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Coronary heart disease and it’s relation to high cholesterol levels: C1 like protein to reduce the risk of development of Coronary heart disease.

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. 303:1201-1204.

Tina Fregeolle

Bio 475

contents
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
american diet
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

cholesterol as an important dietary components
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

dietary cholesterol is absorbed
Dietary cholesterol is absorbed
  • Dietary cholesterol absorption occurs in the small intestine*
  • Travels around body in chylomicrons

*Altmann, 2004

biosynthesis of cholesterol
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
hdl cholesterol
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 alarming*0
  • Protects against heart attack at high levels*

*Simons, 2000

ldl cholesterol
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

cholesterol levels
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

coronary heart disease
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

current methods used to lower cholesterol
Current methods used to lower cholesterol
  • Diet and exercise
  • Statins
      • HMG-CoA Reductase inhibitors
  • Azetidinone
      • Ezetimibe
      • Niemann-Pick C1 like 1 protein
statins
Statins
  • The most widely use treatment for high cholesterol
  • Competitively inhibits HMG-CoA Reductase*

*Schachter, 2004

azetidinone
Azetidinone
  • Inhibit the absorption of dietary and biliary cholesterol
      • Zetia
tissue distribution and localization of npc1l1 mrna
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

localization of npc1l1 mrna in the small intestines
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

Altmann, 2004

localization of npc1l1 mrna in the small intestines1
Localization of NPC1L1 mRNA in the small intestines
  • The levels of NPC1L1 protein was compared by the western blot reiterated the distribution pattern seen with the mRNA

Altmann, 2004

cell specific expression of npc1l1 mrna in rat jejunum
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.
cell specific expression of npc1l1 mrna in rat jejunum2
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

slide22
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
slide23
Intestinal expression of NPC1L1 mRNA and protein in homozygous mutant, homozygous normal and heterozygous mice

Altmann, 2004

cholesterol absorption in npc1l1 homozygous mutant homozygous normal and heterozygous mice
Cholesterol absorption in NPC1L1 homozygous mutant, homozygous normal, and heterozygous mice
  • Compared the uptake of orally administered radiolabel cholesterol in the three mouse types
  • 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 %

Altmann, 2004

cholesterol absorption in npc1l1 homozygous mutant homozygous normal and heterozygous mice1
Cholesterol absorption in NPC1L1 homozygous mutant, homozygous normal, and heterozygous mice
  • 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

cholesterol reduction with azetidinone drug
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
conclusion
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
references
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 clinical benefit: a new look at old data. Circulation, 1995. p 2274-2282.
  • Istvan, E. S. and Deisenhofer, J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001: 292 p 1160-1164
  • Ko, M., Kim, M.T., and Nam, J.J. Assessing risk factors heart disease and its risk prediction among Korean adults: the 2001 Korea national health and nutrition examination survey. International Journal of Cardiology. 2005. p7870-7877
  • Koba, S. , et al. Significance of small dense low-density lipoprotein- cholesterol concentrations in relation to the severity of coronary heart disease. Arthrosclerosis. 2005. p 9320-9329
  • Mayfield, E. A Consumer’s Guide to Fats. FDA Consumer. May 1994. p 15-19.
  • Schachter, Michael. Chemical, pharmacokinetic and pharmacodynamic properties of statins. Clinical pharmacology. 2004: 19. p 117-125.
  • Schwartz, G., et al. Efficacy and safety of rosuvastatin and atorvastation in patients with hypercholesterolemia and a high risk of coronary heart disease: a randomized, controlled trial. American Heart Journal. 2004 . 148 (1).
  • Simons, K. and Ikonen, E. How cells handle cholesterol. Science. 2000:290. p 1721-1726