Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways

Abstract

Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.

TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target

“…A reduction in aortic TXNIP expression levels increased TRX expression levels, leading to the ablation of NADPH oxidase expression 21 , which protected against endothelial dysfunction induced by several disorders. Research on diabetes-related mouse models has demonstrated the generation of oxidative stress and excessive ROS production due to the ablation of TRX activity by TXNIP 23 . In addition, TXNIP regulates the production of ROS through mitochondria and NADPH oxidase under high glucose conditions 23 , 24 .…”

“…Research on diabetes-related mouse models has demonstrated the generation of oxidative stress and excessive ROS production due to the ablation of TRX activity by TXNIP 23 . In addition, TXNIP regulates the production of ROS through mitochondria and NADPH oxidase under high glucose conditions 23 , 24 . These findings demonstrate two-way negative feedback between ROS and TXNIP, and reduced TRX acts as an intermediate 20 .…”