한빛사 논문
Tae Hyun Kim1, Ja Hyun Koo1, Mi Jeong Heo1, Chang Yeob Han1, Yong-In Kim2, Shi-Young Park3, Il Je Cho4, Chang Ho Lee5, Cheol Soo Choi3,6, Jung Weon Lee1,7, Won Kim8,*, Je-Yoel Cho2 and Sang Geon Kim1,*
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.
2Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University , Seoul 08826, Korea.
3Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 21999, Korea.
4College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Korea.
5Department of Pharmacology, Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, Korea.
6Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Korea.
7Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Korea.
8Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul National University, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
*Corresponding author.
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 α-13 (Gα13) 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-α-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 Gα13 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 Gα13 and its reversal by ITIH1 neutralization.
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