Cholesterol Metabolism

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Cholesterol Metabolism

• November 19, 2001
• (Only three more days to Thanksgiving)

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lecture topics

• Overview of cholesterol
• Cholesterol synthesis
• Regulation
• Cholesterol degradation and elimination
• Bile acids and bile salts
• Cholesterol/lipid trafficking/delivery
• Steroid hormones

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Top four reasons we need cholesterol???????
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Top four reasons we need cholesterol???????

• 1)
• 2)
• 3)
• 4)

• Membrane component- controls fluidity
• Precursor of bile acids and bile salts
• Precursor of steroid hormones
• Precursor of vitamin D

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major sources of liver cholesterol
Diet
Cholesterol synthesized in extrahepatic tissues
De novo synthesis
Conversion to bile acids/salts
Secretion of HDL and VLDL
Free cholesterol secreted in bile
major routes by which cholesterol exits liver
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structure of cholesterol
site of attachment of fatty acid in cholesterol
ester
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lecture topics

• Overview of cholesterol
• Cholesterol synthesis
• Regulation
• Cholesterol degradation and elimination
• Bile acids and bile salts
• Cholesterol/lipid trafficking/delivery
• Steroid hormones

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cholesterol biosynthesis

• 50 results from de novo synthesis

IQ gt 200
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cholesterol biosynthesis
_ _ _ _ _ _ - _ _ _
Precursor for cholesterol biosynthesis
CATEGORY

• Also requires NADPH and ATP
• Highly regulated process
• Occurs in the cytoplasm
• Cytosol
• Endoplasmic reticulum

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POLYSACCHARIDES (COMPLEX CARBOS)
LIPIDS
PROTEINS
glucose
fatty acids
amino acids
Glycolysis
ATP
pyruvate
Fatty acid biosynthesis
Cholesterol biosynthesis
acetyl-CoA
FADH2 and NADH (reducing power)
O2
tricarboxylic acid (TCA) cycle
oxidative phosphorylation
ATP
ATP
ATP
ATP
ATP
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the committed step!!!!
acetyl CoA acetoacetyl CoA
ketone bodies
3-hydroxy-3-methylglutaryl CoA HMG CoA
HMG CoA Reductase
Mevalonic acid
A bunch more steps
Cholesterol
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regulation of HMG CoA reductase

• Feedback inhibition
• Hormonal regulation
• Transcriptional regulation

Transcription of HMG CoA mRNA
Glucagon
(-)
Insulin
(-)
()
(-)
HMG CoA Reductase
Mevalonic Acid
HMG CoA
Cholesterol
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HMG CoA Reductase as a clinical target for statins

• lovastatin (Mevacor)
• Zocor
• Lipitor

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lecture topics

• Overview of cholesterol
• Cholesterol synthesis
• Regulation
• Cholesterol degradation and elimination
• Bile acids and bile salts
• Cholesterol/lipid trafficking/delivery
• Steroid hormones

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degradation of cholesterol

• Ring structure not metabolized
• Cholesterol eliminated by two means
• Conversion to bile acids (excreted in feces)
• Secretion into bile (transport to intestine)

Chenodeoxycholic Acid (45) Cholic Acid (31)
Cholesterol
OH
Liver
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bile

• Composed of
• Phosphatidyl choline (phospholipid)
• Bile salts
• Made in the liver
• common bile duct to duodenum
• stored in the gall bladder

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Bile Acid
Taurine
Glycine
Taurocholic Acid
Bile Salts
Glycocholic Acid
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enterohepatic circulation
duodenum
0.5 g/day
bile salts
Bile Duct
bile salts
bile acids
bile acids
Portal Vein
ileum
15/30 g bile salts(acids)/day circulate from
liver to intestine and back
Fecal excretion of 0.5 g/day
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clinical correlation

• cholesterol gallstone disease
• cholelithiasis
• treatment
• gall bladder removal
• chenodiol administration (chenodeoxycholic acid)

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lecture topics

• Overview of cholesterol
• Cholesterol synthesis
• Regulation
• Cholesterol degradation and elimination
• Bile acids and bile salts
• Cholesterol/lipid trafficking/delivery
• Steroid hormones

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cholesterol trafficking/delivery

• Plasma lipoproteins carry cholesterol and other
  lipids (triacylglycerols) throughout the body

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plasma lipoproteins

• Chylomicrons (Intestine)
• Very Low Density Lipoprotein
• VLDL (Liver)
• Low Density Lipoprotein
• LDL
• High Density Lipoprotein
• HDL

Phospholipid, Cholesterol Protein
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composition of plasma lipoproteins
90 TG 5 Chol 3 PL 2 Protein
60 TG20 Chol 15 PL 5 Protein
Chylomicrons
VLDL
8 TG 50 Chol 22 PL 20 Protein
5 TG 25 Chol 30 PL 40 Protein
LDL
HDL
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lipid uptake
lipoprotein lipase endocytosis
Chylomicrons, VLDLs
LDLs
Fatty acids
Fatty acids
Adipose Tissue
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clinical correlation

• Artherosclerosis (next Monday)
• Coronary heart disease
• Hyperlipidemia (lipase deficiency)

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lecture topics

• Overview of cholesterol
• Cholesterol synthesis
• Regulation
• Cholesterol degradation and elimination
• Bile acids and bile salts
• Cholesterol/lipid trafficking/delivery
• Steroid hormones

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steroid hormones

• glucocorticoids (cortisol)
• mineralcorticoids (aldosterone)
• androgens
• estrogens
• progestins

OH
OH
HO
O
Testosterone
Estradiol
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Congenital Adrenal Hyperplasias (CAH)
Cholesterol
NADPH, O2
desmolase
None of the steroids made, salt excretion, death
Pregnenolone
Progesterone
17-a-Hydroxyprogesterone
Testosterone
Aldosterone
Cortisol
Estradiol
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mechanism of steroid hormone action
mRNA transcription
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take home message

• cholesterol is essential (too much is bad)
• synthesis of cholesterol is carefully regulated
• HMG CoA Reductase
• cholesterol is not degraded but eliminated
  through bile
• cholesterol/lipid trafficking requires
  lipoproteins
• cholesterol is the precursor of steroid hormones

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Happy Thanksgiving!!!