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Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A.
- Source :
-
Diabetes [Diabetes] 2018 May; Vol. 67 (5), pp. 818-830. Date of Electronic Publication: 2018 Feb 23. - Publication Year :
- 2018
-
Abstract
- Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet-induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis.<br /> (© 2018 by the American Diabetes Association.)
- Subjects :
- Adult
Aged
Animals
Asian People genetics
Diabetes Mellitus, Type 2 metabolism
F-Box-WD Repeat-Containing Protein 7 metabolism
Female
Genetic Predisposition to Disease
Homeostasis
Humans
Male
Mice, Obese
Middle Aged
Obesity
Polymorphism, Genetic
Blood Glucose metabolism
Diabetes Mellitus, Type 2 genetics
F-Box-WD Repeat-Containing Protein 7 genetics
Liver metabolism
alpha-2-HS-Glycoprotein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 67
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 29475832
- Full Text :
- https://doi.org/10.2337/db17-1348