Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A

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.

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

“…Many studies indicate the molecular mechanisms developing insulin resistance are based on various specific molecules such as cytokines [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. This information [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , ...…”

Peer Review #2 of "Comprehensive analysis of long non-coding RNAs and mRNAs in skeletal muscle of diabetic Goto-Kakizaki rats during the early stage of type 2 diabetes (v0.1)"

“…In addition, skeletal muscle-specific overexpression of Il15 transgenic mice displayed greater insulin sensitivity and decreased glucose concentration (Quinn et al 2011). Liver-specific Fbxw7 knockout mice presented hyperglycemia, glucose intolerance, and insulin resistance (Zhao et al 2018). Thus, the significantly downregulated Stc2, Il15, and…”

“…5B). Among the 18 DEGs, interleukin 15 (Il15), F-box and WD repeat domain containing 7 (Fbxw7) and uncoupling protein 3 (Ucp3) were related to increased glycaemia(Gray & Kamolrat 2011;Zhao et al 2018), glucose intolerance(Fujimoto et al 2019), and increased fatty acid oxidation(Bezaire et al 2005). Among those 32 lncRNA-target mRNA pairs, 5 lncRNA-target mRNA pairs (NONRATG014028.2-Pim1, NONRATG011882.2-Il15, NONRATG013497.2-Fbxw7, NONRATG011747.2-Mrps35, and MSTRG.1662-Ucp3) appeared in 901 co-expressed lncRNA-mRNA pairs with high correlation coefficients, suggesting these dysregulated lncRNA-mRNA pairs might involve in the hyperglycemia and T2D of GK rats at the age of 3 and 4 weeks.…”

Random SNP Events for Diabetes and Their Molecular Interaction Neighborhood

“…RNF4 is a ubiquitin ligase and molecular ubiquitination events were associated with diabetic nephropathy (28). FBXW7, also has a ubiquitin ligase related function, was shown to have role in glucose metabolism and linked to obesity and diabetes (29). These and other genes with high connectivity merit further investigation for their relevance to obesity and diabetes.…”