title: Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis.
abstract: OBJECTIVE
  Pentoxifylline 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.
  
  
  METHODS
  Pentoxifylline (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.
  
  
  RESULTS
  Four 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.
  
  
  CONCLUSIONS
  Pentoxifylline 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.
authors: INSERM, U991, Université de Rennes 1, Rennes, France.
authors: J
authors: J
authors: Massart
authors: M A
authors: MA
authors: Robin
authors: F
authors: F
authors: Noury
authors: A
authors: A
authors: Fautrel
authors: P
authors: P
authors: Lettéron
authors: A
authors: A
authors: Bado
authors: P A
authors: PA
authors: Eliat
authors: B
authors: B
authors: Fromenty
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D005951:Glucose Tolerance Test / Q000379:methods; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects* / Q000235:genetics; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000097:blood; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010431:Pentoxifylline / Q000494:pharmacology*; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000637:Transaminases / Q000097:blood; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers; D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D008055:Lipids; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; C495682:Slc2a2 protein, mouse; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D000637:Transaminases; D005947:Glucose; D010431:Pentoxifylline