reductase

Unsat. Fa acyl CoA

+cholesterol acyltransferase

(ACAT)

CHOLESTEROL

Cholesterol ester


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F) Drug therapy to decrease plasma cholesterol cholesterol taken up

i) The STATINS inhibit cholesterol biosynthesis to decrease plasma LDL cholesterol and cut the risk of heart attacks and strokes by at least 33% even in people with normal cholesterol. Several million Canadians are taking statins.

HMG CoA reductase inhibitors but can induce rhabdomyolysis

Lipitor (Atorvastatin;Pfizer); Zocor (Simvastatin prodrug; Merck)

Crestor (Rosuvastatin; AstraZeneca) lowers risk of heart attack, death and stroke

Merck: Lovastatin:40-80 mg/day, Squibb: Pravastatin: 20mg/day for female patients - best for persons with sleep disorders; need hepatocyte enzyme to open up lactone ring.

3-hydroxy-3-methyl-

glutaryl CoA

Mevinolin

Mevinolin (Fungal), a competitive inhibitor of HMG CoA reductase, resembles 3-hydroxy-3-methyl-glutaryl CoA, the substrate.

Pravastatin (from Penicillin) - hepatotoxic (rare), (intestinal metabolism inhibited by grapefruit juice)


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But Statins may decrease plasma ubiquinone antioxidant cholesterol taken up

HMG-CoA

Isopentenyl-PP

TYROSINE

Dimethylallyl-PP

Peroxisome

4-OH-benzoate

Geranyl-PP

ER, Golgi

Decaprenyl-

4-OH

benzoate

transf.

Polyprenyl-PP

Farnesyl-PP

Decaprenyl-PP

trans-prenyltransf.

Squalene

synthase

Dolichol

N-glycosylates secretory

proteins = Export glycoproteins

Decaprenyl-4-OH-benzoate

Squalene

 cholesterol

 LDL receptors (induced)

 LDL uptake  LDL

 risk of atherosclerosis

Coenzyme Q

Cholesterol

Free Rad. Biol. Med. 29, 285-94 (2000)

Lancet 356, 391-5 (2000)


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  • ii) BILE ACID BINDERS cholesterol taken up

  • Cholesterol is reabsorbed from intestine by forming complexes with bile acids. Liver then replaces bile acids by oxidising cholesterol (catalysed by CYP7A).

  • a) Prescription therapeutic resins bind bile acids and prevent cholesterol reabsorption: problem of constipation, ↓absorption of fat sol. vitamin A,D,E,K

  • e.g. colestipol 20g/day taken mixed with juice or apple sauce

  • cholestyramine

  • colesevelam

  • b) Nonprescription bulk forming laxatives (soluble fibres)

  • Psyllium husks (metamucil)

  • Ispaghula husks

  • Oat bran (-glucan binds bile acids )

  • Action of bile acid binders

  •  cholesterol excretion

  •  hepatic cholesterol 7a hydroxylase (CYP7A) activity which oxidises cholesterol to bile acids. (feedback inhibitor is normally bile acids)


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BILE ACID SYNTHESIS BY LIVER cholesterol taken up

Endoplasmic reticulum (except CYP27)

Biochemistry. 31, 4737-49, (1992)


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BILE ACID SYNTHESIS BY LIVER (cont) cholesterol taken up

Then efflux into bile and stored in gall bladder.

Then released by bile duct into upper-small intestine (ileum).

Then metabolised (deconjugation (CO2), dehydroxylation) by anaerobic bacteria

of colon to deoxycholate, lithocholate, urodeoxycholate.

Then actively reabsorbed and recirculates via liver 8 times / day.


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iii) Hypolipidemic ie antihyperlipidemic FIBRATE drugs cholesterol taken up

Clofibrate: 2g/day

(also: Gemfibrozil)

1. ↑ lipoprotein lipase activity

2. ↑ fatty acid oxidation by inducing

PEROXISOMES

 serum triglycerides

 serum triglyceride-rich lipoprotein

3.Antioxidant action prevent LDL oxidation


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PEROXISOME cholesterol taken up (numerous genetic diseases)

Peroxisomal fatty acid b-oxidation forms H2O2 which is removed by catalase that is also located in the peroxisomes . Medium-chain fatty acids (C8-18) prefer mitochondrial b-oxidation that doesn’t form H2O2 .

