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 6

Hepatic stellate cell activation markers are elevated in Glp2r–/– mice on HFHC diet and in aged mice.

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Hepatic stellate cell activation markers are elevated in Glp2r–/– mice o...
(A) mRNA abundance, relative to Ppia, of hepatic stellate cell activation markers in hepatic RNA from Glp2r+/+ and Glp2r–/– mice on HFHC or CD as outlined in Figure 3A (n = 9–10 per group). (B) Representative Sirius red staining of liver sections with quantification of Sirius red–positive staining (left) and liver mRNA abundance, relative to Ppia, of fibrosis markers Col1a1and Acta2 (right) (n = 9–10 per group). Scale bar: 100 μm. (C) mRNA levels, relative to Ppia, of stellate cell activation markers in livers from Glp2r+/+ and Glp2r–/– male mice age 50 ± 3.5 weeks old (n = 4 each). Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, using 2-way ANOVA with Tukey correction for multiple comparisons or Student’s t test where appropriate.