Pentoxifylline attenuates methionine- and choline-deficient-diet-induced steatohepatitis by suppressing TNF-α expression and endoplasmic reticulum stress.
BACKGROUND
Pentoxifylline (PTX) anti-TNF properties are known to exert hepatoprotective effects in various liver injury models. The aim of this study was to investigate whether PTX has beneficial roles in the development of methionine- and choline-deficient-(MCD-) diet-induced NAFLD SD rats in vivo and TNF-α-induced Hep3B cells in vitro.


METHODS
SD Rats were classified according to diet (chow or MCD diet) and treatment (normal saline or PTX injection) over a period of 4 weeks: group I (chow + saline, n = 4), group II (chow + PTX), group III (MCD + saline), and group IV (MCD + PTX). Hep3B cells were treated with 100 ng/ml TNF-α (24 h) in the absence or presence of PTX (1 mM).


RESULTS
PTX attenuated MCD-diet-induced serum ALT levels and hepatic steatosis. In real-time PCR and western blotting analysis, PTX decreased MCD-diet-induced TNF-alpha mRNA expression and proapoptotic unfolded protein response by ER stress (GRP78, p-eIF2, ATF4, IRE1α, CHOP, and p-JNK activation) in vivo. PTX (1 mM) reduced TNF-α-induced activation of GRP78, p-eIF2, ATF4, IRE1α, and CHOP in vitro.


CONCLUSIONS
PTX has beneficial roles in the development of MCD-diet-induced steatohepatitis through partial suppression of TNF-α and ER stress.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Min Kyung
MK
Chae
Sang Gyu
SG
Park
Sun-Ok
SO
Song
Eun Seok
ES
Kang
Bong Soo
BS
Cha
Hyun Chul
HC
Lee
Byung-Wan
BW
Lee
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002460:Cell Line; D002796:Choline Deficiency / Q000150:complications*; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008715:Methionine / Q000172:deficiency*; D065626:Non-alcoholic Fatty Liver Disease; D010431:Pentoxifylline / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine; D000410:Alanine Transaminase; D010431:Pentoxifylline