Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase.
Journal: 1999/June - British Journal of Clinical Pharmacology
ISSN: 0306-5251
PUBMED: 10233209
Abstract:
OBJECTIVE
To clarify how troglitazone, an insulin-sensitizing agent, affects lipid metabolism and postheparin plasma lipoprotein lipase (LPL).
METHODS
Fifteen patients (3 male, 12 female) (the average age 62+/-7 years; the mean body mass index (BMI) 25+/-3 kg/m2 ) were recruited for this study. The serum lipids and postheparin plasma lipoprotein lipase (LPL) mass before and 4 weeks after oral administration of troglitazone (200 mg day-1 ) were measured. A mouse preadipocyte cell line, 3T3-L1, was incubated with troglitazone and LPL enzyme protein mass in the culture media was measured by an enzyme linked immunosorbent assay. A reverse transcription polymerase chain reaction (RT-PCR) using primers specific for the carboxyl terminal 135 amino acid of mouse LPL cDNA was used to evaluate the effect of troglitazone on expression of LPL and Northern blot analysis carried out to determine expression of LPL.
RESULTS
The average levels before treatment of fasting serum total cholesterol, triglycerides, high density lipoprotein cholesterol, plasma glucose and glycohaemoglobin A1c were 5.6+/-0.9, 1.8+/-1.0, 1.5+/-0.5, 8.1+/-1.7 mmol l-1 and 7.8+/-1.6% respectively. Four weeks after treatment, those levels were 5.4+/-0.9, 1.2+/-0.3 (P=0.004), 1.6+/-0.5 (P=0.02) mmol l-1, 7.7+/-2.3 mmol l-1 and 7. 3+/-0.6% (P=0.01), respectively. The postheparin plasma LPL mass increased from 226+/-39 to 257+/-68 ng ml-1 (P=0.03) during that period. The LPL mass in the media of 3T3 L1 cells cultured in the presence of 10, 20 or 30 microm of this compound increased in a dose dependent manner. RT-PCR revealed that the area of the bands of the RT-PCR products on 1.5% agarose gel analyzed with NIH image from the cell extracts cultured in the presence of 10 microm troglitazone was significantly larger (P=0.0069) than that in the absence of this compound. Northern blot analysis revealed that in the cultured 3T3-L1 cells, the expression of LPL was enhanced in the presence of 10 microm troglitazone.
CONCLUSIONS
Troglitazone improves plasma triglyceride-rich lipoproteins metabolism by enhancing the expression of LPL in adipocytes.
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Br J Clin Pharmacol 47(4): 433-439

Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase

Second Department of Internal Medicine, Chiba University School of Medicine, Japan
Health Sciences Center, Chiba University, 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba 260-0856, Japan
Correspondence: Dr J. Kobayashi, Second Department of Internal Medicine, Chiba University School of Medicine, Chiba University, 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba 260-0856, Japan.
Received 1998 Jul 3; Accepted 1998 Dec 16.

Abstract

Aims

To clarify how troglitazone, an insulin-sensitizing agent, affects lipid metabolism and postheparin plasma lipoprotein lipase (LPL).

Methods

Fifteen patients (3 male, 12 female) (the average age 62±7 years; the mean body mass index (BMI) 25±3 kg/m) were recruited for this study. The serum lipids and postheparin plasma lipoprotein lipase (LPL) mass before and 4 weeks after oral administration of troglitazone (200 mg day) were measured. A mouse preadipocyte cell line, 3T3-L1, was incubated with troglitazone and LPL enzyme protein mass in the culture media was measured by an enzyme linked immunosorbent assay. A reverse transcription polymerase chain reaction (RT-PCR) using primers specific for the carboxyl terminal 135 amino acid of mouse LPL cDNA was used to evaluate the effect of troglitazone on expression of LPL and Northern blot analysis carried out to determine expression of LPL.

Results

The average levels before treatment of fasting serum total cholesterol, triglycerides, high density lipoprotein cholesterol, plasma glucose and glycohaemoglobin A1c were 5.6±0.9, 1.8±1.0, 1.5±0.5, 8.1±1.7 mmol l and 7.8±1.6% respectively. Four weeks after treatment, those levels were 5.4±0.9, 1.2±0.3 (P=0.004), 1.6±0.5 (P=0.02) mmol l, 7.7±2.3 mmol l and 7.3±0.6% (P=0.01), respectively. The postheparin plasma LPL mass increased from 226±39 to 257±68 ng ml (P=0.03) during that period. The LPL mass in the media of 3T3 L1 cells cultured in the presence of 10, 20 or 30 μm of this compound increased in a dose dependent manner. RT-PCR revealed that the area of the bands of the RT-PCR products on 1.5% agarose gel analyzed with NIH image from the cell extracts cultured in the presence of 10 μm troglitazone was significantly larger (P=0.0069) than that in the absence of this compound. Northern blot analysis revealed that in the cultured 3T3-L1 cells, the expression of LPL was enhanced in the presence of 10 μm troglitazone.

