Coronary heart disease and it

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Coronary heart disease and its relation to high
cholesterol levels C1 like protein to reduce the
risk of development of Coronary heart disease.
Tina Fregeolle Bio 475
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Contents

• American diet in perspective
• Coronary heart disease diet
• Coronary heart disease high LDL levels
• Methods for lowering cholesterol
• Niemann-Pick C1 like 1 protein
• Conclusion

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American Diet

• American diet is 35-40 fat
• 15-20 is saturated fat
• A typical American diet contains substantial
  amounts of cholesterol
• egg yolkes
• liver
• meats
• some shellfish
• whole milk dairy products
• Mayfield, 1994

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Cholesterol as an important dietary components

• Cholesterol is required
• cell membrane fluidity
• steroid hormones biosynthesis
• bile acids production
• Weakly amphipathic
• Travels around the body in lipoproteins

Simons, 2000
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Cholesterol as an important dietary components
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Dietary cholesterol is absorbed

• Dietary cholesterol absorption occurs in the
  small intestine
• Travels around body in chylomicrons

Altmann, 2004
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Biosynthesis of cholesterol

• Cholesterol is primarily produced in the liver
• Cholesterol is derived from acetate
• Cholesterol production is highly regulated and is
  determined by the amount of dietary cholesterol

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Cholesterol is transported in lipoproteins
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HDL- Cholesterol

• High density lipoprotein
• contains the good cholesterol
• HDL- carries cholesterol away from the arteries
  back to the liver
• Slows plaque build up
• HDL Levels
• Over 60 mg/dL is optimal
• Below 40 mg/dL is alarming0
• Protects against heart attack at high levels

Simons, 2000
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LDL Cholesterol

• Low Density Lipoprotein
• contains the bad cholesterol
• High amounts of LDL circulating in the blood
  predispose to atherosclerosis, heart attacks, or
  stroke
• LDL Levels
• Optimal Less than 100 mg/dL
• Borderline 100-159 mg/dL
• High Greater than 160 mg/dL
• High levels of LDL increased risk of heart
  disease

Simons, 2000
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Cholesterol levels

• Total blood cholesterol
• Desirable- less that 200 mg/dL
• Borderline high risk- 200-239 mg/dL
• High risk- 240 mg/dL
• High cholesterol is the primary risk factor for
  coronary heart disease

Simons, 2000 Istvan, 2001
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Coronary heart disease

• Major problem in developed countries
• Coronary heart disease is the leading cause of
  death in America
• 57 of American adults have borderline high or
  high total cholesterol
• High levels of LDL cholesterol is a major risk
  factor for coronary heart disease

Istvan, 2001 Mayfield,1994 Koba, 2005
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Current methods used to lower cholesterol

• Diet and exercise
• Statins
• HMG-CoA Reductase inhibitors
• Azetidinone
• Ezetimibe
• Niemann-Pick C1 like 1 protein

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Statins

• The most widely use treatment for high
  cholesterol
• Competitively inhibits HMG-CoA Reductase

Schachter, 2004
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Azetidinone

• Inhibit the absorption of dietary and biliary
  cholesterol
• Zetia

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Altmann, SW, H.R. Davis, L.J. Zhu, X. Yao, L.M.
Hoos, G. Tetzloff, S.P. Iyer, M. Maguire, A.
Golovko, M. Zeng, L. Wang, N. Murgolo, M.P.
Graziano.2004.Niemann-pick C1 like 1 protein is
critical for intestinal cholesterol absorption.
Science. 3031201-1204.

• Niemann-pick C1 like 1 protein is critical for
  intestinal cholesterol absorption.

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Objective

• Better understand the molecular mechanism of
  cholesterol absorption in the small intestines
• To see in NPC1L1 plays a important role in this
  mechanism

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NPC1L1

• NPC1L1 Niemann-Pick C1 Like 1 Protein
• Plays a critical role in the absorption of
  intestinal absorption
• The expression is found in greatest concentration
  within the brush border membrane of the
  enterocytes of the small intestines

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Tissue Distribution and localization of NPC1L1
mRNA

• The NPC1L1 mRNA expression in 15 tissues from
  rat, mouse, and human was assessed
• RT-PCR
• microarray hybridization
• In all three species the small intestines showed
  the highest levels of mRNA expression

Altmann, 2004
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(No Transcript)
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Localization of NPC1L1 mRNA in the small
intestines

• Cholesterol absorption occurs
• duodenum
• proximal jejunum
• NPC1L1 mRNA expression along the duodenum-ileum
  axis
• The levels of NPC1L1 mRNA varied in different
  segments of rat intestine
• Largest expression in the proximal jejunum
• The levels of NPC1L1 protein was compared by the
  western blot reiterated the distribution pattern
  seen with the mRNA

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Localization of NPC1L1 mRNA in the small
intestines
Altmann, 2004
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Cell specific expression of NPC1L1 mRNA in rat
jejunum

• The NPC1L1 mRNA and protein expression in the
  jejunum was only found within the enterocyte
• NPC1L1 is located within the epithelial layer
  bordering the luminal space along the
  crypt-villus axis.
• And the NPC1L1 protein expression was observed
  closest to the luminal space.

