Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis

Abstract

BACKGROUND AND PURPOSEPentoxifylline is in clinical trials for non-alcoholic fatty liver disease and diabetic nephropathy. Metabolic and hepatic effects of pentoxifylline were assessed in a murine model of obesity and type 2 diabetes. EXPERIMENTAL APPROACHPentoxifylline (100 mg·kg -1 ·day -1 ) was administered for 4 days or 3 weeks in lean and obese/diabetic ob/ob mice. Plasma lipids, glucose, other metabolites and relevant enzymes were measured by standard assays. Hepatic lipids in vivo were assessed with magnetic resonance spectroscopy and by histology. Hepatic extracts were also analysed with RT-PCR and Western blotting. KEY RESULTSFour days of pentoxifylline treatment slightly increased liver lipids in ob/ob mice. After 3 weeks, pentoxifylline exacerbated fatty liver and plasma transaminases in ob/ob mice but did not induce liver steatosis in lean mice. Plasma glucose was highest in fed, but not fasted, ob/ob mice treated with pentoxifylline. During the first 10 min of an oral glucose tolerance test, blood glucose increased more rapidly in pentoxifylline-treated mice. Jejunal expression of glucose transporter 2 isoform was increased in pentoxifylline-treated obese mice. Hepatic activity of carbohydrate response element binding protein (ChREBP) increased after pentoxifylline in ob/ob, but not lean, mice. Hepatic expression of lipogenic enzymes was highest in pentoxifylline-treated ob/ob mice. However, pentoxifylline reduced markers of oxidative stress and inflammation in ob/ob liver. CONCLUSION AND IMPLICATIONSPentoxifylline exacerbated fatty liver in ob/ob mice through enhanced intestinal glucose absorption, increased postprandial glycaemia and activation of hepatic lipogenesis. Long-term treatment with pentoxifylline could worsen fatty liver in some patients with pre-existing hyperglycaemia. AbbreviationsACC, acetyl-CoA carboxylase; ALT, alanine aminotransferase; AMPK, AMP-activated protein kinase; AST, aspartate aminotransferase; ChREBP, carbohydrate response element binding protein; FAO, fatty acid oxidation; FAS, fatty acid synthase; GLUT2, glucose transporter 2 isoform; GSH, reduced glutathione; HOMA-IR, homeostatic model assessment of insulin resistance; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; MRS, magnetic resonance spectroscopy; MTP, microsomal triglyceride transfer protein; NEFAs, non-esterified fatty acids; OGTT, oral glucose tolerance test; SGLT-1, Na(+)-dependent glucose transporter-1; TBARs, thiobarbituric acid reactants BJP British Journal of Pharmacology

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

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“…Ϫ⌬⌬Ct method was used to express the relative expression of each selected gene (Begriche et al, 2008a;Massart et al, 2012). Quantification of the mitochondrial DNA (mtDNA) was also performed by RT-qPCR after extraction of total genomic DNA by using the QIAGEN DNeasy tissue kit (QIAGEN, Courtaboeuf, France).…”

Pentoxifylline prevents nonalcoholic steatohepatitis-related liver pre-neoplasms by inhibiting hepatic inflammation and lipogenesis

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Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice

“…In NAFLD induced by a cholineand methionine-deficient diet, pentoxifylline treatment was beneficial because it decreased hepatic inflammation and alanine aminotransferase (ALT) levels [11] . However, in a genetic obesity model, pentoxifylline worsened fatty liver in ob/ob mice because it increased intestinal glucose absorption, and thus, hyperglycemia [12] . Considering that obesity is strongly associated with the development of NAFLD and one of the main causes of epidemic obesity is a hyperlipidic and hypercaloric diet, our study evaluated the effects of pentoxifylline in a high-fat diet (HFD)-induced obesity model.…”