Rondón-Ortiz Alejandro N, Lino Cardenas Christian L, Martínez-Málaga Jimena, Gonzales-Urday Ana L, Gugnani Kuljeet S, Böhlke Mark, Maher Timothy J, Pino-Figueroa Alejandro J
Department of Pharmaceutical Sciences, MCPHS University, Boston, MA, United States.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States.
Front Pharmacol. 2017 Nov 14;8:772. doi: 10.3389/fphar.2017.00772. eCollection 2017.
Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor involved in the uptake of a variety of molecules, such as apoE, α2-macroglobulin, and the amyloid β peptide (Aβ), for either transcellular transport, protein trafficking or lysosomal degradation. The gene can be transcribed upon activation of peroxisome proliferator receptor activated-γ (PPARγ) by the potent PPARγ agonist, rosiglitazone (RGZ). In previous studies, RGZ was shown to upregulate LRP1 levels in concentrations between 0.1 and 5 μM in HepG2 cells. In this study, we sought to replicate previous studies and to investigate the molecular mechanism by which high concentrations of RGZ reduce LRP1 levels in HepG2 cells. Our data confirmed that transcriptional activation of occurred in response to RGZ at 3 and 10 μM, in agreement with the study reported by Moon et al. (2012a). On the other hand, we found that high concentrations of RGZ decreased both mRNA and protein levels of LRP1. Mechanistically, transcriptional dysregulation of was affected by the downregulation of PPARγ in a time- and concentration-dependent manner. However, downregulation of PPARγ was responsible for only 40% of the LRP1 reduction and thereby the remaining loss of LRP1 (60%) was found to be through degradation in the lysosomal system. In conclusion, our findings demonstrate the mechanisms by which high concentrations of RGZ caused LRP1 levels to be reduced in HepG2 cells. Taken together, this data will be helpful to better explain the pharmacological modulation of this pivotal membrane receptor by PPARγ agonists.
低密度脂蛋白受体相关蛋白1（LRP1）是一种内吞受体，参与多种分子的摄取，如载脂蛋白E、α2-巨球蛋白和淀粉样β肽（Aβ），用于跨细胞运输、蛋白质运输或溶酶体降解。该基因可在强效过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮（RGZ）激活PPARγ后转录。在先前的研究中，RGZ在0.1至5μM浓度下可上调HepG2细胞中LRP1的水平。在本研究中，我们试图重复先前的研究，并探究高浓度RGZ降低HepG2细胞中LRP1水平的分子机制。我们的数据证实，3和10μM的RGZ可诱导转录激活，这与Moon等人（2012a）报道的研究一致。另一方面，我们发现高浓度的RGZ会降低LRP1的mRNA和蛋白质水平。从机制上讲，转录失调受PPARγ下调的时间和浓度依赖性影响。然而，PPARγ的下调仅导致LRP1减少的40%，因此其余60%的LRP1损失是通过溶酶体系统降解造成的。总之，我们的研究结果揭示了高浓度RGZ导致HepG2细胞中LRP1水平降低的机制。综上所述，这些数据将有助于更好地解释PPARγ激动剂对这一关键膜受体的药理调节作用。
