Abstract
Impairment of unfolded protein response‐mediated lysosomal function contributes to obesity‐associated hepatic insulin resistance
The FASEB journal, Vol.33(S1), pp.765.10-765.10
04/2019
DOI: 10.1096/fasebj.2019.33.1_supplement.765.10
Abstract
Obesity greatly increases the risk of developing a wide range of diseases including insulin resistance, type 2 diabetes, cardiovascular and fatty liver disease. Mechanistically, it has been shown that lysosomal malfunction and failure to initiate the adaptive unfolded protein response (UPR) against endoplasmic reticulum (ER) stress contribute to many aspects of obesity‐associated metabolic dysfunction. The ER provides lysosomal enzymes as well as lysosomal and autophagic vesicle membranes. However, the extent and mechanisms by which unresolved ER stress contributes to the defective lysosomal‐autophagic process, and how it is related to the progression of obesity‐associated insulin resistance are essentially unknown. Previously we have demonstrated that obesity suppresses the expression of hepatic spliced X‐box binding protein 1 (sXBP1), a key transcription factor that promotes the adaptive branch of the UPR. In this study, we identified several novel potential XBP1 binding sites on the promoter of the transcription factor EB (Tfeb), a master transcription factor that controls autophagy and lysosomal biogenesis, by using RNAseq analysis performed in the livers of mice exposed to nutrient‐limited conditions. Chromatin immunoprecipitation(ChIP) analyses in primary hepatocytes and livers from mice undergoing fasting further confirmed this prediction by identifying ‐743‐523 site of Tfeb as the sXBP1 occupancy site. To determine whether hepatic Tfeb‐mediated activity requires sXBP1 binding, we generated a Tfeb‐luc reporter construct lacking this sXBP1‐binding site. Our results show that starvation‐induced activation of Tfeb is significantly suppressed in primary hepatocytes overexpressing the mutant Tfeb‐luc reporter. Furthermore, we found that expression of Tfeb and autophagy are suppressed in the livers from mice deficient for hepatic XBP1. Conversely, hepatic Tfeb activity is enhanced and autophagy is improved in liver‐specific sXBP1 transgenic mice with diet‐induced obese (DIO). These features are associated with improved systemic glucose homeostasis and ameliorated hepatic steatosis. Lastly, overexpression of Tfeb in livers of mice with liver‐specific XBP1 deficiency protects against development of obesity‐induced insulin resistance and steatosis, indicating direct functional consequences of sXBP1‐Tfeb signaling in the context of obesity. Together, these data provide novel insight into how the UPR regulates autophagy which may lead to the development of new therapeutic targets for treating obesity‐associated metabolic diseases including diabetes and non‐alcoholic fatty liver disease.
Support or Funding Information
L.Y. is supported by an American Heart Association Scientist Development Grant (15SDG25510016), an American Diabetes Association Innovative Basic Science Award (1‐18‐IBS‐149), and R01 DK108835‐01A1.
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Details
- Title: Subtitle
- Impairment of unfolded protein response‐mediated lysosomal function contributes to obesity‐associated hepatic insulin resistance
- Creators
- Zeyuan Zhang - University of IowaQingwen Qian - University of IowaMark Li - University of IowaFan Shao - University of IowaHuojun Cao - University of IowaLing Yang - University of Iowa
- Resource Type
- Abstract
- Publication Details
- The FASEB journal, Vol.33(S1), pp.765.10-765.10
- DOI
- 10.1096/fasebj.2019.33.1_supplement.765.10
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Publisher
- The Federation of American Societies for Experimental Biology
- Number of pages
- 1
- Grant note
- American Diabetes Association Innovative Basic Science Award (1‐18‐IBS‐149) American Heart Association (15SDG25510016)
- Language
- English
- Date published
- 04/2019
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Endodontics; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Dental Research
- Record Identifier
- 9984288748202771
Metrics
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