1 obesity high plasma triglycerides adipose cells adipocytokines
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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
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.
adipocyte dysfunction metabolic disease
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
fatness increases cancer risk
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
adipocyte dysfunction metabolic disease4
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
slide5

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.)

2 high plasma cholesterol and atherosclerosis

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

slide7

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
slide8

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

slide9

A lipoprotein:

Horton Fig 17-5

slide11

B) Stage 1 - Fat Absorption

  • 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)
slide12

Dietary cholesterol  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)

slide13

C) Stage 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%.

slide14

Liver cell synthesis of LDL,VLDL and HDL

B-100

A,C,E

i.e. LDL, VLDL, HDL

slide15

Electron micrograph of a

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

slide16

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)

slide17

Steps (cont’d)

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

slide18

The LDL receptor

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

slide19

Mutations affecting LDL receptors

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

slide20

Genetic disorders

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

slide21

Extrahepatic tissues take up cholesterol via LDL receptors

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

Voet et al., Fig 19-37

cholesterol ester synthesis
Cholesterol Ester Synthesis

Endoplasmic reticulum

slide23

LYSOSOMES

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).

slide24

G) Atherosclerosis - metabolic biochemistry

An atherosclerotic plaque

(marked by the arrow)

blocks most of the lumen of

this blood cell. The plaque

is rich in cholesterol.

slide27

D) Stage 4 HDL : Reverse cholesterol transport and function

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

raising hdl to decrease tissue cholesterol
Raising HDL to decrease tissue cholesterol
  • 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
slide29

E) Cholesterol synthesis

Step 1 Mitochondria

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

slide30

Step 2

Synthesis of isopentenyl

pyrophosphate from

Mevalonate occurs in the cytosol

Stryer Fig 27-12

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

slide31

Step 3

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)

slide32

Step 4

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

slide33

F) Drug therapy to decrease plasma cholesterol

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)

slide34

But Statins may decrease plasma ubiquinone antioxidant

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)

slide35

ii) BILE ACID BINDERS

  • 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)
slide36

BILE ACID SYNTHESIS BY LIVER

Endoplasmic reticulum (except CYP27)

Biochemistry. 31, 4737-49, (1992)

slide37

BILE ACID SYNTHESIS BY LIVER (cont)

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.

slide38

iii) Hypolipidemic ie antihyperlipidemic FIBRATE drugs

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

slide39

PEROXISOME (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)

iv niacin vitamin b 3
iv. 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

slide41

NIACIN INHIBITS 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

v blocking intestinal cholesterol permease
v.Blocking intestinal cholesterol permease
  • Ezetimibe , a new drug that blocks cholesterol uptake by inhibiting intestinal sterol permease (packaged with a statin).
  • Plant sterols eg sitosterol , a natural method
slide43

Non prescription ways of preventing cholesterol absorption

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

vi natural ways of binding dietary cholesterol to prevent absorption
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)
slide45

CONCLUSIONS

  • 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.
slide46
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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