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Updated: Jan 22, 2026

Hepatocyte-specific Ablation in Zebrafish to Study Biliary-driven Liver Regeneration
Published on: May 20, 2015
Hepatocyte-specific HIF-1α ablation improves obesity-induced glucose intolerance by reducing first-pass GLP-1
Yun Sok Lee1, Matthew Riopel1, Pedro Cabrales2
1Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Abstract:
The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity-induced changes in liver oxygen homeostasis, we found that liver HIF-1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. Deletion of hepatocyte HIF-1α protected obesity-induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. In-depth mouse metabolic phenotyping revealed that obesity increased first-pass degradation of an incretin hormone GLP-1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP-1 levels in peripheral circulation. Hepatocyte HIF-1α KO blocked these changes induced by obesity. Deletion of hepatocyte HIF-2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity-induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter-organ communications.
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