Leptin decreases the expression of low-density lipoprotein receptor via PCSK9 pathway: linking dyslipidemia with obesity
© The Author(s) 2016
Received: 16 May 2016
Accepted: 8 September 2016
Published: 23 September 2016
Previous studies have suggested that people with obesity showed elevated serum levels of leptin as well as lipid dysfunction and proprotein convertase subtilisin/kexin type 9 (PCSK9) played an important role in the regulation of lipid metabolism recently. The aim of this study was to determine if leptin participated in regulating the uptake of low-density lipoproteins (LDL) in hepatocytes via PCSK9.
HepG2 cells were treated with human recombinant leptin. The impact of leptin on cellular low density lipoprotein receptor (LDLR) and PCSK9 protein levels was determined by Western blot. Dil-LDL uptake assay was performed to examine the LDLR function. Specific small interfering RNAs (siRNAs) were used to interfere the expressions of target proteins.
The expression of LDLR and LDL uptake could be significantly down-regulated by leptin treatment while the expressions of PCSK9 and hepatocyte nuclear factor 1α (HNF1α) were enhanced in HepG2 cells. Furthermore, inhibition of PCSK9 or HNF1α expression by siRNAs rescued the reduction of LDLR expression and LDL uptake by leptin. We found that leptin activated the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. Moreover, the changes of the expressions of HNF1α, PCSK9, LDLR, and LDL uptake induced by leptin could be blocked by p38MAPK inhibitor (SB203580). Additionally, leptin attenuated the up-regulation of LDLR caused by atorvastatin in HepG2 cells.
These findings indicated firstly that leptin reduced LDLR levels in hepatocyte via PCSK9 pathway, suggesting that PCSK9 might be a alternative target for dyslipidemia in the obesity.
KeywordsLeptin PCSK9 LDLR
Obesity is one of the most serious chronic diseases worldwide represented by an excess of body fat . A number of previous studies indicated that obesity increased risk for atherosclerotic cardiovascular disease (ASCVD) [2, 3]. Dyslipidemia is the earliest risk factor of ASCVD in obesity  which includes the elevated serum levels of low density lipoprotein cholesterol (LDL-C) . It has been demonstrated that elevated LDL-C plays a major role in the initiation and development of atherosclerosis in patients with overweight and obesity [5–7]. Unfortunately, the underlying mechanism responsible for elevated LDL-C levels in obesity is not fully understood.
As well established, low density lipoprotein receptors (LDLRs) in the surface of hepatocyte membranes function as critical regulators for circulating LDL-C homeostasis mainly through controlling the rate of liver uptake and the clearance of LDL particles [8, 9]. Several physiological factors which could affect the hepatic LDLR level are recognized. For instance, resistin, which was increased in both circulation and adipose-tissue adipocytes in obesity [10, 11], could reduce LDLR expression in human hepatocytes mediated in part by proprotein convertase subtilisin-kexin type 9 (PCSK9) . In fact, PCSK9 is a secreted protein which plays a key role in regulation of LDL-C level in the circulation by binding directly to the hepatic LDLRs and blocking their recycling via promoting its degradation in lysosome . So far, there are two best-described trans activator of PCSK9 gene expression in hepatocytes, sterol response element binding proteins (SREBP)  and hepatocyte nuclear factor 1 alpha (HNF1α) .
Besides resistin, leptin is another increased physiological factor in obesity  which also comes from adipose tissue . The major function of leptin is that it decreases food intake and increase energy consumption by acting on specific hypothalamic nuclei CART and NPY . Recently, studies in vitro and in vivo have suggested that leptin could also be involved in the pathophysiology of atherosclerosis [19–21]. Furthermore, clinical data have shown the plasma leptin level as an independent predictor for CVD incident . As such, we hypothesized that hyperleptinemia might be another potential mechanism linking obesity to ASCVD and leptin could regulate the expression of LDLR in the liver just like resistin. Leptin has been reported to stimulate p38 mitogen-activated protein kinase (p38MAPK) pathway in different cell types [23–25] and the p38MAPK pathway also participated in the regulation of physiological processes associated with atherosclerosis [25, 26]. Therefore, we supposed that whether p38MAPK pathway could play a role in the regulation of PCSK9 and LDLR by leptin. In addition, statins are the major class of drugs to treatment patients with increased serum LDL-C by upregulating the LDLR expression in hepatocytes . It might be, therefore, interesting to investigate whether leptin could diminish the enhanced LDLR expression induced by atorvastatin treatment. These results will help us to find out whether leptin could affect the statin-induced increase of LDLRs.
