Targeting hepatic cholesterol sensing to tackle metabolic dysfunction–associated steatohepatitis
Mengwei Zang, Yu Li
Mengwei Zang, Yu Li
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Commentary

Targeting hepatic cholesterol sensing to tackle metabolic dysfunction–associated steatohepatitis

Abstract

Metabolic dysfunction–associated steatohepatitis (MASH) affects 1.5%–6.5% of the global population, yet its mechanisms remain incompletely understood. Cholesterol overload is a key driver of MASH, suggesting that targeting cholesterol sensing may offer therapeutic benefits. In this issue, Deng et al. identified nuclear factor erythroid 2–related factor 1 (NFE2L1) as a critical regulator linking cholesterol sensing to VLDL-mediated lipid export. Mechanistically, NFE2L1 interacts with insulin-induced gene 1 (INSIG1) and promotes its degradation in hepatocytes. This cholesterol-dependent NFE2L1-INSIG1 interaction sustains SREBP activation and VLDL secretion to maintain hepatic and systemic lipid homeostasis. Moreover, the study by Deng et al. indicates that hepatic NFE2L1 overexpression decreases INSIG1 abundance and ameliorates MASH progression, highlighting its therapeutic potential.

Authors

Mengwei Zang, Yu Li

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Figure 1

The NFE2L1/INSIG1 axis couples hepatic cholesterol sensing to VLDL secretion and maintains lipid homeostasis.

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The NFE2L1/INSIG1 axis couples hepatic cholesterol sensing to VLDL secre...
Deng et al. (16) showed that under cholesterol overload, NFE2L1 acts as a sterol-responsive regulator that physically interacts with INSIG1 at the ER membrane in hepatocytes. This cholesterol-dependent interaction promotes ubiquitination and proteasomal degradation of INSIG1, relieving ER retention of SREBP precursors. Loss of INSIG1 permits ER-to-Golgi translocation of SREBP, where it undergoes proteolytic cleavage to generate the transcriptionally active mature form. The active SREBP enters the nucleus to induce transcription of sterol-responsive genes, enhancing cholesterol synthesis and lipogenesis. This structural lipid pool is functionally coupled to VLDL assembly and secretion, redirecting lipid flux from intracellular lipid synthesis to export. Newly synthesized lipids are incorporated into nascent VLDL particles and secreted via the sinusoidal membrane, preventing intracellular cholesterol accumulation. This adaptive process establishes a “synthesis-export balance,” in which the NFE2L1/INSIG1 axis synchronizes SREBP-mediated lipid synthesis with VLDL-mediated lipid export, thereby preventing hepatic cholesterol accumulation. By balancing lipid synthesis and export, the NFE2L1/INSIG1 axis attenuates VLDL secretion defects, limits intrahepatic cholesterol accumulation, and mitigates MASH progression, underscoring its therapeutic potential.