Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

108 cetp expression

SHAPE Society

Related Books

Free with a 30 day trial from Scribd

See all

Related Audiobooks

Free with a 30 day trial from Scribd

See all
  • Be the first to comment

  • Be the first to like this

108 cetp expression

  1. 1. Cholesteryl Ester Transfer Protein (CETP) Expression Prevents Diet- Induced Atherosclerotic Lesions in Male db/db Mice Paul S. MacLean1 , Joseph F. Bower1 , Satyaprasad Vadlamudi1 , Jody N. Osborne2 , John F. Bradfield2 , Hubert W. Burden3 , William H. Bensch4 , Raymond F. Kauffman4 , Hisham A. Barakat1 Departments of Biochemistry1 , Comparative Medicine2 , and Anatomy and Cell Biology3 , in the Brody School of Medicine, East Carolina University, Greenville, NC, 27858; Lilly Research Laboratories4 , a Division of Eli Lilly and Company, Indiannapolis, IN, 46285
  2. 2. Cholesterol Ester Transfer Protein • Structural Information – Plasma glycoprotein, 4 glycosylation sites – 2.2 kb mRNA, alternative splicing • Functional Information – Catalyzes the heteroexchange of neutral lipids between the plasma lipoproteins • Can modulate the composition and concentration of the lipoproteins. • Important role in Reverse Cholesterol Transport.
  3. 3. HDLHDL CETPCETPHDLHDL VLDLVLDL TGTG TGTG CECE CECE LDLLDL CECE LiverLiver TGTG CECE HTGLHTGL TissuesTissues TGTG LPLLPL LDLRLDLR TissuesTissues CECE ABC1/ABC1/ LCATLCAT RCT LDLRLDLR CECE SRBISRBI
  4. 4. CETP and Vascular Health? • Anti-Atherogenic –Role in RCT, clearing peripheral cholesterol. – Foger et al, 1999; Zhong et al, 1996; Hayek et al, 1995; Breslow, 1995; Sakai et al, 1995; Hirano et al, 1995; Yamashita et al, 1995; Hennessy et al, 1993; Kinoshita et al, 1993; Stein et al, 1985; Morton, 1988. • Pro-Atherogenic –Lowers HDL-C, increases VLDL- C and LDL-C. – Rittershaus et al, 2000; Okamoto et al, 2000; Mabuchi et al, 1995; Inazu et al, 1994; Marotti et al, 1993; Bhatnagar et al, 1993; Kinoshita et al, 1993; Agellon et al, 1992; Quinet et al, 1991.
  5. 5. Why Study CETP? • Perturbations in CETP expression could lead to abnormal lipid/lipoprotein profiles and contribute to vascular disease. – Excess or deficiency in CETP expression • CETP is viewed as a potential target in the treatment of vascular disease, a tool to modify atherogenic lipoproteins. – CETP inhibitors, activators
  6. 6. CETP and the Insulin Resistance Syndrome • IRS – dyslipidemia, obesity, diabetes, insulin resistance, vascular disease, hypertension, etc. • Alterations in CETP expression in IRS – elevated in obesity – type 2 diabetes?
  7. 7. Plasma CETP Activity and Mass 50 55 60 65 70 75 80 85 90 Activity nmol/mL/hr ♣ ♦ Values are given as means ± SEM (n). ♣ significantly different from the non-obese, p<0.001. ♦ significantly different from the obese, p<0.001. 1.5 1.75 2 2.25 2.5 Mass ug/mL ♦ ♣ (129) (95) (25) (20)(42)(57) Values are given as means ± SEM (n). ♣ significantly different from the non-obese, p<0.05. ♦ significantly different from the obese, p<0.05. Non-Obese Obese Obese NIDDM
  8. 8. How does Type 2 Diabetes influence the characteristics of Obese Patients? CVD Risk ↑ over twice the risk (Manson et al, 1990; Abbott et al, 1988) Lipid Abnormalities ↑ ↑TG, ↑LDL-C, ↓HDL-C (Barakat et al, 1990; Barakat et al, 1992) Lipoprotein Abnormalities ↑ ↓LDLs, ↓HDLs, ↑VLDLs (MacLean et al, 2000; Barakat et al, 1990-2) Plasma CETP Levels ↓ ~20%lower (MacLean et al, 2000; Kahri et al, 1994)
  9. 9. Purpose • To examine the effects of CETP overexpression on vascular health in a murine model of diabetic obesity (db/db).
  10. 10. Experimental Design CETP (+/+C/C) db/CETP (db/dbC/C) db (db/db-/-) Atherogenic Diet 16 Weeks lesions in the proximal aorta cholesterol distribution among lipoproteins (+/db-/C) (+/db-/C)
  11. 11. CETP Lesions found in: - 0/23 mice db Lesions found in: - 15/17 mice - (26,098 ± 7486 µm2 ) db/CETP Lesions found in: - 0/22 mice
  12. 12. Plasma Total Cholesterol 0 200 400 600 0 30 60 90 120 Days on Atherogenic Diet mg/dL CETP db db/CETP
  13. 13. 0 100 200 300 400 500 600 15 20 25 30 35 40 Elution Time, min Cholresponse,mV CETP db db/CETP VLDL IDL/LDL HDL FPLC Cholesterol Subfractioning
  14. 14. VLDL and IDL/LDL Cholesterol 0 20 40 60 80 100 0 30 60 90 120 Days on Atherogenic Diet v-sec VLDL Cholesterol 0 7 14 21 28 35 0 30 60 90 120 Days on Atherogenic Diet v-sec IDL/LDL Cholesterol CETP db db/CETP
  15. 15. Characteristics of the mice
  16. 16. Summary • The overexpression of CETP in db/db mice: –lowers total cholesterol concentrations –lowers the amount of cholesterol in VLDL and IDL/LDL subfractions –prevented the formation of diet-induced atherosclerotic plaques
  17. 17. Conclusions • In this murine model of diabetic obesity, CETP is clearly anti-atherogenic. • In the metabolic context of diabetic obesity in humans, CETP may play an important role in maintaining vascular health. • The suppressive effect of diabetes on CETP expression in obese humans may contribute to the higher risk of atherosclerosis.

    Be the first to comment

    Login to see the comments

SHAPE Society

Views

Total views

189

On Slideshare

0

From embeds

0

Number of embeds

1

Actions

Downloads

3

Shares

0

Comments

0

Likes

0

×