ABSTRACT Background: Insulin resistance is linked to dyslipidemia, characterized by a decrease in high density lipo-proteins and an increase in low density lipoproteins. Thiazolidinediones (TZDs) are insulin-sensitizing agents used to improve glycemic control in patients with type 2 diabetes. Recently, the safety of certain TZD regimens has been questioned because of associated adverse effects on the plasma lipid profile. We examined the effect of a TZD, Ciglitazone, on apolipoprotein synthesis and secretion in human liver HepG2 cells. Methods and Results: The effect of Ciglitazone treatment on apolipoprotein synthesis was addressed at the level of transcription, translation and secretion. RT-PCR showed that Ciglitazone increased the transcription of apoE and apoAI but reduced the levels of apoCI and apoB mRNA. Western blot analysis showed an increase in apoAI and apoE secreted in the cell culture media, whereas the amounts of apoB100 and apoCI were reduced. To confirm that Ciglitazone regulates apolipoprotein translation, its effect on de novo protein synthesis was evaluated by metabolic labeling with [35S]-methionine/cysteine, and a similar pattern of regulation was observed. The change in apolipoprotein levels was not secondary to cholesterol biosynthesis or clearance, since Ciglita-zone did not regulate the transcription of HMGCoA reductase, or the LDL receptor. However, mRNA levels for both PPAR-γ and LXRα were induced, suggesting a role for either or both receptors in modulating the hepatic apolipoprotein profile. The involvement of these nuclear receptor transcription factors was confirmed since direct activation of these receptors by endogenous PPAR-γ ligand, 15d-prostaglandin J2, or LXRα ligand, 22(R)hydroxycholesterol, similarly upregulated apoAI and apoE, but down-regulated apoB100 protein synthesis. Conclusion: Our results suggest that Ciglita-zone treatment results in an atheroprotective lipoprotein profile in liver cells. Thus, while the adipose and muscle tissues may be primary targets in TZD-mediated glucose homeostasis, liver PPAR-γ contributes significantly to the regulation of plasma lipoprotein profile.
Cite this paper
Dahabreh, D. and Medh, J. (2012) Activation of peroxisome proliferator activated receptor-gamma results in an atheroprotective apolipoprotein profile in HepG2 cells. Advances in Biological Chemistry, 2, 218-225. doi: 10.4236/abc.2012.23026.
 Olefsky, J.M. (2000) Treatment of insulin resistance with pe-roxisome proliferators-activated receptor γ agonists. Journal of Clinical Investigation, 106, 467-472.
 Smith, U. (2002) Thiazolidinedi-one-induced effects beyond glycemic control. British Journal of Diabetes & Vascular Disease, 2, S24-S27.
 Walczak, R. and Tontonoz, P. (2002) PPRadigms and PPARadoxes: Expanding roles for PPAR-gamma in the control of lipid metabolism. Journal of Lipid Research, 43, 177-186.
 Kersten, S. (2008) Peroxisome proliferator activated receptors and lipo-protein metabolism. PPAR Research, 2008, 132960. doi:10.1155/2008/132960
 Goldberg, R.B., Kendall, D.M., Deeg, M.A., Buse, J.B., Zagar, A.J., Pinaire, J.A. Tan, M.H., Khan, M.A., Perez, A.T. and Jacober, S.J. (2005) A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care, 28, 1547-1554.
 Van Wijk, J.P.H., De Koning, E.D.P., Martens, E.P. and Rabelink, T.J. (2003) Thiazolidinediones and blood lipids in type 2 diabetes. Arteri-osclerosis, Thrombosis, and Vas- cular Biology, 23, 1744-1749.
 Lee, C., Ol-son, P. and Evans, R.M. (2003) Minireview: Lipid metabolism, metabolic diseases, and peroxisome proliferators-activated receptors. Endocrinology, 144, 2201- 2207. doi:10.1210/en.2003-0288
 Wolf, G. (2004) Tissue-specific knockout defines peroxisome proliferators-activated receptor gamma function in muscle and liver. Nutrition Reviews, 62, 253-255.