In this study, the major goal was to determine if human leptin played a role in regulating the uptake of LDL by PCSK9 in hepG2 cells for the sake of exploring the potential links of leptin with PCSK9 in obesity.
Cell culture and treatment
The human hepatoma cell line HepG2 was purchased from Cell Resource Center, IBMS, CAMS/PUMC. HepG2 cells were cultured in 10 % fetal bovine serum (FBS) (Gibco)-containing DMEM (Gibco) supplemented with 1 % NEAA (Life technologies), 1 % penicillin- streptomycin at 37 °C, 5 % (v/v) CO2. HepG2 cells were treated with human recombinant leptin protein (R&D Systems, Minneapolis, MN, USA) at various doses (0, 5, 25, 50, 100 and 200 ng/ml) for 24 h or with 50 ng/ml leptin for various times (0, 6, 12, 24, 48 h). In other experiments, the p38MAPK inhibitor-SB203580, was administered at 10 μM, either alone or combined with 50 ng/ml leptin for 24 h. Atrovastatin (Sigma, MO) was administered at 10 μM, either alone or combined with 50 ng/ml leptin for 24 h.
Cultured cells were collected with cell lysis buffer (Beyotime, Shanghai, China). Protein samples were separated by precast NuPAGE Novex 4–12 % (w/v) Bis–Tris gels (Life technologies, Carlsbad, CA, USA) and then transferred onto nitrocellulose membrane using the iBlotTM dry blotting system as described by the manufacturer (Invitrogen, Carlsbad, CA, USA). Membranes were blocked in TBST buffer (20 mM Tris, pH 7.5, 150 mM NaCl, 0.1 % tween 20) containing 5 % milk for 1 h at room temperature and incubated with primary antibodies specific for LDLR (Biovision, Mountain View, CA), PCSK9 (Cayman Chemicals, MI), HNF1α (Cell Signaling) and GAPDH (Abcam) overnight at 4 °C, and then incubated with a secondary antibody conjugated with horseradish peroxidase (HRP) for 2 h at room temperature. Blots were developed using chemoluminescence (ECL, Thermo Fisher Scientific, Waltham, MA, USA) on FluorChem M image system.
DiI-LDL uptake assay
HepG2 cells were changed to serum-free media and incubated with 10 μg/ml DiI-LDL (lifetech) for 24 h at 37 °C in the dark. After incubation, the cells were washed with PBS and fixed in the presence of a 4 % paraformaldehyde, and the nuclei were subsequently stained with Hoechst dye. Finally, the cells were examined with fluorescence microcopy (DMI-4000B, Leica).
Small interfering ribonucleic acid (siRNA) transfection
PCSK9 and HNF1α Stealth siRNA duplexes are followings: PCSK9 Stealth siRNA duplexes (Life tech, Carlsbad, CA, USA) targeting sequences: 5′-GAC AUC AUU GGU GCC UCC AGC GAC U-3′ and 5′-AGU CGC UGG AGG CAC CAA UGA UGU C-3′ and HNF1α Stealth siRNA duplexes (Life tech, Carlsbad, CA, USA) targeting sequences: 5′-UCG AUA CCA CUG GCC UCA ATT-3′ and 5′-UUG AGG CCA GUG GUA UCG ATT-3′. The negative controls siRNA Duplexes (Life tech, Carlsbad, CA, USA) were used as a control. siRNA were transfected into HepG2 cells using Lipofectamine TM RNAiMAX (Life tech, Carlsbad, CA, USA) according to manufacturer’s protocol.