Long chain or 3 or branched fatty acids

MITOCHONDRIA

b-oxidation

Acyl

carnitine

Synthase

Acetyl CoA

oxidase*

Shorter-chain fatty acid

Fatty acyl CoA

NADH

+

Acetyl CoA

O2

H2O2

heat

catalase

Cholesterol

CoQ10*

Bile acids

H2O + O2

H2O2 also formed by peroxisomal glycolate/glyoxylate oxidases,

xanthine oxidase, uricase

* Peroxisomes induced by peroxisome proliferators via a cytosolic receptor (PPAR)

e.g., hypolipidemic drugs, e.g., clofibrate; plasticizers, e.g., phthalate (DEHP); endogenous steroids formed by the adrenal glands e.g., dehydroepiandrosterone.

Ann Rev Biochem. 61, 157-97 (1992)

Ann Rev Nutr. 14, 343-70 (1994)


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iv. cholesterol taken up NIACIN(Vitamin B3)

  • Deficiency (maize,indian millet) causes pellagra (rough photosensitive skin, dementia ,GI).

    Flour now fortified with niacin ; B 1 thiamine; B2 riboflavin

    tryptophan niacin nicotinamide NAD  NADP NADPH

  • Niacin 1.5-3g/day ↓ plasma LDLcholesterol & triglycerides; best for ↑ HDL (not nicotinamide)

    but early hot flashes, rare hepatotox., rare hyperglycemia


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NIACIN INHIBITS cholesterol taken up 1) DGAT (Synthesizes triglycerides, 2) Fatty Acyl CoA Synthase

AND 3) Blocks HDL uptake, 4) Prevents LDL Oxidation

Daniel Meyers Current Opinion in Lipidology 2004, 15: 659-665


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v.Blocking intestinal cholesterol permease cholesterol taken up

  • Ezetimibe , a new drug that blocks cholesterol uptake by inhibiting intestinal sterol permease (packaged with a statin).

  • Plant sterols eg sitosterol , a natural method


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Non prescription ways of preventing cholesterol absorption cholesterol taken up

Plant sterol/stanols

H

O

SITOSTEROL

(a sterol)

H

O

SITOSTANOL

(a stanol)

Cholesterol lowering action of plant sterols in the diet

H

H

H

Plant sterol not absorbed by gut (2g/day) and inhibit gut absorption of cholesterol)

(ester in “functional margarine”eg Benecol,Take Control)

H

H

H


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vi Natural ways of binding dietary cholesterol to prevent absorption

  • Chitosan (shellfish exoskeleton) (LIBRACOL is polychitosamine: amine groups bind cholesterol)

  • Policosanol (sugar cane wax or rice wax alcohol ie. octacosanol CH3(CH2)26CH2OH)


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CONCLUSIONS absorption

  • DIETARY WAYS OF DECREASING THE ATHEROSCLEROSIS RISK:

    •  cholesterol and saturated fatty acids

       plant stanols

    •  polyunsaturated fatty acids

    • which  cholesterol oxidation to bile acids

      •  LDL catabolism

      •  cholesterol excretion into intestine

    • 3. smoking, obesity, lack of exercise, low Ca2+

    • high HDL in premenopausal women protects

    • but not after menopause.


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Dietary mechanisms to decrease cholesterol are additive (e.g., in patients resistant or intolerant to statins).

  • Bind bile acids to viscous fibres, e.g., oats (b-glucan), barley, psyllium (metamucil), eggplant, okra.

  • Competitive inhibition of cholesterol absorption from the gut, e.g., plant sterols (stanols) margarine, almonds, flaxseed.

  • Inhibit cholesterol synthesis and esterification, e.g., soy proteins, garlic (diallyl disulfide)

  • Increase LDL receptor-mediated LDL cholesterol uptake and degradation, e.g., soy proteins.

  • Decrease oxidized LDL using antioxidants, e.g., almonds (Vit E), soy proteins (isoflavones).

    Risk factor modification center, St. Michael’s Hospital, Toronto

Metabolism 51(12):1596-1604 (2002)


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