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CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses

TXNIP is a critical regulator of glucose homeostasis, fatty acid synthesis, and cholesterol accumulation in the liver, and it has been reported that metabolic diseases, such as obesity, atherosclerosis, hyperlipidemia, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), are associated wit...

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Autores principales: Han, Jung-Hwa, Nam, Dae-Hwan, Kim, Seon-Hui, Hwang, Ae-Rang, Park, So-Young, Lim, Jae Hyang, Woo, Chang-Hoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9951908/
https://www.ncbi.nlm.nih.gov/pubmed/36830016
http://dx.doi.org/10.3390/antiox12020458
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author Han, Jung-Hwa
Nam, Dae-Hwan
Kim, Seon-Hui
Hwang, Ae-Rang
Park, So-Young
Lim, Jae Hyang
Woo, Chang-Hoon
author_facet Han, Jung-Hwa
Nam, Dae-Hwan
Kim, Seon-Hui
Hwang, Ae-Rang
Park, So-Young
Lim, Jae Hyang
Woo, Chang-Hoon
author_sort Han, Jung-Hwa
collection PubMed
description TXNIP is a critical regulator of glucose homeostasis, fatty acid synthesis, and cholesterol accumulation in the liver, and it has been reported that metabolic diseases, such as obesity, atherosclerosis, hyperlipidemia, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), are associated with endoplasmic reticulum (ER) stress. Because CHIP, an E3 ligase, was known to be involved in regulating tissue injury and inflammation in liver, its role in regulating ER stress-induced NAFLD was investigated in two experimental NAFLD models, a tunicamycin (TM)-induced and other diet-induced NAFLD mice models. In the TM-induced NAFLD model, intraperitoneal injection of TM induced liver steatosis in both CHIP(+/+) and CHIP(+/−) mice, but it was severely exacerbated in CHIP(+/−) mice compared to CHIP(+/+) mice. Key regulators of ER stress and de novo lipogenesis were also enhanced in the livers of TM-inoculated CHIP(+/−) mice. Furthermore, in the diet-induced NAFLD models, CHIP(+/−) mice developed severely impaired glucose tolerance, insulin resistance and hepatic steatosis compared to CHIP(+/+) mice. Interestingly, CHIP promoted ubiquitin-dependent degradation of TXNIP in vitro, and inhibition of TXNIP was further found to alleviate the inflammation and ER stress responses increased by CHIP inhibition. In addition, the expression of TXNIP was increased in mice deficient in CHIP in the TM- and diet-induced models. These findings suggest that CHIP modulates ER stress and inflammatory responses by inhibiting TXNIP, and that CHIP protects against TM- or HF–HS diet-induced NAFLD and serves as a potential therapeutic means for treating liver diseases.
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spelling pubmed-99519082023-02-25 CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses Han, Jung-Hwa Nam, Dae-Hwan Kim, Seon-Hui Hwang, Ae-Rang Park, So-Young Lim, Jae Hyang Woo, Chang-Hoon Antioxidants (Basel) Article TXNIP is a critical regulator of glucose homeostasis, fatty acid synthesis, and cholesterol accumulation in the liver, and it has been reported that metabolic diseases, such as obesity, atherosclerosis, hyperlipidemia, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), are associated with endoplasmic reticulum (ER) stress. Because CHIP, an E3 ligase, was known to be involved in regulating tissue injury and inflammation in liver, its role in regulating ER stress-induced NAFLD was investigated in two experimental NAFLD models, a tunicamycin (TM)-induced and other diet-induced NAFLD mice models. In the TM-induced NAFLD model, intraperitoneal injection of TM induced liver steatosis in both CHIP(+/+) and CHIP(+/−) mice, but it was severely exacerbated in CHIP(+/−) mice compared to CHIP(+/+) mice. Key regulators of ER stress and de novo lipogenesis were also enhanced in the livers of TM-inoculated CHIP(+/−) mice. Furthermore, in the diet-induced NAFLD models, CHIP(+/−) mice developed severely impaired glucose tolerance, insulin resistance and hepatic steatosis compared to CHIP(+/+) mice. Interestingly, CHIP promoted ubiquitin-dependent degradation of TXNIP in vitro, and inhibition of TXNIP was further found to alleviate the inflammation and ER stress responses increased by CHIP inhibition. In addition, the expression of TXNIP was increased in mice deficient in CHIP in the TM- and diet-induced models. These findings suggest that CHIP modulates ER stress and inflammatory responses by inhibiting TXNIP, and that CHIP protects against TM- or HF–HS diet-induced NAFLD and serves as a potential therapeutic means for treating liver diseases. MDPI 2023-02-11 /pmc/articles/PMC9951908/ /pubmed/36830016 http://dx.doi.org/10.3390/antiox12020458 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Han, Jung-Hwa
Nam, Dae-Hwan
Kim, Seon-Hui
Hwang, Ae-Rang
Park, So-Young
Lim, Jae Hyang
Woo, Chang-Hoon
CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses
title CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses
title_full CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses
title_fullStr CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses
title_full_unstemmed CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses
title_short CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses
title_sort chip haploinsufficiency exacerbates hepatic steatosis via enhanced txnip expression and endoplasmic reticulum stress responses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9951908/
https://www.ncbi.nlm.nih.gov/pubmed/36830016
http://dx.doi.org/10.3390/antiox12020458
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