PMID- 25003952 OWN - NLM STAT- MEDLINE DCOM- 20150626 LR - 20161125 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 61 IP - 5 DP - 2014 Nov TI - Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1alpha regulation in vitro and in vivo. PG - 1151-7 LID - S0168-8278(14)00462-0 [pii] LID - 10.1016/j.jhep.2014.06.032 [doi] AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and type 2 diabetes. Thioredoxin-interacting protein (TXNIP) regulates the cellular redox state and metabolism and has been linked to many diseases, including diabetes. Therefore, we examined the role of TXNIP in hepatic steatosis in vitro and in vivo. METHODS: Lipogenic and inflammatory proteins produced by hepatocytes treated with palmitic acid (PA) or transfected with TXNIP or Txnip siRNA were measured by Western blotting. Lipid accumulation was assessed using Oil Red O staining. Protein interactions were assessed by immunoprecipitation and proximity ligation assay. Hepatic protein levels were measured by Western blotting from wild type or Txnip(-/-) mice fed a high-fat diet (HFD) or chow diet. Livers from NAFLD patients were compared with normal liver by immunohistochemistry. RESULTS: PA increased TXNIP, and inflammatory and lipogenic proteins in both AML12 and H4IIE cells. It also increased the peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha), which mediated the expression of lipogenic markers and lipid accumulation. In addition, PA increased protein arginine methyltransferase-1 (PRMT1) and PRMT1 siRNA abolished the increase in lipogenic markers with PGC-1alpha. Furthermore, TXNIP interacted with PRMT1 in PA-treated hepatocytes. In vivo, levels of lipogenic proteins, inflammatory molecules, PGC-1alpha, and PRMT1 were increased in the livers of HFD mice compared with those fed a chow diet, and were ameliorated in HFD Txnip(-/-) mice. Moreover, TXNIP, PRMT1, and PGC-1alpha were elevated in the livers of human NAFLD patients. CONCLUSIONS: TXNIP mediates hepatic lipogenesis via PRMT1 and PGC-1alpha regulation and inflammation in vitro and in vivo, implying that targeting TXNIP and PRMT1 is a potential therapeutic approach for treatment of NAFLD. CI - Copyright (c) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Park, Min-Jung AU - Park MJ AD - College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea. FAU - Kim, Dong-Il AU - Kim DI AD - College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea. FAU - Lim, Seul-Ki AU - Lim SK AD - Metabolism and Functionality Research Group, R & D Division, World Institute of Kimchi, Gwangju, Republic of Korea. FAU - Choi, Joo-Hee AU - Choi JH AD - College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea. FAU - Kim, Jong-Choon AU - Kim JC AD - College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea. FAU - Yoon, Kyung-Chul AU - Yoon KC AD - Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. FAU - Lee, Jee-Bum AU - Lee JB AD - Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. FAU - Lee, Jae-Hyuk AU - Lee JH AD - Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. FAU - Han, Ho-Jae AU - Han HJ AD - Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea. FAU - Choi, In-Pyo AU - Choi IP AD - Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Republic of Korea. FAU - Kim, Hyoung-Chin AU - Kim HC AD - Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea. FAU - Park, Soo-Hyun AU - Park SH AD - College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea. Electronic address: parksh@chonnam.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140706 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Carrier Proteins) RN - 0 (NF-kappa B) RN - 0 (PPARGC1A protein, human) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (Repressor Proteins) RN - 0 (TXNIP protein, human) RN - 0 (Transcription Factors) RN - 0 (Txnip protein, mouse) RN - 2V16EO95H1 (Palmitic Acid) RN - 52500-60-4 (Thioredoxins) RN - EC 2.1.1.319 (PRMT1 protein, human) RN - EC 2.1.1.319 (Prmt1 protein, mouse) RN - EC 2.1.1.319 (Protein-Arginine N-Methyltransferases) SB - IM MH - Animals MH - Carrier Proteins/antagonists & inhibitors/genetics/*metabolism MH - Cell Line MH - Diet, High-Fat/adverse effects MH - Disease Models, Animal MH - Hepatocytes/drug effects/metabolism MH - Humans MH - Lipogenesis MH - Liver/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - NF-kappa B/metabolism MH - Non-alcoholic Fatty Liver Disease/*etiology/*metabolism/pathology MH - Palmitic Acid/pharmacology MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MH - Protein-Arginine N-Methyltransferases/*metabolism MH - Repressor Proteins/metabolism MH - Signal Transduction/drug effects MH - Thioredoxins/antagonists & inhibitors/genetics/*metabolism MH - Transcription Factors/*metabolism OTO - NOTNLM OT - Hepatic steatosis OT - PGC-1alpha OT - PRMT OT - TXNIP EDAT- 2014/07/09 06:00 MHDA- 2015/06/27 06:00 CRDT- 2014/07/09 06:00 PHST- 2013/11/09 00:00 [received] PHST- 2014/06/17 00:00 [revised] PHST- 2014/06/30 00:00 [accepted] PHST- 2014/07/09 06:00 [entrez] PHST- 2014/07/09 06:00 [pubmed] PHST- 2015/06/27 06:00 [medline] AID - S0168-8278(14)00462-0 [pii] AID - 10.1016/j.jhep.2014.06.032 [doi] PST - ppublish SO - J Hepatol. 2014 Nov;61(5):1151-7. doi: 10.1016/j.jhep.2014.06.032. Epub 2014 Jul 6.