Alogliptin alleviates liver fibrosis via suppression of activated hepatic stellate cell

https://doi.org/10.1016/j.bbrc.2019.02.065Get rights and content

Highlights

  • Alogliptin suppresses the activation of hepatic stellate cell.

  • Alogliptin ameliorates the progression of liver fibrosis.

  • DPP4 may be a potential target for liver fibrosis therapy.

Abstract

Liver fibrosis occurs in most types of chronic liver diseases. The understanding of the pathogenesis of liver fibrosis has grown considerably, but the effective treatments are still lacking. Alogliptin, a classical Dipeptidyl peptidase-4 (DPP4) inhibitor with great effects on type 2 diabetes, has shown the potential to protect liver, but its effects on the progression of liver fibrosis have not been clarified. Herein, we explored the anti-fibrosis effects of alogliptin. In vitro, we demonstrated that alogliptin suppressed the activation of LX-2 upon transforming growth factor-β (TGF-β) challenge. In vivo, chronic treatment with alogliptin alleviated hepatic steatosis and protected from the liver injury in ob/ob mice, which delayed the progression of liver fibrosis. Furthermore, alogliptin significantly relieved the hepatic fibrosis in CCl4-induced liver fibrosis mouse model. In conclusion, our results demonstrate that negatively modulation of alogliptin on hepatic stellate cell (HSC) activation might contribute to liver fibrosis alleviation. Our research provides the potential possibility of alogliptin on the application for liver fibrosis therapy and suggests that DPP4 may be a novel target for liver fibrosis therapy.

Introduction

Liver fibrosis is becoming global epidemics. Pathogenic factors including viral hepatitis, chemical or drug induced-liver disease, alcoholic or nonalcoholic fatty liver, and autoimmune liver disease may cause liver fibrosis [1]. When liver tissue is repeatedly or continuously damaged or inflamed, scarring response occurs in liver parenchyma [2]. Due to the long-term progress of liver fibrosis, therapies should be tolerated and safe, with good targeting to the liver and less side effects on other organs [3]. The fibrogenic process is reversible, and the best anti-fibrotic therapy is to eliminate the underlying disease process. Although the understanding of the cellular and molecular mechanisms of hepatic fibrosis has progressed immensely [4], there is still no effective anti-fibrotic drug to reverse liver fibrosis. Thus, finding a clinically drug which shows anti-fibrotic effects as a candidate may be a feasible approach.

Liver fibrosis is a wound-healing process with the pathological characteristic of excessive extracellular matrix (ECM) accumulation and activated HSC in perisinusoidal space [5]. HSC belongs to resident mesenchymal cell type, localized in the perisinusoidal space between hepatocytes and sinusoidal endothelial cells [6]. HSC is the main cell source of ECM in liver tissue [7]. When liver injury occurs, various mediators drive HSC to activate and transdifferentiate into myofibroblasts, which plays a key role in ECM remodeling and contributes to promotion of hepatic fibrosis [8].

Alogliptin, a highly specific inhibitor of DPP4, is a therapeutic option for type 2 diabetes which has been approved by FDA in 2013 [9]. And it is the first DPP4 inhibitor for type 2 diabetes treatment that has been confirmed with cardiovascular safety in China [10]. Alogliptin plays an important role in the prevention of heart failure-induced atrial fibrillation [11]. In addition, alogliptin has potential anti-atherosclerotic properties [12].

Several studies have reported that DPP4 inhibitor sitagliptin improved Non-Alcoholic Fatty Liver Disease (NAFLD) clinically and pre-clinically [[13], [14], [15]], but studies of alogliptin on the progress of liver fibrosis are limited. Herein, we wondered the potential effects of alogliptin on anti-fibrosis. In our study, we found that alogliptin effectively suppressed HSC activation and improved the symptoms of liver fibrosis. Thus, researches about the anti-fibrotic effects of alogliptin may provide a novel strategy for treating liver fibrosis.

Section snippets

Reagents and antibodies

Recombinant human TGF-β1 Protein (10804-HNAC) was from Sino Biological. DPP4 inhibitor alogliptin Benzoate (HY-A0023) was from MedChemExpress. Anti-α-SMA (ab5694) antibody was from abcam. Anti-collagen I (A1352), anti-fibronectin (A16678), anti-Smad2 (A7699), anti-Smad3 (A7536) and anti-phospho-Smad2-S465/467 + Smad3-S423/425 (AP0548) antibodies were purchased from ABclonal. Anti-phospho-Akt (Ser473) (4060S) and anti-Akt (4691S) antibodies were from Cell Signaling Technology.

Animal experiments

All animal

Alogliptin inhibits TGF-β-induced HSC activation and regulates the Smad and non-Smad pathways

Previous studies showed that HSC activation is an important contributor in the progression of liver fibrosis [16]. Thus, we demonstrated the effects of alogliptin on HSC activation. TGF-β is the most important cytokine for liver fibrosis [17]. TGF-β modulates downstream pathway and promotes HSC activation and ECM synthesis [18]. As expected, the gene and protein expressions of α-SMA, collagen I and fibronectin were significantly induced by TGF-β in LX-2 cells, suggested that LX-2 cells were

Discussion

DPP4 is a glycoprotein which is ubiquitously expressed on the surface of various cell types [22]. This exopeptidase selectively cleaves N-terminal dipeptides from a variety of substrates, including cytokines, growth factors, neuropeptides, and the incretin hormones. DPP4 contributes to various physiological and pathological events such as cancer, angiogenesis, and organ fibrosis development [23]. Recent studies have demonstrated that sitagliptin, one of DPP4 inhibitor, has anti-fibrotic

Acknowledgements

This work is supported by the National Natural Science Foundation of China (Grant 31871414, 81673489), Science and Technology Commission of Shanghai Municipality (Grant 16430724100), and K. C. Wong Education Foundation.

References (30)

  • C. Yin et al.

    Hepatic stellate cells in liver development, regeneration, and cancer

    J. Clin. Invest.

    (2013)
  • L. Cordero-Espinoza et al.

    The balancing act of the liver: tissue regeneration versus fibrosis

    J. Clin. Invest.

    (2018)
  • T. Fujita et al.

    Roles of hepatic stellate cells in liver inflammation: a new perspective

    Inflamm. Regen.

    (2016)
  • W.B. White et al.

    Alogliptin after acute coronary syndrome in patients with type 2 diabetes

    N. Engl. J. Med.

    (2013)
  • Z. Faiez et al.

    Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial

    Lancet

    (2015)
  • Cited by (0)

    1

    Equal contribution as first authors.

    View full text