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Upregulation of Hepatic LRP1 by Rosiglitazone: a Possible Novel Mechanism of the Beneficial Effect of Thiazolidinediones on Atherogenic Dyslipidemia

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Upregulation of Hepatic LRP1 by Rosiglitazone: a Possible Novel Mechanism of the Beneficial Effect of Thiazolidinediones on Atherogenic Dyslipidemia 165 Upregulation of hepatic LRP1 by rosiglitazone: a possible novel mechanism of the beneficial effect of thiazolidinediones on atherogenic dyslipidemia Jae Hoon Moon1,2†, Hyung Jun Kim3, Hyun Min Kim1, Ae Hee Yang3, Byung-Wan Lee1, Eun Seok Kang1, Hyun Chul Lee1 and Bong Soo Cha1,3 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Republic of Korea 2Department of Internal Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Kyunggi-do 463-707, Republic of Korea 3Brain Korea 21 Project for Medical Science, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Republic of Korea (Correspondence should be addressed to B S Cha at Department of Internal Medicine, Yonsei University College of Medicine; Email: [email protected]) †(J H Moon is now at Department of Internal Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Kyunggi-do 463-707, Republic of Korea) Abstract Hepatic LDL receptor-related protein 1 (LRP1) plays a role in the clearance of circulating remnant lipoproteins. In this study, we investigated the effect of rosiglitazone treatment on the expression and function of hepatic LRP1. HepG2 cells were incubated with various concentrations of rosiglitazone. Male Long-Evans Tokushima Otsuka (LETO) rats and Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats were treated with rosiglitazone for 5 weeks. The expression and function of LRP1 in HepG2 cells and liver samples of rats were analyzed. LRP1 mRNA and protein expressions were increased by 0.5 and 5 mM rosiglitazone in HepG2 cells. However, at concentrations above 50 mM rosiglitazone, LRP1 mRNA and protein expressions did not change compared with those in nontreated cells. Reporter assay showed that 0.5 and 5 mM rosiglitazone increased the transcriptional activity of the LRP1 promoter in HepG2 cells. The uptake of apolipoprotein E through LRP1 in HepG2 cells was also increased by rosiglitazone. Hepatic LRP1 was reduced in OLETF rats compared with that of LETO rats and rosiglitazone treatment increased hepatic LRP1 in OLETF rats. A high glucose condition (25 mM glucose in culture media) reduced the expression of LRP1 in HepG2 cells, and this reduced LRP1 expression was recovered with rosiglitazone. In conclusion, our data suggest that decreased hepatic LRP1 in a diabetic condition is associated with the development of atherogenic dyslipidemia and that increased hepatic LRP1 by thiazolidinediones could contribute to an improvement in atherogenic lipid profiles in diabetic patients. Journal of Molecular Endocrinology (2012) 49, 165–174 Introduction endothelial dysfunction, foam cell formation, and vascular smooth muscle cell proliferation (Fujioka & Diabetes mellitus (DM) is a major risk factor for Ishikawa 2009). Several studies have reported that cardiovascular disease. DM can cause atherogenic the level of remnant-like particle cholesterol (RLP-C) dyslipidemia including elevated triglycerides and low is increased in diabetic patients (Taniguchi et al. HDL cholesterol (HDL-C; Gordon et al. 1989, Assmann 2000, Schaefer et al. 2002) and is associated with an & Schulte 1992). Increased free fatty acid due to insulin increased risk of cardiovascular disease (Fukushima resistance in adipose tissue promotes the hepatic et al. 2001, 2004). production of triglycerides, which are packaged in LDL receptor-related protein 1 (LRP1) is a member apolipoprotein B-containing VLDLs (Bell et al. 2011). of the LDD receptor gene family and is a multi- Increased triglyceride-rich lipoproteins, such as chylo- functional scavenger and signaling receptor that binds micron and VLDL, are hydrolyzed to remnant particles and internalizes diverse ligands (Herz & Strickland (Merkel 2009). Recent studies have focused on these 2001). This cell surface glycoprotein binds apolipopro- remnant lipoproteins as atherogenic particles, showing tein E (ApoE) and serves as a receptor for remnant that remnant lipoproteins can penetrate the endo- lipoproteins such as chylomicron remnant and thelial wall and remain in the subendothelial space VLDL remnant in the liver (Herz & Strickland (Fujioka & Ishikawa 2009). Remnant lipoproteins have 2001). Furthermore, this receptor plays an important also been reported to be associated with inflammation, role in the clearance of remnant lipoproteins Journal of Molecular Endocrinology (2012) 49, 165–174 DOI: 10.1530/JME-12-0119 0952–5041/12/049–165 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/29/2021 06:22:52AM via free access 166 J H MOON and others . Effect of PPARg agonist on hepatic LRP1 (Willnow et al. 1994, 1995, Rohlmann et al. 1998). A Otsuka (LETO) rats (Tokushima Research Institute, thiazolidinedione drug, such as rosiglitazone or piogli- Otsuka Pharmaceuticals) were used as nondiabetic tazone, is an oral hypoglycemic agent that improves