Conclusions

Troglitazone improves plasma triglyceride-rich lipoproteins metabolism by enhancing the expression of LPL in adipocytes.

Keywords: troglitazone, lipoprotein lipase, 3T3-L1 cells, insulin
Abstract

Acknowledgments

We thank Dr Tarou Matsumoto for his excellent technique to conduct the present study.

Acknowledgments

References

  • 1. Fujiwara T, Yoshida S, Yoshida T, Ushiyama I, Horikoshi H. Characterization of new oral antibiotic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988;37:1549–1558.[PubMed]
  • 2. Chang AY, Wyse BM, Gilchrist BJ, Peterson T, Diani AR. Ciglitazone, a new hypoglycemic agent. I. Studies in ob/ob and db/db mice, diabetic Chinese hamsters and normal and streptozocin-diabetic rats. Diabetes. 1983;32:830–838.[PubMed]
  • 3. Fujita T, Sugiyama Y, Taketomi S, et al Reduction of insulin resistance in obese and/or diabetic animal by 5-[4-(1-methylcyclohexymethoxy) benzyl]-thiazolidine-2,4 dione (ADD-3878, U -63,287, ciglitazone) a new antidiabetic agent. Diabetes. 1983;32:804–810.[PubMed][Google Scholar]
  • 4. Sugiyama Y, Shimura Y, Ikeda HEffect of pioglitazone on hepatic and peripheral insulin resistance in Wistar fatty rats. Arzneimittel Forsch. 1990;40:436–440.[PubMed][Google Scholar]
  • 5. Blackmore PF, McPherson R K, Stevenson RWActions of the novel antidiabetic englitazone in rat hepatocytes. Metabolism. 1993;42:1583–1587.[PubMed][Google Scholar]
  • 6. Ciaraldi TP, Gilmore A, Oelfsky JM, Goldberg M, Heidenreich KA. In vitro studies on the action of CS 045. A new antibiotics agent. Metabolism. 1990;39:1056–1062.[PubMed]
  • 7. Szalkowsk D, White-Carrington S, Berger J, Zhang BAntidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. Endocrinol. 1995;136:1474–1481.[PubMed][Google Scholar]
  • 8. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SAAn antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPAR γ) J Biol Chem. 1995;270:12953–12956.[PubMed][Google Scholar]
  • 9. Ong JM, Kirchgessner TG, Schotz MC, Kern PAInsulin increases the synthetic rate and messenger RNA level of lipoprotein lipase in isolated rat adipocytes. J Biol Chem. 1988;263:12933–12938.[PubMed][Google Scholar]
  • 10. Semenkovich CF, Wims M, Noe L, Etinne J, Chan LInsulin regulation of lipoprotein lipase activity in 3T3-L1 adipocytes is mediated at posttranscriptional and posttranslational levels. J Biol Chem. 1989;264:9030–9038.[PubMed][Google Scholar]
  • 11. Kobayashi J, Hashimoto H, Fukamachi I, et al Lipoprotein lipase mass and activity in severe hypertriglyceridemia. Clin Chim Acta. 1993;216:113–123.[PubMed][Google Scholar]
  • 12. Becker A, Reith A, Napiwotszki J, Kadenbach BA quantitative method of determining initial amounts of DNA by polymerase chain reaction cycle titrating using digital imaging and a novel DNA stain. Anal Biochem. 1996;237:204–207.[PubMed][Google Scholar]
  • 13. Hasel KW, Glass JR, Godbout M, Sutcliffe JGAn endoplasmic reticulum-specific cyclophilin. Mol Cell Biol. 1991;11:3484–3491.[Google Scholar]
  • 14. Yost TJ, Froyd KK, Jensen DR, Eckel RHChanges in skeletal muscle lipoprotein lipase activity in response to insulin/glucose in non-insulin-dependent diabetes mellitus. Metabolism: Clinical and Experimental. 1995;44:786–790.[PubMed][Google Scholar]
  • 15. Iwamoto T, Kuzuya T, Matsuda A, Awata T, Inooka G, Shiraishi IEffects of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Care. 1991;14:1083–1086.[PubMed][Google Scholar]
  • 16. Mimura K, Umeda F, Hiramatsu S, et al Effect of a new oral hypoglycemic agent (CS-045) on metabolic abnormalities and insulin resistance in type II diabetes. Diabetic Med. 1994;11:685–691.[PubMed][Google Scholar]
  • 17. Kobayashi J, Tashiro J, Murano S, Morisaki N, Saito YLipoprotein lipase mass and activity in post-heparin plasma from subjects with intra-abdminial visceral fat accumulation. Clin Endocrinol. 1998;48:515–520.[PubMed][Google Scholar]
  • 18. Shibata H, Arai S, Kobayashi M, et al Phase I study of a new hypoglycemic agent CS-045 in healhy volunteers. Rinsho Iyaku. 1993;9:1503–1518.[PubMed][Google Scholar]
  • 19. Watkins PB, Whitcomb RWHepatic dysfunction associated with troglitazone. N Engl J Med. 1998;338:916.[PubMed][Google Scholar]
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