Increased hepatic Fatty Acid uptake and esterification contribute to tetracycline-induced steatosis in mice.
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.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
You-Jin
YJ
Choi
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Chae-Hyeon
CH
Lee
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Kang-Yo
KY
Lee
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Seung-Hwan
SH
Jung
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea lee@snu.ac.kr.
Byung-Hoon
BH
Lee
D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004951:Esterification; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008813:Mice, Inbred ICR; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D013752:Tetracycline; D014162:Transfection; D015854:Up-Regulation
D018955:CD36 Antigens; D005227:Fatty Acids; D047428:Protein Kinase Inhibitors; C494885:DGAT2 protein, human; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D048049:Extracellular Signal-Regulated MAP Kinases; D013752:Tetracycline
CD36; DGAT; drug-induced liver injury; fatty liver; tetracycline