Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice.
作者： Zhao Zhang , Emre Turer , Xiaohong Li , Xiaoming Zhan , Mihwa Choi
关键词:
摘要: We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The was ascribed to mutation of kelch repeat BTB (POZ) domain containing 2 (Kbtbd2) mimicked CRISPR/Cas9-targeted null allele the same gene. Kbtbd2 encodes BTB-Kelch family substrate recognition subunit Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, regulatory phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination proteasome-mediated degradation. In absence KBTBD2, accumulated 30-fold greater levels than wild-type adipocytes, excessive p110-free blocked binding p85α-p110 heterodimers IRS1, interrupting signal. Both transplantation adipose tissue homozygous germ line inactivation p85α-encoding gene Pik3r1 rescued diabetes steatosis phenotypes Kbtbd2-/- mice. down-regulated diet-induced obese insulin-resistant leptin-dependent manner. is an essential regulator insulin-signaling pathway, modulating sensitivity limiting abundance.
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