 Glass, C.K. (2001) Potential roles of the peroxisome proliferator-activated receptorγ in macrophage biology and atherosclerosis. Journal of Endo-crinology, 169, 461-464. doi:10.1677/joe.0.1690461
 Galetto, R., Albajar, M., Polanco, J.I., Zakin, M.M., Rodriguez-Rey, J.C. (2001) Identification of a peroxisome proliferator-activated receptor response element in the apolipoprotein E gene control region. Biochemical Journal, 357, 521-527. doi:10.1042/0264-6021:3570521
 Mak, P.A., Laffitte, B.A., Desrumaux, C., Joseph, S.B., Curtiss, L.K., Mangelsdorf, D.J., Tontonoz, P. and Edwards, P.A. (2002) Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. Journal of Biological Chemistry, 277, 31900-31908. doi:10.1074/jbc.M202993200
 Willson, T.M., Cobb, J.E., Cowan, D.J., Wiethe, R.W., Correa, I.D., Prakesh, S.R., Beck, K.D., Moore, L.B., Kliewer, S.A. and Lehmann, J.M. (1996) The structure-activity relationship between peroxisome proliferator-activated receptor-γ agonism and the antihyperglycemic activity of thiazolidinediones. Journal of Medicinal Chemistry, 39, 665-668. doi:10.1021/jm950395a
 Livak, K.J. and Schmittgen, T.D. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔC T method. Methods, 25, 402-408.
 Jackson, R.L., Sparrow, J.T., Baker, H.N., Morrisett, J.D., Taunton, O.D. and Gotto, A.M. Jr. (1974) The primary structure of apolipoprotein-serine. Journal of Biological Chemistry, 249, 5308-5313.
 Laffitte, B.A., Joseph, S.B., Walczak, R., Pei, L., Wilpitz, D.C., Collins, J.L. and Tontonoz, P. (2001) Autoregulation of the human liver X receptor α promoter. Molecular and Cellular Biology, 21, 7558-7568.
 Goldberg, I.J. (2001) Diabetic dyslipidemia: Causes and consequences. Journal of Clinical Endocrinology & Metabolism, 86, 965-971. doi:10.1210/jc.86.3.965
 Yue, L. and Mazzone, T. (2009) Peroxisome proliferator-activated receptor-γ stimulation of adipocyte apoE gene transcription mediated by the liver receptor X pathway. Journal of Biological Chemistry, 284, 10453-10461.
 Berbee, J.F.P., Van der Hoogt, C.C., Sundararaman, D., Havekes, L.M. and Rensen, P.C.N. (2005) Severe hypertriglyceridemia in human apoC1 transgenic mice is caused by apoC-I-induced inhibition of LPL. Journal of Lipid Research, 46, 297-306. doi:10.1194/jlr.M400301-JLR200
 Malik, S. (2003) Transcriptional regulation of the apolipoprotein AI gene. Frontiers in Bioscience, 8, 360-368.
 Staels, B. and Auwerx, J. (1998) Regulation of apoA-I gene expression by fibrates. Atherosclerosis, 137, S19- S23. doi:10.1016/S0021-9150(97)00313-4
 Qin, S., Liu, T., Kamanna, A.S. and Kashyap, M.L. (2007) Pioglitazone stimulates apolipoprotein A-I production without affecting HDL removal in HepG2 cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 2428- 2434. doi:10.1161/ATVBAHA.107.150193
 Gavrilova, O., Haluzik, M., Matsusue, K., Cutson, J.J., Johnson, L., Dietz, K.R., Nicol, C.J., Vinson, C., Gonzales, F.J. and Reitman, M.L. (2003) Liver peroxisome proliferator-activated receptor-γ con-tributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. Journal of Biological Chemistry, 278, 34268-34276.