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Updated: Sep 25, 2026
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
PDCD4-driven steatosis via the HNF4A/GK axis is attenuated by the natural compound isosinensetin
Xiaona Cheng1, Kaikai Lu2, Luyun Yang3
1Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Background:
Programmed cell death factor 4 (PDCD4) has been implicated in various metabolic disorders. However, its role and underlying mechanisms in metabolic dysfunction-associated steatotic liver disease (MASLD) have not been fully elucidated.
Purpose:
This study aimed to define the role of PDCD4 in hepatic steatosis and identify potential therapeutic strategies targeting its downstream metabolic pathway.
Methods:
RNA sequencing was performed on liver tissues from wild-type and PDCD4-knockout mice to identify dysregulated metabolic pathways and candidate downstream genes. The PDCD4-HNF4A-GK regulatory pathway was investigated using genetic, histological, biochemical, and molecular analyses in mouse models and hepatocytes. Virtual screening and molecular docking were used to identify candidate GK-targeting compounds.
Results:
Hepatocyte-specific PDCD4 deletion increased hepatic GK expression and aggravated lipid accumulation. GK knockout markedly attenuated PDCD4 deficiency-induced lipid accumulation in hepatocytes. Mechanistically, PDCD4 suppressed HNF4A translation, thereby limiting HNF4A-dependent GK transcription. Virtual screening identified isosinensetin as a candidate GK inhibitor. Isosinensetin inhibited GK activity and reduced lipid accumulation in hepatocytes and CDAHFD-fed mice.
Conclusions:
These results suggest that GK may warrant further investigation for ameliorating hepatic steatosis, and provide preliminary evidence for the PDCD4-HNF4A-GK axis in the regulation of hepatic triglyceride metabolism. Further studies are required to establish the relevance of this axis to the full spectrum of MASLD pathology.
