Hepatic GHR deletion alters bile acid composition and links reduced FXR signaling to hepatic steatosis
- 1Metabolism and Disease Research Center, Central Hospital Affiliated to Shandong First Medical University
- 2School of Laboratory Animal and Shandong Laboratory Animal Center, Shandong First Medical University
- 3Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital Affiliated to Shandong First Medical University
Abstract
Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern. Growth hormone (GH) signaling regulates hepatic lipid metabolism, but its relationship with the bile acid–farnesoid X receptor (FXR) axis in MASLD remains unclear. We investigated the effects of hepatic GH receptor (GHR) deletion on bile acid metabolism and hepatic steatosis and evaluated the response to pharmacological FXR activation.
Materials and methods: Liver-specific Ghr knockout (LKO) mice and LL controls were examined using targeted metabolomics, bile acid profiling, biochemical assays, histology, and gene and protein expression analyses. Public human MASLD transcriptomic datasets were analyzed for GHR/IGF1–FXR expression relationships. The effects of the FXR agonist GW4064 were evaluated in LKO mice and primary LKO hepatocytes.
Results: Hepatic GHR deletion promoted steatosis, increased hepatic total and conjugated bile acids, including TαMCA, TβMCA, and TUDCA, and reduced BSEP and FXR/SHP expression. Gallbladder total and conjugated bile acids were lower in LKO mice. Hepatic GHR or IGF1 expression correlated positively with FXR expression in human MASLD datasets. GW4064 ameliorated steatosis and reduced serum markers of liver injury in LKO mice and decreased lipid accumulation in primary LKO hepatocytes. Treatment increased lipolysis-associated gene expression without significantly changing the measured lipogenic genes or Bsep expression.
Conclusions: Hepatic GHR deletion disrupts bile acid homeostasis and promotes steatosis. GW4064 improves steatosis in this model, supporting FXR activation as a potential intervention for GHR-deficient steatosis. The altered bile acid pool may contribute to reduced hepatic FXR signaling.
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BibTeX
@article{ran2026hepatic,
title = {{Hepatic GHR deletion alters bile acid composition and links reduced FXR signaling to hepatic steatosis}},
author = {Liyuan Ran and Ruolan Li and Yu Wang and Xinyu Liu and Yingjie Wu and Zichao Yu},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1919362},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1919362/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hepatic GHR deletion alters bile acid composition and links reduced FXR signaling to hepatic steatosis
AU - Liyuan Ran
AU - Ruolan Li
AU - Yu Wang
AU - Xinyu Liu
AU - Yingjie Wu
AU - Zichao Yu
PY - 2026
DA - 2026/10/15
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1919362
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1919362/full
AB - Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern. Growth hormone (GH) signaling regulates hepatic lipid metabolism, but its relationship with the bile acid–farnesoid X receptor (FXR) axis in MASLD remains unclear. We investigated the effects of hepatic GH receptor (GHR) deletion on bile acid metabolism and hepatic steatosis and evaluated the response to pharmacological FXR activation. Materials and methods: Liver-specific Ghr knockout (LKO) mice and LL controls were examined using targeted metabolomics, bile acid profiling, biochemical assays, histology, and gene and protein expression analyses. Public human MASLD transcriptomic datasets were analyzed for GHR/IGF1–FXR expression relationships. The effects of the FXR agonist GW4064 were evaluated in LKO mice and primary LKO hepatocytes. Results: Hepatic GHR deletion promoted steatosis, increased hepatic total and conjugated bile acids, including TαMCA, TβMCA, and TUDCA, and reduced BSEP and FXR/SHP expression. Gallbladder total and conjugated bile acids were lower in LKO mice. Hepatic GHR or IGF1 expression correlated positively with FXR expression in human MASLD datasets. GW4064 ameliorated steatosis and reduced serum markers of liver injury in LKO mice and decreased lipid accumulation in primary LKO hepatocytes. Treatment increased lipolysis-associated gene expression without significantly changing the measured lipogenic genes or Bsep expression. Conclusions: Hepatic GHR deletion disrupts bile acid homeostasis and promotes steatosis. GW4064 improves steatosis in this model, supporting FXR activation as a potential intervention for GHR-deficient steatosis. The altered bile acid pool may contribute to reduced hepatic FXR signaling.
SN - 1664-2392
ER -