Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1α regulation in vitro and in vivo.

Abstract

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-1α (PGC-1α), 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-1α. Furthermore, TXNIP interacted with PRMT1 in PA-treated hepatocytes. In vivo, levels of lipogenic proteins, inflammatory molecules, PGC-1α, 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-1α were elevated in the livers of human NAFLD patients.

CONCLUSIONS:

TXNIP mediates hepatic lipogenesis via PRMT1 and PGC-1α regulation and inflammation in vitro and in vivo, implying that targeting TXNIP and PRMT1 is a potential therapeutic approach for treatment of NAFLD.

• Authors: Min-Jung Park, Dong-Il Kim, Seul-Ki Lim, Joo-Hee Choi, Jong-Choon Kim, Kyung-Chul Yoon, Jee-Bum Lee, Jae-Hyuk Lee, Ho-Jae Han, In-Pyo Choi, Hyoung-Chin Kim, Soo-Hyun Park
• Journal: Journal of hepatology (J Hepatol) Vol. 61 Issue 5 Pg. 1151-7 (Nov 2014) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 25003952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Carrier Proteins
• NF-kappa B
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Repressor Proteins
• TXNIP protein, human
• Transcription Factors
• Txnip protein, mouse
• Palmitic Acid
• Thioredoxins
• PRMT1 protein, human
• Prmt1 protein, mouse
• Protein-Arginine N-Methyltransferases

Topics

• Animals
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Line
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Hepatocytes (drug effects, metabolism)
• Humans
• Lipogenesis
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Non-alcoholic Fatty Liver Disease (etiology, metabolism, pathology)
• Palmitic Acid (pharmacology)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Protein-Arginine N-Methyltransferases (metabolism)
• Repressor Proteins (metabolism)
• Signal Transduction (drug effects)
• Thioredoxins (antagonists & inhibitors, genetics, metabolism)
• Transcription Factors (metabolism)