Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Oct 28, 2015; 7(24): 2551-2558
Published online Oct 28, 2015. doi: 10.4254/wjh.v7.i24.2551
Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice
Simone Coghetto Acedo, Cintia Rabelo e Paiva Caria, Érica Martins Ferreira Gotardo, José Aires Pereira, José Pedrazzoli, Marcelo Lima Ribeiro, Alessandra Gambero
Simone Coghetto Acedo, Cintia Rabelo e Paiva Caria, Érica Martins Ferreira Gotardo, José Aires Pereira, José Pedrazzoli, Marcelo Lima Ribeiro, Alessandra Gambero, Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, Bragança Paulista SP 12916-900, Brazil
Author contributions: Acedo SC, Caria CRP, Gotardo ÉMF and Pereira JA performed the experiments; Pedrazzoli J analyzed the data and wrote the manuscript; Ribeiro ML and Gambero A designed the experiments, analyzed the data and wrote the manuscript.
Supported by The Fundação de Amparo à Pesquisa do Estado de São Paulo, No. FAPESP 2011/00518-4.
Institutional review board statement: This work received approval from the Ethics Committee of São Francisco University, Bragança Paulista, SP, Brazil (Protocol CEA/USF 00.02.11).
Institutional animal care and use committee statement: This work was performed in accordance with the principles outlined by the National Council for the Control of Animal Experimentation (CONCEA, Brazil) and it was approved by Ethics Committee of São Francisco University, Bragança Paulista, SP, Brazil (Protocol CEA/USF 00.02.11).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Alessandra Gambero, PhD, Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, Av. São Francisco de Assis 218, Bragança Paulista SP 12916-900, Brazil. alessandra.gambero@usf.edu.br
Telephone: +55-11-245488982 Fax: +55-11-24548974
Received: June 17, 2015
Peer-review started: June 17, 2015
First decision: July 3, 2015
Revised: July 28, 2015
Accepted: September 29, 2015
Article in press: September 30, 2015
Published online: October 28, 2015
Processing time: 135 Days and 11.2 Hours
Abstract

AIM: To study pentoxifylline effects in liver and adipose tissue inflammation in obese mice induced by high-fat diet (HFD).

METHODS: Male swiss mice (6-wk old) were fed a high-fat diet (HFD; 60% kcal from fat) or AIN-93 (control diet; 15% kcal from fat) for 12 wk and received pentoxifylline intraperitoneally (100 mg/kg per day) for the last 14 d. Glucose homeostasis was evaluated by measurements of basal glucose blood levels and insulin tolerance test two days before the end of the protocol. Final body weight was assessed. Epididymal adipose tissue was collected and weighted for adiposity evaluation. Liver and adipose tissue biopsies were homogenized in solubilization buffer and cytokines were measured in supernatant by enzyme immunoassay or multiplex kit, respectively. Hepatic histopathologic analyses were performed in sections of paraformaldehyde-fixed, paraffin-embedded liver specimens stained with hematoxylin-eosin by an independent pathologist. Steatosis (macrovesicular and microvesicular), ballooning degeneration and inflammation were histopathologically determined. Triglycerides measurements were performed after lipid extraction in liver tissue.

RESULTS: Pentoxifylline treatment reduced microsteatosis and tumor necrosis factor (TNF)-α in liver (156.3 ± 17.2 and 62.6 ± 7.6 pg/mL of TNF-α for non-treated and treated obese mice, respectively; P < 0.05). Serum aspartate aminotransferase levels were also reduced (23.2 ± 6.9 and 12.1 ± 1.6 U/L for non-treated and treated obese mice, respectively; P < 0.05) but had no effect on glucose homeostasis. In obese adipose tissue, pentoxifylline reduced TNF-α (106.1 ± 17.6 and 51.1 ± 9.6 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) and interleukin-6 (340.8 ± 51.3 and 166.6 ± 22.5 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) levels; however, leptin (8.1 ± 0.7 and 23.1 ± 2.9 ng/mL for non-treated and treated lean mice, respectively; P < 0.05) and plasminogen activator inhibitor-1 (600.2 ± 32.3 and 1508.6 ± 210.4 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) levels increased in lean adipose tissue. TNF-α level in the liver of lean mice also increased (29.6 ± 6.6 and 75.4 ± 12.6 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) while triglycerides presented a tendency to reduction.

CONCLUSION: Pentoxifylline was beneficial in obese mice improving liver and adipose tissue inflammation. Unexpectedly, pentoxifylline increased pro-inflammatory markers in the liver and adipose tissue of lean mice.

Keywords: Pentoxifylline, Steatosis, Obesity, Adipose tissue, Adipokine, Tumor necrosis factor-α

Core tip: Pentoxifylline is prescribed to patients with severe alcoholic hepatitis, which suggest that this drug could also be beneficial to non-alcoholic steatohepatitis (NASH) patients. However, experimental results with pentoxifylline have shown conflicting data depending on the NASH model employed. Considering that obesity is strongly associated with the development of NASH, our study evaluated the effects of pentoxifylline in a high-fat diet induced obesity model. Our results showed that pentoxifylline was beneficial in obesity-associated NASH improving liver and adipose tissue inflammation. Unexpectedly, pentoxifylline treatment resulted in undesirable effects in adipose tissue and liver inflammatory markers in lean mice.