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Overproduction of inter-alpha-trypsin inhibitor heavy chain 1 after loss of G alpha(13) in liver exacerbates systemic insulin resistance in mice

Title
Overproduction of inter-alpha-trypsin inhibitor heavy chain 1 after loss of G alpha(13) in liver exacerbates systemic insulin resistance in mice
Author
이창호
Keywords
HYALURONAN-BINDING PROTEINS; O-GLCNAC TRANSFERASE; N-ACETYLGLUCOSAMINE; PROTEOMIC ANALYSIS; GLCNACYLATION; CELLS; SHAP; DEGRADATION; CONTRIBUTES; ACTIVATION
Issue Date
2019-10
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Citation
SCIENCE TRANSLATIONAL MEDICINE, v. 11, no. 513, article no. eaan4735
Abstract
The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein alpha-13 (G alpha(13)) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the Gna13 gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in Gna13-deficient mice. Liver expression of ITIH1 positively correlated with surrogate markers for diabetes in patients with impaired glucose tolerance or overt diabetes. Mechanistically, a decrease in hepatic G alpha(13) caused ITIH1 oversecretion by liver through induction of O-GlcNAc transferase expression, facilitating ITIH1 deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle. Neutralization of secreted ITIH1 ameliorated glucose intolerance in obese mice. Our findings demonstrate systemic insulin resistance in mice resulting from liver-secreted ITIH1 downstream of G alpha(13) and its reversal by ITIH1 neutralization.
URI
https://stm.sciencemag.org/content/11/513/eaan4735https://repository.hanyang.ac.kr/handle/20.500.11754/154543
ISSN
1946-6234; 1946-6242
DOI
10.1126/scitranslmed.aan4735
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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