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Cell specific expression of NPC1L1 mRNA in rat
jejunum
Anti-sense Sense
Anti-sense Sense
Altmann, 2004
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Cell specific expression of NPC1L1 mRNA in rat
jejunum

• The western blot analysis
• NPC1L1 expression in enterocytes from the
  proximal jejunum
• Not found within the distal ileum region

Altmann, 2004
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Intestinal expression of NPC1L1 mRNA and protein
in homozygous mutant, homozygous normal and
heterozygous mice

• Compared homozygous mutant, homozygous normal,
  heterozygous mice
• Homozygous normal and heterozygous mice showed
  NPC1L1 mRNA and protein expression in the jejunal
  enterocytes
• Homozygous mutant mice
• showed no detectable NPC1L1 expression
• showed no physical or developmental differences
  from the other mice
• No differences between the three types of mice in
  plasma cholesterol and triglyceride levels

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Intestinal expression of NPC1L1 mRNA and protein
in homozygous mutant, homozygous normal and
heterozygous mice
Altmann, 2004
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Cholesterol absorption in NPC1L1 homozygous
mutant, homozygous normal, and heterozygous mice

• Compared the uptake of orally administered
  radiolabel cholesterol in the three mouse types
• Using the fecal excretion
• Mice were feed a cholesterol chow diet
• Cholesterol absorption
• Heterozygous mice absorbed 45
• Homozygous normal mice absorbed 51
• Homozygous mutant mice absorbed only 15.6

Standard diet
Altmann, 2004
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Cholesterol absorption in NPC1L1 homozygous
mutant, homozygous normal, and heterozygous mice
1 Sodium Cholic diet

• A similar reduction was observed in mice lacking
  the bile acid synthetic enzymes
• Mice feed with a diet containing 0.1 cholic acid
  
• The cholesterol absorption increased
• Homozygous normal mice absorption was 66
• Heterozygous mice absorption was 52
• No effect in the homozygous mutant mice

Altmann, 2004
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Cholesterol reduction with azetidinone drug

• Azetidinone drugs, ezetimibe, work by inhibiting
  the absorption of dietary and binary cholesterol
• Cholesterol absorption
• Homozygous normal mice the drug lowered
  cholesterol absorption
• Heterozygous mutant mice there was no change in
  the cholesterol absorption
• NPC1L1 plays an essential role in the ezetimibe
  pathway
• Within the study the cholesterol absorption was
  reduced by 86 and intestinal uptake was
  inhibited by 72
• Triglyceride absorption
• Not changed in the homozygous mutant mice
• Enterocyte cholesterol uptake resulted in a 3.3
  fold up-regulation of the mRNA encoding the
  cholesterol synthesis enzyme HMG-CoA sythase in
  the intestine
• Caused an up-regulation of hepatic HMG-CoA
  sythase mRNA
• Responsible for the normal plasma cholesterol
  levels

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Cholesterol reduction with azetidinone drug
Altmann, 2004
Altmann, 2004
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Conclusion

• NPC1L1 is critical for the uptake of cholesterol
  across the plasma membrane of the intestinal
  enterocyte
• NPC1L1 may be associated with the molecular
  target of ezetimibe drugs
• Cholesterol active transport of cholesterol may
  have many different cofactors

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References

• Altmann, S.W., et al. Niemann-pick C1 like 1
  protein is critical for intestinal cholesterol
  absorption. Science. 2004 303. p. 1201-1204
• Gould, A.L., et al. Cholesterol reduction yields
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• Istvan, E. S. and Deisenhofer, J. Structural
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  among Korean adults the 2001 Korea national
  health and nutrition examination survey.
  International Journal of Cardiology. 2005.
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• Koba, S. , et al. Significance of small dense
  low-density lipoprotein- cholesterol
  concentrations in relation to the severity of
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• Mayfield, E. A Consumers Guide to Fats. FDA
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