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Title: NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease

Abstract

Highlights: • FXR, PGC1α and PPARγ levels are upregulated in NHE1 deficient livers. • NHE1 deficiency downregulates expression of pro-lipogenic genes in liver. • Chronic exposure to high-fat diet upregulates hepatic NHE1 expression. • Loss of NHE1 better preserves hepatic insulin signaling in high-fat diet-fed mice. - Abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na{sup +}/H{sup +} exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress,more » which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.« less

Authors:
 [1];  [1];  [2];  [1]
  1. Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine (United States)
  2. Department of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, OH 45267 (United States)
Publication Date:
OSTI Identifier:
22416670
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 450; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; CARBOXYLASE; CHRONIC EXPOSURE; FIBROSIS; GENES; HOMEOSTASIS; HYDROGEN IONS 1 PLUS; INSULIN; LIPIDS; LIVER; METABOLIC DISEASES; MICE; PATHOGENESIS; PHOSPHORYLATION; POLYMERASE CHAIN REACTION; RECEPTORS; SODIUM IONS

Citation Formats

Prasad, Vikram, E-mail: prasadvm@ucmail.uc.edu, Chirra, Shivani, Kohli, Rohit, and Shull, Gary E. NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease. United States: N. p., 2014. Web. doi:10.1016/J.BBRC.2014.06.095.
Prasad, Vikram, E-mail: prasadvm@ucmail.uc.edu, Chirra, Shivani, Kohli, Rohit, & Shull, Gary E. NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease. United States. doi:10.1016/J.BBRC.2014.06.095.
Prasad, Vikram, E-mail: prasadvm@ucmail.uc.edu, Chirra, Shivani, Kohli, Rohit, and Shull, Gary E. Fri . "NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease". United States. doi:10.1016/J.BBRC.2014.06.095.
@article{osti_22416670,
title = {NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease},
author = {Prasad, Vikram, E-mail: prasadvm@ucmail.uc.edu and Chirra, Shivani and Kohli, Rohit and Shull, Gary E.},
abstractNote = {Highlights: • FXR, PGC1α and PPARγ levels are upregulated in NHE1 deficient livers. • NHE1 deficiency downregulates expression of pro-lipogenic genes in liver. • Chronic exposure to high-fat diet upregulates hepatic NHE1 expression. • Loss of NHE1 better preserves hepatic insulin signaling in high-fat diet-fed mice. - Abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na{sup +}/H{sup +} exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.},
doi = {10.1016/J.BBRC.2014.06.095},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 450,
place = {United States},
year = {Fri Jul 25 00:00:00 EDT 2014},
month = {Fri Jul 25 00:00:00 EDT 2014}
}
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