Pentoxifylline ameliorates non-alcoholic fatty liver disease in hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation.

Jia-Hung Ye,Jiunn-Wang Liao,Jung Chao,Li-Heng Pao,Hao-Yuan Cheng,Ming-Ling Chang,Wen-Huang Peng

doi:10.1038/srep33102

Abstract

Nonalcoholic fatty liver disease (NAFLD), which includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis, is characterised by abnormal fat accumulation in the liver in the absence of excessive alcohol intake. In patients with type 2 diabetes (T2D), concurrent NAFLD might increase the risk of chronic kidney disease and the mortality rate. Although several studies have examined the effectiveness of pentoxifylline (PTX) in NAFLD treatment, no results are available to verify the effectiveness of PTX in treating T2D associated with NAFLD. In this study, we developed a combined high-fat diet-induced obesity and low-dose streptozocin-induced hyperglycaemia mouse model to mimic the concurrent NAFLD and T2D pathological condition. By combining physiological assessments, pathological examinations, metabolomics studies on blood, urine, and liver, and measurements of gene and protein expression, we elucidated the effectiveness and the underlying mechanism of action of PTX in the hyperglycaemic and dyslipidaemic mice. Our results revealed that PTX ameliorated NAFLD in the hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation. Furthermore, the glycolysis pathway and branched-chain amino acid-related pathways in these mice were restored by PTX.

Highlights

Nonalcoholic fatty liver disease (NAFLD), which includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis, is characterised by abnormal fat accumulation in the liver in the absence of excessive alcohol intake
We developed a combined high-fat diet (HFD)-induced obesity and low-dose streptozocin (STZ)-induced hyperglycaemia mouse model to mimic the NAFLD-plus-type 2 diabetes (T2D) pathological condition, and used this combined mouse model to estimate the effectiveness of PTX in the treatment of concurrent NAFLD and T2D
The HOMA-IR relies on fasting blood glucose levels for evaluation, and mostly describes hepatic IR and steady-state insulin secretion[41]

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), which includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis, is characterised by abnormal fat accumulation in the liver in the absence of excessive alcohol intake. The common pharmacological mechanism of PTX was regarded as the inhibition of tumour necrosis factor-α(TNF-α) synthesis[18], and because (1) TNF-αplays a critical role in obesity and IR19 and (2) PTX can inhibit TNF-αsynthesis, several small clinical trials have been performed to verify the effectiveness of PTX in NAFLD treatment[20]. These clinical results have shown that PTX markedly lowers the levels of glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) and may ameliorate liver histopathological changes in NASH patients, further large and well-designed studies are necessary to confirm the observed effects[20]

Methods

Results

Conclusion