Journal Article

Increased Hepatic Fatty Acid Uptake and Esterification Contribute to Tetracycline-Induced Steatosis in Mice

You-Jin Choi, Chae-Hyeon Lee, Kang-Yo Lee, Seung-Hwan Jung and Byung-Hoon Lee

in Toxicological Sciences

Volume 145, issue 2, pages 273-282
Published in print June 2015 | ISSN: 1096-6080
Published online March 2015 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfv049
Increased Hepatic Fatty Acid Uptake and Esterification Contribute to Tetracycline-Induced Steatosis in Mice

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Tetracycline induces microvesicular steatosis, which has a poor long-term prognosis and a higher risk of steatohepatitis development compared with macrovesicular steatosis. Recent gene expression studies indicated that tetracycline treatment affects the expression of many genes associated with fatty acid transport and esterification. In this study, we investigated the role of fatty acid transport and esterification in tetracycline-induced steatosis. Intracellular lipid accumulation and the protein expression of fatty acid translocase (FAT or CD36) and diacylglycerol acyltransferase (DGAT) 2 were increased in both mouse liver and HepG2 cells treated with tetracycline at 50 mg/kg (intraperitoneal injection, i.p.) and 100 μM, respectively. Tetracycline increased the cellular uptake of boron-dipyrromethene-labeled C16 fatty acid, which was abolished by CD36 RNA interference. Oleate-induced cellular lipid accumulation was further enhanced by co-incubation with tetracycline. Tetracycline downregulated extracellular signal-regulated kinase (ERK) phosphorylation, which negatively regulated DGAT2 expression. U0126, a specific ERK inhibitor, also increased DGAT2 expression and cellular lipid accumulation. DGAT1 and 2 knock-down with specific small interfering (si)-RNA completely abrogated the steatogenic effect of tetracycline in HepG2 cells. Taken together, our data showed that tetracycline induces lipid accumulation by facilitating fatty acid transport and triglyceride esterification by upregulating CD36 and DGAT2, respectively.

Keywords: tetracycline; fatty liver; drug-induced liver injury; CD36; DGAT

Journal Article.  5331 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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