Results were presented as mean ± SEM at least three independent experiments. Significant differences between control and treatment groups were assessed by One-way ANOVA with proper posttest or Student two-tailed t test.
Leptin down-regulates expression of LDLR and up-regulates expression of PCSK9
PCSK9 inhibition blocks the effect of leptin on LDLR expression and LDL uptake
HNF1α inhibition blocks the effect of leptin on LDLR expression and LDL uptake
Leptin down-regulates LDLR and up-regulates PCSK9 through p38MAPK pathway
Leptin inhibits the up-regulation of LDLR mediated by atorvastatin
In this study, we, for the first time, demonstrated that leptin significantly increased PCSK9 expression and suppressed LDLR in HepG2 cells. The major novel findings of the present study were as follows: (1) leptin could suppress LDLR level, LDL uptake and elevate PCSK9 expression; (2) the changes of LDLR, PCSK9 levels and LDL uptake were regulated by enhanced expression in HNF1α and the elevated activation of p38MAPK pathway; (3) leptin could abolish the statin-induced up-regulation of hepatic LDLR level. This study revealed a novel role of leptin in the regulation of hepatic LDLR and PCSK9 expression, which might provide additional information to understand the mechanism responsible for dyslipidemia in obesity.
It is well known that leptin is an adipose tissue-derived hormone, which plasma level is positive correlated with the body fat mass [16, 17]. The major function of leptin is to regulate human body weight and energy homeostasis by the brain . Considering the roles of leptin in physiological processes associated with cardiovascular disease, such as blood pressure , platelet aggregation , arterial thrombosis , angiogenesis , and inflammatory vascular responses , it, logically, may have a close relationship with the development of CVD . Interestingly, study from Kwakernaak et al. found that plasma leptin had a positive association with plasma PCSK9 in healthy people . Their results suggested that leptin might be involved in the regulation of hepatic PCSK9 expression. Therefore, illuminating the relationship of leptin and PCSK9 in vitro is the major goal of this study.
In the beginning of this study, we found that leptin could cause the decrease of LDLR expression and LDL uptake (Additional file 1: Figure S1) in HepG2 cells. Then, we sought to illuminate the mechanisms by which leptin regulates the hepatic LDLR levels. Definitely, PCSK9 have been reported to regulate LDL levels by mediating LDLR protein degradation . That is, PCSK9 could bind to the extracellular domain of the LDLRs and then lead LDLRs to lysosome-mediated degradation instead of recycling to the cell surface . Therefore, PCSK9 stood a good chance to mediate the regulation of hepatic LDLR levels. Consisting with our assumption, the present study showed that PCSK9 levels were increased by leptin stimulation. Subsequently, we further investigated the role of PCSK9 in the leptin-mediated reduction in LDLR levels. In our study, inhibition of PCSK9 gene expression were carried out by transfecting PCSK9 siRNA into HepG2 cells. Negative control siRNAs were used as controls, which did not affect expression PCSK9 and LDLR (Additional file 2: Figure S2). And the relative transfection efficiency was shown by using the positive control–GAPDH siRNA and it was great in our experiments (Additional file 3: Figure S3). As a result, we found that the suppression of LDLR expression and LDL uptake by leptin stimulation could be reversed by the inhibition of PCSK9 expression. These findings suggested that leptin could suppress the LDLR expression by increasing hepatic PCSK9 level.
HNF1α is one of the transcriptional regulation factors which regulates PCSK9 expression by binding to its promoter . To determine whether HNF1α was involved in the regulation of LDLR and PCSK9 by leptin, HNF1α siRNAs were used to knockdown its expression. It was found that elevation of PCSK9 expression and the reduction of LDLR expression and function by leptin stimulation could be abolished by the inhibition of HNF1α expression. It is well known that another transcription factor, SREBP2 is the most important trans-activator of PCSK9 which can also induce LDLR expression . Hence, we also examined the SREBP2 expression under leptin treatment for 24 h. Interestingly, we found that there was no significant change of SREBP2 expression by leptin in both mRNA and protein level (Additional file 4: Figure S4 and Additional file 5: Figure S5). Although the exact reason for this unique phenomenon is unclear, we supposed that SREBP2 may not be involved in the regulation of LDLR mediated by PCSK9 under leptin treatment.
