Hepatic NFE2L1 overexpression ameliorates MASH progression by degrading INSIG1 and sustaining SREBP activation

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), affects a significant portion of the global population, ranging from 1.5% to 6.5%. It is strongly linked to obesity and type 2 diabetes mellitus (T2D), and can advance to advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. Despite its rising prevalence and severe consequences, effective pharmacological therapies for MASH remain critically limited. A key pathological driver of MASH is cholesterol overload within the liver, suggesting that targeting hepatic cholesterol sensing pathways could offer a promising therapeutic strategy to interrupt disease progression and restore metabolic balance.

Researchers investigated the role of nuclear factor erythroid 2-related factor 1 (NFE2L1) in hepatic cholesterol sensing and its impact on metabolic dysfunction-associated steatohepatitis (MASH). The study aimed to identify critical regulators linking cholesterol sensing to very-low-density lipoprotein (VLDL)-mediated lipid export. Mechanistic investigations likely involved molecular biology techniques to characterize the interaction between NFE2L1 and insulin-induced gene 1 (INSIG1), and its influence on sterol regulatory element-binding protein (SREBP) activation. Furthermore, the therapeutic potential was assessed by inducing hepatic NFE2L1 overexpression in relevant models of MASH, with endpoints focused on markers of disease progression, lipid homeostasis, and the abundance of key regulatory proteins. Control arms would have included non-overexpression or wild-type conditions for comparison in these experimental models.

Deng et al. identified NFE2L1 as a critical and novel regulator that directly links hepatic cholesterol sensing to VLDL-mediated lipid export, a crucial process for maintaining lipid homeostasis. Mechanistically, they discovered that NFE2L1 physically interacts with INSIG1 in hepatocytes. This interaction is pivotal as NFE2L1 actively promotes the degradation of INSIG1, thereby reducing its abundance within liver cells. The cholesterol-dependent NFE2L1-INSIG1 interaction was found to sustain SREBP activation, which in turn drives VLDL secretion. This intricate regulatory loop is essential for maintaining both hepatic and systemic lipid homeostasis, preventing the harmful accumulation of lipids.

Crucially, the study demonstrated that hepatic NFE2L1 overexpression significantly decreased INSIG1 abundance and, as a direct consequence, ameliorated the progression of MASH, highlighting a clear therapeutic potential for modulating this pathway. These findings establish NFE2L1 as a key player in the complex interplay between cholesterol metabolism and MASH pathogenesis.