Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in mice
Shai Fuchs, … , Dianne Matthews, Daniel J. Drucker
Shai Fuchs, … , Dianne Matthews, Daniel J. Drucker
Published March 19, 2020
Citation Information: JCI Insight. 2020;5(8):e136907. https://doi.org/10.1172/jci.insight.136907.
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Research Article Endocrinology Metabolism

Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in mice

Abstract

A glucagon-like peptide-2 (GLP-2) analog is used in individuals with intestinal failure who are at risk for liver disease, yet the hepatic actions of GLP-2 are not understood. Treatment of high-fat diet–fed (HFD-fed) mice with GLP-2 did not modify the development of hepatosteatosis or hepatic inflammation. In contrast, Glp2r–/– mice exhibited increased hepatic lipid accumulation, deterioration in glucose tolerance, and upregulation of biomarkers of hepatic inflammation. Both mouse and human liver expressed the canonical GLP-2 receptor (GLP-2R), and hepatic Glp2r expression was upregulated in mice with hepatosteatosis. Cell fractionation localized the Glp2r to hepatic stellate cells (HSCs), and markers of HSC activation and fibrosis were increased in livers of Glp2r–/– mice. Moreover, GLP-2 directly modulated gene expression in isolated HSCs ex vivo. Taken together, these findings define an essential role for the GLP-2R in hepatic adaptation to nutrient excess and unveil a gut hormone-HSC axis, linking GLP-2R signaling to control of HSC activation.

Authors

Shai Fuchs, Bernardo Yusta, Laurie L. Baggio, Elodie M. Varin, Dianne Matthews, Daniel J. Drucker

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Figure 7

GLP-2 treatment does not change CCl4-mediated liver injury and fibrosis.

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GLP-2 treatment does not change CCl4-mediated liver injury and fibrosis....
Fibrosis, liver enzymes, and RNA levels of genes reflecting hepatic stellate cell (HSC) activation in C57BL/6 mice treated with CCl4 or mineral oil vehicle, together with daily GLP-2 (0.2 mg/kg, SC) or vehicle. (A) Mice were pretreated with once-daily GLP-2 or vehicle starting 2 days prior to initiation of CCl4 treatment. A total of 4 CCl4 (0.7 ml/kg) or vehicle i.p. injections were administered (once every 3 days), and then mice were sacrificed 3 days after the last CCl4 injection. GLP-2 was continued until the final day (n = 8–11 per group). (B) Plasma ALT levels at sacrifice. (C) Representative Sirius red staining of liver sections (scale bar: 100 μm) and quantification of Sirius red–positive area. (D) mRNA abundance of genes corresponding to markers of fibrosis and stellate cell activation in whole liver, normalized to Ppia. (E) mRNA abundance of reporters in purified hepatic stellate cells (HSC), normalized to Pdgfrb. Each data point represents cells combined from 1–4 mice. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, §P < 0.05 significant effect of treatment on gene expression variance, using 2-way ANOVA with Tukey correction for multiple comparisons.