Protein degradation pathways in hepatic ER stress and insulin resistance

Wang, H 2015, Protein degradation pathways in hepatic ER stress and insulin resistance, Doctor of Philosophy (PhD), Health Sciences, RMIT University.

Document type: Thesis
Collection: Theses

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Title Protein degradation pathways in hepatic ER stress and insulin resistance
Author(s) Wang, H
Year 2015
Abstract Over consumption of high-fat or high-carbohydrate diet has been shown to cause insulin resistance in both animals and humans. Although both diets can result in an accumulation of lipids to interfere with insulin signal transduction, the mechanisms and pathways involved are different. This thesis focused on the crosstalk of pathways in relation to the pathogenesis of hepatic insulin resistance using mouse models, especially in the context of over consumption of a lipogenic carbohydrate, fructose. The results showed high-fructose diet lead to insulin resistance primarily through the induction of endoplasmic reticulum (ER) stress, which impaired insulin signalling through the activation of inflammatory enzymes.

Since ER stress results from an accumulation of unfolded proteins, this thesis further investigated two major pathways responsible for protein degradation, namely autophagy and ubiquitin proteasome system (UPS) and found both were altered along with ER stress. Autophagy was suppressed by fructose and restoration of autophagy was able to diminish ER stress and normalize insulin signalling. On the other hand, Nedd4-2, which is part of the UPS, was upregulated by fructose and ER stress inducers. Overexpression of Nedd4-2 was shown to induce autophagy and attenuate ER stress. These data suggest that the alteration in protein degradation pathways is causal to high-carbohydrate diet-induced insulin resistance and also provide a scientific rationale for targeting the degradation pathways for the treatment of insulin resistance and associated metabolic disorders.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Health Sciences
Keyword(s) Type 2 diabetes
Insulin resistance
ER stress
Protein degradation
Ubiquitin ligase
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Created: Fri, 06 Nov 2015, 09:12:00 EST by Denise Paciocco
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