Leptin has been reported to signal via various kinases. The activity of p38MAPK pathway is also modulated by leptin in different cell types. For instance, leptin reduced the activity of the Na+/K+ ATPase significantly by activating p38MAPK in Caco-2 cells ; leptin could inhibit glucose intestinal absorption by activation of p38MAPK ; Besides, leptin also could activate human B cells to secrete cytokines via activation of p38MAPK/ERK1/2 signaling pathways, which may contribute to its inflammatory and immunoregulatory properties . Furthermore, the p38MAPK pathway has also been demonstrated to be participated in the regulation of physiological process associated with atherosclerosis. Activation of p38MAPK pathway could regulate interleukin-16 -induced migration and invasion of vascular smooth muscle cells  and be involved in the suppression in oxidized low-density lipoprotein- induced endothelial cell apoptosis by paenonl . Therefore, we examined whether p38MAPK pathway could be activated by leptin treatment. Interestingly, we found that the phosphorylation of p38 could be increased by leptin (Fig. 4a, b). In addition, the inhibition of p38MAPK pathway by its inhibitor SB203580 could abolish the elevation in PCSK9 expression and the suppression of LDLR expression and LDL uptake by leptin stimulation (Fig. 4c, d, e; Additional file 6: Figure S6). On the contrary to our results, Pham DD et al. recently reported that nerve growth factor (NGF) could increase LDLR expression by stimulation of p38MAPK and activation of caspase-3 and SREBP2 cleavage in hepatocytes . In this study, the activation of SREBP2 was mediated by signaling pathway triggered by ligand-activated p75NTR which were induced by p38MAPK and caspase-3. In their study, Caspase-3 activation was caused by p38MAPK following NGF stimulations. In our study, leptin did not change the levels of SREBP2 proteins including both uncleaved and mature form (Additional file 5: Figure S5) but activate the p38MAPK. The possible reason is that leptin could suppress caspase-3 activity in HepG2 cells . Thereby the p75NTR could not be activated and then SREBP2 cleavage would not be affected by letpin.
Additionally, statins are the major-class therapy currently used for patients with increased serum LDL-C by upregulating the LDLR expression in hepatocytes . Therefore, it might be interesting to investigate whether leptin could diminish the enhanced LDLR expression induced by atorvastatin treatment. Our results showed that leptin could block the increase of LDLR expression induced by atorvastatin treatment (Fig. 5). This inhibition in the statin-induced LDLR up-regulation by leptin was partially contributed by increasing PCSK9 protein level. These results suggested that inhibitors for leptin might enhance hepatic LDLR expression and reduce plasma LDL-C level when it was administered combined with statins. Further studies are needed to conform our findings and test our hypothesis in the future.
atherosclerotic cardiovascular disease
human hepatocarcinoma cell line 2
hepatocyte nuclear factor 1 alpha
low density lipoprotein
low density lipoprotein receptor
mitogen-activated protein kinase
proprotein convertase subtilisin-kexin type 9
sterol response element binding proteins
DY and LS completed the project, and analyzed the data, and wrote the manuscript. LJJ established the study, interpreted the data, and contributed to reviewed/edited the manuscript. The other co-authors for this manuscript contributed to collect the data and conduct the experiments. We thank the staff and participants of this study for their important contributions. All authors read and approved the final manuscript.
This work was partially supported by the National Natural Science Foundation of China (81070171, 81241121), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20111106110013), the Capital Special Foundation of Clinical Application Research (Z121107001012015), the Capital Health Development Fund (2011400302, 2016-1-4035), and the Beijing Natural Science Foundation (7131014) awarded to Dr. Jian-Jun Li, MD, PhD.
The authors declare that they have no competing interests.
Availability of data and materials
The relevant raw data will not be shared because the data from cell described and presented in the manuscript are completed and clear for testing by reviewers.
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