CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses.
Jung-Hwa HanDae-Hwan NamSeon-Hui KimAe-Rang HwangSo-Young ParkJae Hyang LimChang-Hoon WooPublished in: Antioxidants (Basel, Switzerland) (2023)
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.
Keyphrases
- high fat diet induced
- high throughput
- circulating tumor cells
- insulin resistance
- type diabetes
- endoplasmic reticulum
- metabolic syndrome
- nlrp inflammasome
- stress induced
- oxidative stress
- poor prognosis
- high fat diet
- adipose tissue
- fatty acid
- wild type
- small molecule
- blood pressure
- high glucose
- skeletal muscle
- weight loss
- blood glucose
- signaling pathway
- weight gain
- long non coding rna
- acute heart failure
- estrogen receptor
- glycemic control