counterparts. The rats were housed in a temperature- insulin resistance by activating the peroxisome prolif- controlled environment under a 12 h light:12 h erator-activated receptor-g (PPARg). This agent has darkness cycle and allowed ad libitum access to also been known to modify the atherogenic lipid standard chow and water. profile. In clinical studies, pioglitazone decreased the All rats were fed standard chow until the age of serum level of triglycerides and RLP-C and increased 20 weeks. Thereafter, OLETF rats were fed a high-fat serum HDL-C (Goldberg et al. 2005, Berhanu et al. 2006, diet (40% lard, Wellga, Inc., Seoul, Korea). OLETF Berneis et al. 2008, Igarashi et al. 2008). Rosiglitazone rats were randomly divided into two groups: the also decreased serum triglycerides in some animal and vehicle (normal saline)-treated group (nZ9) and the clinical studies (van Wijk et al. 2005, Ackerman et al. rosiglitazone-treated group (nZ8). The rosiglitazone- 2010, Yang et al. 2011). Pioglitazone has been reported treated rats were administered 4 mg/kg per day com- to reduce serum triglycerides by increasing their pound in saline via oral gavage using 20 G feeding clearance from the circulation, most likely through needles. LETO rats received standard chow without increased lipoprotein lipase-mediated lipolysis of any drug (nZ8). All the animals were treated for 5 VLDLs (Hanefeld 2009). One in vitro study reported weeks. One day after the OGTT at the age of that LRP1 is regulated by PPARg and that rosiglita- 25 weeks, all the rats were killed; the livers were zone induced LRP1 expression in human adipocytes extracted, processed, and embedded in paraffin for (Gauthier et al. 2003). On the basis of these data, we hypothesized that thiazolidinediones may increase histological analysis. The remaining tissues were flash- K 8 hepatic LRP1 and the hepatic clearance of remnant frozen in liquid nitrogen and stored at 80 C until analysis. Blood was collected by cardiac puncture and lipoproteins. In this study, the effect of rosiglitazone K on the expression and function of hepatic LRP1 was stored at 20 8C for biochemical tests. investigated. Our study may present a novel mechanism of the improvement of atherogenic Oral glucose tolerance test dyslipidemia by a thiazolidinedione drug in diabetic patients. All the rats underwent an OGTT after an overnight fast using 20% glucose solution (2 g/kg). Blood samples were obtained by tail snipping, and blood glucose levels were measured with a glucose analyzer Materials and methods (Accu-Check; Roche Diagnostics). Glucose levels were recorded at 0, 15, 30, 60, and 120 min after glucose Cell culture and preparation administration. The HepG2 cells were cultured in MEM containing 10% fetal bovine serum, penicillin (100 IU/ml), and Biochemical analysis streptomycin (100 mg/ml) at 5% CO2/95% air and 37 8C. Rosiglitazone was provided by GlaxoSmithKline K Blood samples were obtained from the heart at the time and prepared in DMSO at 20 8C. HepG2 cells were of killing and were immediately centrifuged at 5000 g incubated with the indicated concentrations of rosigli- for 5 min. Total cholesterol and triglycerides were tazone for 48 h by adding the stock solution to the determined using an ADVIA 1650 (Bayer). culture media. The final concentration of DMSO in the culture media was adjusted to 0.5% (vol/vol). Total RNA and cDNA preparation Animals, diet, and treatment Total RNA was isolated from HepG2 cells and the rat Laboratory animals for all experiments were cared for liver tissues using Trizol reagent (Invitrogen) and was in accordance with the National Institute of Health’s quantified using a NanoDrop ND-1000 spectro- guidelines. The animals were maintained according photometer (Thermo Scientific, Rockford, IL, USA). to the ethical guidelines of our institution, and the Following the RNA extraction, 4 mg RNA were treated experimental protocol was approved by the Committee with 1 U RNase-free DNase I to remove all contami- on Animal Investigations of Yonsei University. Male nating genomic DNA. After removing the DNase I, Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats DNase-treated RNA was subsequently used for cDNA (Tokushima Research Institute, Otsuka Pharma- synthesis using MMLV reverse transcriptase (Promega) ceuticals, Tokushima, Japan) were used as a diabetic according to the manufacturer’s protocol. The animal model and Male Long-Evans Tokushima synthesized cDNA was stored at K20 8C for later use. Journal of Molecular Endocrinology (2012) 49, 165–174 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/29/2021 06:22:52AM via free access Effect of PPARg agonist on hepatic LRP1 . J H MOON and others 167 Quantitative real-time PCR proliferator response element (PPRE) in human LRP1 promoter (50-CCCCGCTCCTTGAACTCTGA- Quantitative real-time PCR (RT-PCR) analysis was CATGCAGACACCTA-30) were synthesized and end performed using TaqMan assay kits for LRP1 labeled with biotin (Gauthier et al. 2003). Also, the (Hs00233856_m1, R701503964 g1) with the ABI oligonucleotides of the mutated form of the LRP1 7500 instrument (Applied Biosystems).
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