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Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice

Elevated circulating homocysteine (Hcy) has been proposed to be associated with non-alcoholic fatty liver disease (NAFLD). It is also reported that Hcy causes protein misfolding in the endoplasmic reticulum (ER). In this study, we used a high methionine diet (HMD)-fed mouse model and cultured primar...

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Autores principales: Ai, Yanbiao, Sun, Zhenzhen, Peng, Chuan, Liu, Lingli, Xiao, Xiaoqiu, Li, Jibin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409685/
https://www.ncbi.nlm.nih.gov/pubmed/28368295
http://dx.doi.org/10.3390/nu9040346
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author Ai, Yanbiao
Sun, Zhenzhen
Peng, Chuan
Liu, Lingli
Xiao, Xiaoqiu
Li, Jibin
author_facet Ai, Yanbiao
Sun, Zhenzhen
Peng, Chuan
Liu, Lingli
Xiao, Xiaoqiu
Li, Jibin
author_sort Ai, Yanbiao
collection PubMed
description Elevated circulating homocysteine (Hcy) has been proposed to be associated with non-alcoholic fatty liver disease (NAFLD). It is also reported that Hcy causes protein misfolding in the endoplasmic reticulum (ER). In this study, we used a high methionine diet (HMD)-fed mouse model and cultured primary hepatocytes to investigate the effects of Hcy on hepatic lipids metabolism. C57BL/6J mice received either standard chow diet (CT, n = 10) or diet supplemented with 2% methionine (MET, n = 10) for 16 weeks. In in vitro experiments, cultured mouse primary hepatocytes were treated with Hcy, or Hcy combined with 4-phenylbutyric acid (4-PBA), or tunicamycin (TM), respectively. HMD-fed mice exhibited a mild increase in plasma Hcy level. There was no significant difference of body weight gain between the two groups. Nevertheless, HMD feeding increased epididymal fat/body weight ratio, elevated plasma triglyceride (TG) level, and decreased high-density lipoprotein cholesterol (HDL) level. Similarly, mice on HMD displayed higher liver/body weight ratio, plasma aspartate aminotransferase (AST) and its ratio to alanine aminotransferase (ALT), which was supported by the morphological observations of hepatic triglyceride accumulation in liver tissue as well as primary hepatocytes. Activation of the sterol response element-binding protein 1c (SREBP1c) in Hcy-treated hepatocytes with increased expression of genes involved in hepatic de novo lipogenesis was partially reduced by pretreatment of 4-PBA. Hcy-induced ER stress was also ameliorated by 4-PBA pretreatment, thus demonstrating an important role of Hcy-induced ER stress response in hepatic steatosis. These findings suggest that elevated Hcy was a critical factor in the pathogenesis of NAFLD. Activation of the ER stress response may be involved in Hcy-induced hepatic steatosis.
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spelling pubmed-54096852017-05-03 Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice Ai, Yanbiao Sun, Zhenzhen Peng, Chuan Liu, Lingli Xiao, Xiaoqiu Li, Jibin Nutrients Article Elevated circulating homocysteine (Hcy) has been proposed to be associated with non-alcoholic fatty liver disease (NAFLD). It is also reported that Hcy causes protein misfolding in the endoplasmic reticulum (ER). In this study, we used a high methionine diet (HMD)-fed mouse model and cultured primary hepatocytes to investigate the effects of Hcy on hepatic lipids metabolism. C57BL/6J mice received either standard chow diet (CT, n = 10) or diet supplemented with 2% methionine (MET, n = 10) for 16 weeks. In in vitro experiments, cultured mouse primary hepatocytes were treated with Hcy, or Hcy combined with 4-phenylbutyric acid (4-PBA), or tunicamycin (TM), respectively. HMD-fed mice exhibited a mild increase in plasma Hcy level. There was no significant difference of body weight gain between the two groups. Nevertheless, HMD feeding increased epididymal fat/body weight ratio, elevated plasma triglyceride (TG) level, and decreased high-density lipoprotein cholesterol (HDL) level. Similarly, mice on HMD displayed higher liver/body weight ratio, plasma aspartate aminotransferase (AST) and its ratio to alanine aminotransferase (ALT), which was supported by the morphological observations of hepatic triglyceride accumulation in liver tissue as well as primary hepatocytes. Activation of the sterol response element-binding protein 1c (SREBP1c) in Hcy-treated hepatocytes with increased expression of genes involved in hepatic de novo lipogenesis was partially reduced by pretreatment of 4-PBA. Hcy-induced ER stress was also ameliorated by 4-PBA pretreatment, thus demonstrating an important role of Hcy-induced ER stress response in hepatic steatosis. These findings suggest that elevated Hcy was a critical factor in the pathogenesis of NAFLD. Activation of the ER stress response may be involved in Hcy-induced hepatic steatosis. MDPI 2017-04-01 /pmc/articles/PMC5409685/ /pubmed/28368295 http://dx.doi.org/10.3390/nu9040346 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ai, Yanbiao
Sun, Zhenzhen
Peng, Chuan
Liu, Lingli
Xiao, Xiaoqiu
Li, Jibin
Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice
title Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice
title_full Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice
title_fullStr Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice
title_full_unstemmed Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice
title_short Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice
title_sort homocysteine induces hepatic steatosis involving er stress response in high methionine diet-fed mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409685/
https://www.ncbi.nlm.nih.gov/pubmed/28368295
http://dx.doi.org/10.3390/nu9040346
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