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Effect of atorvastatin (Lipitor™) on VLDL-APOB and VLDL-triglyceride overproduction in vivo in an insulin resistant hamster model
POSTER ABSTRACTS
Results:
25
Method (x)
IRMA
Regression Slope Intercept sy/x r
1,09 ⫺0,14 53,8 0,97
Immuno 1
Axsym
Access
1,14 0,11 55,6 0,97
1,00 0,21 48,0 0,98
1,23 ⫺0,30 47,2 0,97
Samples ⱕ 5 g/L, ECi mean ⫽ 2,47 Eci-method mean ⫺0,01 0,38 p (Wilcoxon) 0,41 0,001
0,29 0,06
0,31 0,08
Conclusions: The systematic differences observed are of little significance. But, occasionally, we observed sample related differences between the five methods that are clinically significant. When changing methods, we recommend obtaining a baseline value with the new assay for patients being serially monitored.
24 DOWN-REGULATION OF THE NORMAL EPITHELIAL CELL-SPECIFIC 1 (NES1) GENE IS ASSOCIATED WITH UNFAVORABLE OUTCOME OF PROSTATE CANCER. Luo, L. Y., and Diamandis, E. P. Dept of Laboratory Medicine and Pathobiology, University of Toronto, Dept of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada Objectives: The Normal Epithelial Cell-specific 1 (NES1) gene encodes a novel serine protease, which is a new member of the expanding human kallikrein gene family. The NES1 gene was thought to act as a tumor suppressor gene. It has been found to be down-regulated in many established breast cancer cell lines. In order to investigate the role of NES1 gene in prostate cancer, we examined its expression at the mRNA level in 20 pair of normal and cancerous prostatic tissues. Methods: The NES1 expression levels between the cancerous prostatic tissue and its adjacent normal tissue were compared with the semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Results: Comparing the NES1 expression level between the cancerous prostatic tissue and its normal adjacent part, among these 20 pair of tissues, it was up-regulated in 8 pairs, down-regulated in 8 pairs and has no change in 4 pairs. However, among those 8 pairs that are upregulated, 7 pairs are R0positive (surgical margin negative). For those 8 pairs that are down-regulated, 7 pairs are R1 positive (surgical margin positive), indicating the down-regulation of NES1 is closely associated with R1 positive (p ⬍ 0.01). Conclusion: Considering R0 positive is a tumor pathological marker that indicates good prognosis, R1 positive is an unfavorable marker, we conclude that the down-regulation of NES1 in prostate cancer is closely related to unfavorable outcome. Its role as a new prognostic marker in prostate cancer should be explored further. CLINICAL BIOCHEMISTRY, VOLUME 33, APRIL 2000
EFFECT OF ATORVASTATIN (LIPITOR™) ON VLDLAPOB AND VLDL-TRIGLYCERIDE OVERPRODUCTION IN VIVO IN AN INSULIN RESISTANT HAMSTER MODEL Mangaloglu, L., Van-Iderstine, S., Chen, B., Taghibiglou, C., Cheung, R., and Adeli, K. Department of Laboratory Medicine & Pathobiology, Hospital for Sick Children University of Toronto, Toronto, Ontario, Canada M5G 1X8 Objective: A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the effect of atorvastatin, a potent HMG-CoA reductase inhibitor, on hepatic VLDL overproduction. Methods & Results: Fructose feeding for a two week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance. Fructose feeding also induced a significant increase in hepatic secretion of VLDL-triglyceride and VLDL-apoB. In vivo feeding experiments were also performed in which several groups of three hamsters were fed a fructose-enriched diet for 14 days to induce the state of insulin resistance, followed by a fructose-enriched diet supplemented with 40 mg/kg atorvastatin for 7 to 14 days. Feeding protocol was as follows: Day 1–14, fructose feeding; Day 15–28, fructose ⫹/⫺ atorvastatin). Fructose feeding in the first two weeks caused a significant increase in plasma total cholesterol and triglyceride in both groups. However, there was a significant decline in plasma triglyceride levels following supplementation of the fructoseenriched diet with atorvastatin. This decline was not observed in control animals receiving a fructose-enriched diet without the drug. In addition, there was an average 43% decrease in VLDL-apoB production in hepatocytes isolated from hamsters fed atorvastatin compared to the control group. Intracellular apoB turnover was also significantly increased in livers of drug treated hamsters. Conclusions: Taken together, these data suggest that the assembly and secretion of VLDL particles in hamster hepatocytes can be acutely inhibited by atorvastatin in a process involving enhanced intracellular apoB degradation. 26 INVESTIGATION OF THE ROLE OF THE NC3 REGION OF THE COL9A1 GENE IN HEREDITARY EARLY ONSET PRIMARY OSTEOARTHRITIS OF THE KNEE AND HIP Nassar, B.A.,1 Ramsey, U.1,2 Gross, M.,2 Amon, M.A.1,2 Departments of Pathology1 and Surgery2, Dalhousie University, Halifax, Nova Scotia, Canada Objective: Osteoarthritis (OA) is characterized by breakdown of hyaline cartilage resulting in increased water content of articular cartilage. Recent studies have shown that early onset OA may be due to alterations in genes encoding the collagen matrix of hyaline cartilage. Of these, mutations in the COL9A1 gene, which encodes the interrupted helical (1 (IX) subunit of the type IX collagen molecule, were shown to cause OA-like symptoms in mice. 233
Results:
25
Method (x)
IRMA
Regression Slope Intercept sy/x r
1,09 ⫺0,14 53,8 0,97
Immuno 1
Axsym
Access
1,14 0,11 55,6 0,97
1,00 0,21 48,0 0,98
1,23 ⫺0,30 47,2 0,97
Samples ⱕ 5 g/L, ECi mean ⫽ 2,47 Eci-method mean ⫺0,01 0,38 p (Wilcoxon) 0,41 0,001
0,29 0,06
0,31 0,08
Conclusions: The systematic differences observed are of little significance. But, occasionally, we observed sample related differences between the five methods that are clinically significant. When changing methods, we recommend obtaining a baseline value with the new assay for patients being serially monitored.
