The impact of obesity-associated nitrosative stress on organelle function
Creators: name: Zhang, Zeyuan
Publisher: name: University of Iowa
Year: 2022
Subjects: public abstract

description: The global prevalence of obesity has increased significantly in recent decades. Obesity has been shown to be associated with many metabolic diseases, including type 2 diabetes, hypertension and cardiovascular diseases. At the cellular level, obesity promotes chronic inflammation and impairs organelle functions in different organs, consequentially leading to disturbance of metabolic homeostasis. However, in the obese condition, the molecular mechanism underlying the link between inflammation and abnormalities is incomplete. In my thesis study, we demonstrated the impact of obesity-associated nitrosative stress on the organelle function in different organs. Nitric oxide (NO) is one of the markers of inflammation. Normal level of NO is critical for physical process. However, in the obese condition, the intracellular NO level increases. We found that the protein S-nitrosylation (SNO) modification accompanied by the overproduction of NO is one of the main drivers that caused the obesity related organelle abnormalities. In both liver and brown adipose tissue (BAT), obesity elevates the SNO of proteins that are critical to maintain the proper tissue homeostasis. In the liver, local lysosomal inducible nitric oxide synthase (iNOS) expression and NO level are significantly elevated in the context of obesity, which can be attenuated by the NO scavenger. While overexpression of mTOR and the arginine transporter (SLC38A9) enhances the lysosome NO production and impairs hepatic autophagy. Furthermore, we demonstrated that deletion of iNOS improves the nitrosative stress and hepatic insulin sensitivity in the liver with diet induced obesity (DIO), which the protective effect is abolished by the deletion of transcription factor EB (TFEB) and autophagy related 7 (ATG7).
description: Previous studies including ours demonstrated that defective autophagy and a failure to initiate the adaptive unfolded protein response (UPR) in response to the endoplasmic reticulum (ER) stress contributes to obesity-associated metabolic dysfunction. However, how these two key stress responses integrate in the obese condition is unclear. Our RNA-seq analysis demonstrate that x-box binding protein 1 (XBP1, the key transcription factor regulates the adaptive unfolded protein responses) governs several lysosomal gene expressions. Our chromatin immunoprecipitation (ChIP) assay showed that XBP1 directly binds to the promoter of Tfeb to regulate the hepatic autophagy. Furthermore, our gain and loss of function of Tfeb in the mice reveal that sXbp1-TFEB axis has important role in regulating hepatic autophagy and systemic glucose homeostasis in the mice with diet-induced obesity.
description: In the BAT, the thermogenesis activity is tightly regulated by the cellular redox status. Obesity and acute cold exposure increased the general protein SNO level, including SNO of UCP1, the BAT specific thermogenesis protein. The cellular nitroso-redox status is controlled by the S-nitrosoglutathione reductase (alcohol dehydrogenase 5: ADH5). The deletion of ADH5 impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction. Mechanistically, we showed that the heat shock factor 1 (HSF1) binds to the promoter of Adh5 and administration of HFS1 activator in BAT increases the Adh5 expression and improves UCP1-mediated respiration.