CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses
- 주제(키워드) carboxyl terminus of the Hsc70-interacting protein (CHIP) , thioredoxin-interacting protein (TXNIP) , non-alcoholic fatty liver disease (NAFLD) , endoplasmic reticulum (ER) stress , metabolic disease
- 주제(기타) Biochemistry & Molecular Biology; Chemistry, Medicinal; Food Science & Technology
- 설명문(일반) [Han, Jung-Hwa] Pusan Natl Univ, PNU GRAND Convergence Med Sci Educ Res Ctr, Sch Med, Yangsan 50612, South Korea; [Nam, Dae-Hwan] Seegene Med Fdn, Immune Res Inst, Seoul 04805, South Korea; [Kim, Seon-Hui; Hwang, Ae-Rang; Woo, Chang-Hoon] Yeungnam Univ, Dept Pharmacol, Coll Med, 170 Hyeonchung ro, Daegu 42415, South Korea; [Park, So-Young] Yeungnam Univ, Dept Physiol, Coll Med, 170 Hyeonchung ro, Daegu 42415, South Korea; [Park, So-Young; Woo, Chang-Hoon] Yeungnam Univ, Senotherpy Based Metab Dis Control Res Ctr, Coll Med, 170 Hyeonchung ro, Daegu 42415, South Korea; [Lim, Jae Hyang] Ewha Womans Univ, Dept Microbiol & Ewha Educ, Coll Med, 25 Magokdong ro 2-gil, Seoul 07804, South Korea; [Lim, Jae Hyang] Ewha Educ, 25 Magokdong ro 2-gil, Seoul 07804, South Korea; [Lim, Jae Hyang] Ewha Womans Univ, Res Ctr Infect, Coll Med, 25 Magokdong ro 2-gil, Seoul 07804, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 MDPI
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000204281
- 본문언어 영어
- Published As https://doi.org/10.3390/antiox12020458
초록/요약
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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