24 DOWN-REGULATION OF THE NORMAL EPITHELIAL CELL-SPECIFIC 1 (NES1) GENE IS ASSOCIATED WITH UNFAVORABLE OUTCOME OF PROSTATE CANCER. Luo, L. Y., and Diamandis, E. P. Dept of Laboratory Medicine and Pathobiology, University of Toronto, Dept of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada Objectives: The Normal Epithelial Cell-specific 1 (NES1) gene encodes a novel serine protease, which is a new member of the expanding human kallikrein gene family. The NES1 gene was thought to act as a tumor suppressor gene. It has been found to be down-regulated in many established breast cancer cell lines. In order to investigate the role of NES1 gene in prostate cancer, we examined its expression at the mRNA level in 20 pair of normal and cancerous prostatic tissues. Methods: The NES1 expression levels between the cancerous prostatic tissue and its adjacent normal tissue were compared with the semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Results: Comparing the NES1 expression level between the cancerous prostatic tissue and its normal adjacent part, among these 20 pair of tissues, it was up-regulated in 8 pairs, down-regulated in 8 pairs and has no change in 4 pairs. However, among those 8 pairs that are upregulated, 7 pairs are R0positive (surgical margin negative). For those 8 pairs that are down-regulated, 7 pairs are R1 positive (surgical margin positive), indicating the down-regulation of NES1 is closely associated with R1 positive (p ⬍ 0.01). Conclusion: Considering R0 positive is a tumor pathological marker that indicates good prognosis, R1 positive is an unfavorable marker, we conclude that the down-regulation of NES1 in prostate cancer is closely related to unfavorable outcome. Its role as a new prognostic marker in prostate cancer should be explored further. CLINICAL BIOCHEMISTRY, VOLUME 33, APRIL 2000
EFFECT OF ATORVASTATIN (LIPITOR™) ON VLDLAPOB AND VLDL-TRIGLYCERIDE OVERPRODUCTION IN VIVO IN AN INSULIN RESISTANT HAMSTER MODEL Mangaloglu, L., Van-Iderstine, S., Chen, B., Taghibiglou, C., Cheung, R., and Adeli, K. Department of Laboratory Medicine & Pathobiology, Hospital for Sick Children University of Toronto, Toronto, Ontario, Canada M5G 1X8 Objective: A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the effect of atorvastatin, a potent HMG-CoA reductase inhibitor, on hepatic VLDL overproduction. Methods & Results: Fructose feeding for a two week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance. Fructose feeding also induced a significant increase in hepatic secretion of VLDL-triglyceride and VLDL-apoB. In vivo feeding experiments were also performed in which several groups of three hamsters were fed a fructose-enriched diet for 14 days to induce the state of insulin resistance, followed by a fructose-enriched diet supplemented with 40 mg/kg atorvastatin for 7 to 14 days. Feeding protocol was as follows: Day 1–14, fructose feeding; Day 15–28, fructose ⫹/⫺ atorvastatin). Fructose feeding in the first two weeks caused a significant increase in plasma total cholesterol and triglyceride in both groups. However, there was a significant decline in plasma triglyceride levels following supplementation of the fructoseenriched diet with atorvastatin. This decline was not observed in control animals receiving a fructose-enriched diet without the drug. In addition, there was an average 43% decrease in VLDL-apoB production in hepatocytes isolated from hamsters fed atorvastatin compared to the control group. Intracellular apoB turnover was also significantly increased in livers of drug treated hamsters. Conclusions: Taken together, these data suggest that the assembly and secretion of VLDL particles in hamster hepatocytes can be acutely inhibited by atorvastatin in a process involving enhanced intracellular apoB degradation. 26 INVESTIGATION OF THE ROLE OF THE NC3 REGION OF THE COL9A1 GENE IN HEREDITARY EARLY ONSET PRIMARY OSTEOARTHRITIS OF THE KNEE AND HIP Nassar, B.A.,1 Ramsey, U.1,2 Gross, M.,2 Amon, M.A.1,2 Departments of Pathology1 and Surgery2, Dalhousie University, Halifax, Nova Scotia, Canada Objective: Osteoarthritis (OA) is characterized by breakdown of hyaline cartilage resulting in increased water content of articular cartilage. Recent studies have shown that early onset OA may be due to alterations in genes encoding the collagen matrix of hyaline cartilage. Of these, mutations in the COL9A1 gene, which encodes the interrupted helical (1 (IX) subunit of the type IX collagen molecule, were shown to cause OA-like symptoms in mice. 233