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Updated: Jul 16, 2026
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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Cholesterol-responsive NFE2L1-INSIG1 interaction controls VLDL secretion and metabolic dysfunction-associated
Shijun Deng1, Jessica E Freed1, Grace Y Lee1
1Department of Molecular Metabolism and Center for Prevention and Treatment of Cardiovascular Disease, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.
The Journal of Clinical Investigation
|July 15, 2026
Summary
Nuclear factor erythroid 2 related factor-1 (NFE2L1) preserves cholesterol homeostasis by regulating VLDL secretion. This interaction with INSIG1 prevents liver injury and may offer a therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH).
Area of Science:
- Hepatology
- Molecular Biology
- Lipid Metabolism
Background:
- Cholesterol overload exacerbates metabolic dysfunction-associated steatohepatitis (MASH).
- Very-low-density lipoprotein (VLDL) secretion is a key pathway for hepatic cholesterol export.
- A paradox exists where VLDL secretion persists despite insulin-induced gene 1 (INSIG1) suppressing sterol regulatory element-binding protein (SREBP) activity under high cholesterol.
Purpose of the Study:
- To identify the mechanism maintaining VLDL secretion under cholesterol excess.
- To investigate the role of nuclear factor erythroid 2 related factor-1 (NFE2L1) in hepatic cholesterol homeostasis.
- To explore the NFE2L1/INSIG1 interaction as a therapeutic target for MASH.
Main Methods:
- Liver-specific NFE2L1 deletion in mice.
- Analysis of INSIG1 abundance, SREBP activation, and VLDL secretion.
- Mechanistic studies involving NFE2L1 domains and cholesterol binding.
- Lipidomics analysis of serum triglycerides.
- Murine MASH model with NFE2L1 overexpression.
Main Results:
- Liver-specific NFE2L1 deletion increased INSIG1, suppressed SREBP1, impaired VLDL secretion, and caused liver injury.
- NFE2L1 binds INSIG1 via its NHB2 domain; cholesterol strengthens this interaction, promoting INSIG1 degradation and SREBP1 activation.
- Restoration of SREBP1 activity and VLDL secretion was dependent on NFE2L1's ability to interact with INSIG1.
- NFE2L1 deficiency reduced serum triglycerides, which WT NFE2L1 restored.
- NFE2L1 overexpression in a MASH model reduced hepatic cholesterol, liver injury, inflammation, and fibrosis without increasing atherogenic lipoproteins.
Conclusions:
- The NFE2L1/INSIG1 axis is a critical regulator of hepatic cholesterol homeostasis and VLDL secretion.
- NFE2L1 acts as a sterol-responsive safeguard, preventing hepatic cholesterol accumulation and injury.
- Targeting the NFE2L1/INSIG1 pathway holds potential for MASH therapy.
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