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Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies.

ABSTRACT: Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-?B-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.

SUBMITTER: de Mesquita FC

PROVIDER: S-EPMC5468330 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies.

de Mesquita Fernanda Cristina FC Guixé-Muntet Sergi S Fernández-Iglesias Anabel A Maeso-Díaz Raquel R Vila Sergi S Hide Diana D Ortega-Ribera Martí M Rosa José Luís JL García-Pagán Juan Carlos JC Bosch Jaime J de Oliveira Jarbas Rodrigues JR Gracia-Sancho Jordi J

Scientific reports 20170612 1

Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or veh ...[more]

PMID: 28607430

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Project description:BackgroundTianxiangdan (TXD) is used in traditional Chinese medicine because of its therapeutic and preventive effects in the treatment of coronary heart disease. However, the underlying mechanism of TXD in coronary microvascular disease (CMD) remains unclear.MethodsA rat model of CMD was developed to study the mechanism of TXD activity. Sodium laurate was injected into the left ventricle of Sprague-Dawley rats to induce CMD. The rats were divided into six groups: a sham-operated (sham) group, an untreated CMD group, a low-dose TXD group (0.81 g·kg-1·d-1), a mid-dose TXD (TXD-M) group (1.62 g·kg-1·d-1), a high-dose TXD (TXD-H) group (3.24 g·kg-1·d-1), and a nicorandil (NCR) group (1.35 mg·kg-1·d-1). The effect of TXD on rats with CMD was observed after four weeks, and the mechanism of TXD in lipopolysaccharide (LPS)-induced cardiac microvascular endothelial cells (CMECs) was explored through treatment with 50 μg/mL TXD.ResultsCompared with the rats in the untreated CMD group, rats in the TXD-M and TXD-H groups showed higher left ventricular ejection fraction values, improved pathological structures, decreased expressions of interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), phosphorylated nuclear factor-κB inhibitor α (IκBα) and phosphorylated p65, and increased expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (P < 0.05). These effects were more pronounced in the TXD-H group than in the TXD-M group. In vitro experiments showed that TXD treatment increased the viability of LPS-induced CMECs and decreased the expression of IL-1β, TNF-α, phosphorylated IκBα, and phosphorylated p65 (P < 0.05). However, the effects of TXD on CMECs were markedly reversed upon treatment with ML385 (Nrf2 inhibitor).ConclusionThe results showed that TXD exerts a protective effect on rats with CMD and related inflammatory injuries, and its anti-inflammatory mechanism is related to the activation of Nrf2 signalling.

Project description:BackgroundAlthough several risk factors for erectile dysfunction may be present in patients with cirrhosis, data on the actual prevalence and cause of erectile dysfunction is limited. The International Index of Erectile Function-5 (IIEF-5) is a well-validated survey to determine the presence and severity of erectile dysfunction in men. We assessed (i) the prevalence and severity of erectile dysfunction, and (ii) risk factors for erectile dysfunction in patients with cirrhosis.MethodsIn this prospective study, erectile dysfunction was defined as: absent (>21 IIEF-5-points), mild (12-21) and severe (5-11). Patients with overt hepatic encephalopathy, active alcohol abuse, extrahepatic malignancy, previous urologic surgery, previous liver transplantation and severe cardiac conditions were excluded.ResultsAmong n = 151 screened patients, n = 41 met exclusion criteria and n = 30 were sexually inactive. Thus, a final number of n = 80 male patients with cirrhosis were included. Patient characteristics: age: 53 ± 9 years; model for end-stage liver disease score (MELD): 12.7 ± 3.9; Child-Pugh score (CPS) A: 30 (37.5%), B: 35 (43.8%), C: 15 (18.7%); alcohol: 38 (47.5%), viral: 25 (31.3%), alcohol/viral: 7 (8.8%) and others: 10 (12.5%). The presence of erectile dysfunction was found in 51 (63.8%) patients with 44 (55%) and 7 (8.8%) suffering from mild-to-moderate and moderate-to-severe erectile dysfunction. Mean MELD and hepatic venous pressure gradient (HVPG) were significantly higher in patients with erectile dysfunction (P = .021; P = .028). Child-Pugh score C, MELD, creatinine, age, arterial hypertension, diabetes, low libido, low testosterone and high HVPG were associated with the presence of erectile dysfunction. Interestingly, beta-blocker therapy was not associated with an increased risk. In multivariate models, arterial hypertension (OR: 6.36 [1.16-34.85]; P = .033), diabetes (OR: 7.40 [1.31-41.75]; P = .023), MELD (OR: 1.19 [1.03-1.36]; P = .015) and increasing HVPG (n = 48; OR: 1.11 [1.002-1.23]; P = .045) were independent risk factors for the presence of erectile dysfunction.ConclusionAbout two-thirds of male patients with cirrhosis show erectile dysfunction. Severity of liver dysfunction, portal hypertension, arterial hypertension and diabetes were identified as risk factors for erectile dysfunction.

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Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies.

Publications

Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies.

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