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Use of a Hanging-weight System for Liver Ischemia in Mice
Published on: August 7, 2012
KLF9 drives intermittent hypoxia-induced MASLD by suppressing the NR4A1-p38 MAPK hepatic metabolic axis
Hongting Hua1,2, Dong Wang1, Lanqiaofeng He1
1Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Background And Aims:
Obstructive sleep apnea (OSA), characterized by recurrent episodes of intermittent hypoxia (IH), is increasingly recognized as a contributor to metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). However, the causal relationship and underlying molecular mechanisms linking IH and MASLD remain incompletely understood, hindering the development of effective therapeutic strategies.
Approach And Results:
We established murine and cellular models of IH and performed comprehensive metabolic and molecular profiling, including glucose and insulin tolerance tests, biochemical analyses, histology, lipidomics, real-time quantitative PCR, western blotting, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, ChIP assay, co-immunoprecipitation, and luciferase reporter gene assays, to investigate the impact of IH and the role of KLF9 in hepatic lipid metabolism. The findings showed IH exposure induced hepatic lipid accumulation and insulin resistance in both normal and obese mice, accompanied by transcriptional reprogramming of lipid metabolic pathways. Transcriptomic analysis identified KLF9 as significantly upregulated by IH treatment. Functional studies demonstrated that hepatic overexpression of KLF9 exacerbated, while its knockdown alleviated, IH-induced steatosis, lipogenesis, and inflammation. Mechanistically, KLF9 directly binds to a conserved GC-rich motif within the NR4A1 promoter, suppressing NR4A1 transcription and downstream p38 MAPK activation. Pharmacologic modulation of NR4A1 further confirmed its regulatory role in mediating KLF9-driven lipogenesis under IH.
Conclusions:
This study identifies KLF9 as a key transcriptional regulator driving IH-associated MASLD by repressing NR4A1 and inhibiting p38 MAPK signaling, thereby promoting hepatic lipogenesis. Targeting the KLF9-NR4A1 axis may offer a novel therapeutic approach for managing MASLD in patients with OSA and other hypoxia-related disorders.
Insights
Intermittent hypoxia (IH) from sleep apnea drives liver fat accumulation by upregulating KLF9. This KLF9 protein then suppresses NR4A1, worsening metabolic dysfunction-associated steatotic liver disease (MASLD).
Area of Science:
- Hepatology
- Sleep Medicine
- Molecular Biology
Background:
- Obstructive sleep apnea (OSA) and intermittent hypoxia (IH) are linked to metabolic dysfunction-associated steatotic liver disease (MASLD).
- The precise molecular mechanisms connecting IH to MASLD are not fully understood.
- Effective therapeutic strategies for IH-induced MASLD are limited.
Purpose of the Study:
- To investigate the causal relationship between IH and MASLD.
- To elucidate the molecular mechanisms underlying IH-induced hepatic lipid metabolism.
- To identify key regulatory factors involved in IH-associated MASLD.
Main Methods:
- Murine and cellular models of IH were utilized.
- Comprehensive metabolic and molecular profiling was performed, including transcriptomics (RNA-seq) and epigenomics (ChIP-seq).
- Key molecular interactions were validated using biochemical assays (co-IP, luciferase assays).
Main Results:
- IH exposure induced hepatic lipid accumulation and insulin resistance in mice.
- Transcriptomic analysis identified KLF9 as significantly upregulated by IH.
- KLF9 directly suppresses NR4A1 transcription, leading to lipogenesis and inflammation, exacerbating IH-induced MASLD.
Conclusions:
- KLF9 is a critical transcriptional regulator of IH-associated MASLD.
- The KLF9-NR4A1 axis promotes hepatic lipogenesis and inflammation under IH conditions.
- Targeting the KLF9-NR4A1 pathway presents a potential therapeutic strategy for MASLD in OSA patients.
