Article Impact Level: HIGH Data Quality: STRONG Summary of Circulation https://doi.org/10.1161/CIRCULATIONAHA.125.076468 Dr. Yiao Jiang et al.
Points
- Researchers at UT Southwestern identified the HELZ2 protein as a critical molecular control point that regulates the amount of cholesterol carrying lipoproteins released from the liver into the systemic bloodstream.
- This specific protein works by shortening the lifespan of apolipoprotein B messenger RNA which prevents the liver cells from producing the proteins necessary for transporting cholesterol and fats through blood.
- Genetic studies using mouse models demonstrated that a gain of function mutation in this protein led to significantly lower levels of circulating low density lipoprotein cholesterol and triglycerides overall.
- While mice with high levels of this protein were protected from atherosclerosis they showed increased liver fat accumulation indicating a regulatory tradeoff between blood cholesterol levels and hepatic lipid storage.
- Targeting this protein at the RNA level offers a promising new therapeutic strategy for treating cardiovascular disease and fatty liver conditions that differs from traditional statin based lipid lowering approaches.
Summary
This research identifies HELZ2 as a critical regulator of apolipoprotein B (apoB) production, offering a novel molecular mechanism for managing atherosclerotic cardiovascular disease and metabolic dysfunction–associated steatotic liver disease (MASLD). While previous studies emphasized the post-translational degradation of apoB during lipoprotein maturation, this study demonstrates that HELZ2 modulates lipid metabolism by controlling the stability of APOB messenger RNA (mRNA). By accelerating the decay of the APOB transcript, HELZ2 effectively limits the translation of apoB proteins, thereby reducing the hepatic assembly and secretion of cholesterol-carrying lipoproteins into the systemic circulation.
Using large-scale genetic screening and murine models, investigators identified a gain-of-function mutation in HELZ2 that significantly decreased APOB mRNA stability within hepatic tissues. Consequently, mice harboring this mutation exhibited reduced levels of circulating low-density lipoprotein (LDL) cholesterol and triglycerides compared to wild-type controls. This metabolic shift resulted in pronounced protection against atherosclerosis; however, it also led to increased hepatic lipid accumulation. This phenotypic tradeoff characterizes HELZ2 as a physiological “dial” that balances systemic lipidemia against hepatic storage, suggesting a dual-role regulatory function.
These findings represent a paradigm shift from traditional statin-based therapies by targeting cholesterol regulation at the pre-translational stage. Pharmacological modulation of HELZ2 activity presents a promising therapeutic lever to reduce harmful circulating lipoproteins without relying solely on standard pathway inhibition. Furthermore, fine-tuning HELZ2 activity may provide a strategic approach to managing MASLD by recalibrating the export of triglycerides. Future clinical investigations are required to determine the long-term safety and efficacy of RNA-level interventions in humans to address global cardiovascular and metabolic disease burdens.
Link to the article: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.125.076468
References
Jiang, Y., & Zhang, Z. (2025). Helz2 regulates apob mrna stability to modulate fatty liver disease and atherosclerosis. Circulation, CIRCULATIONAHA.125.076468. https://doi.org/10.1161/CIRCULATIONAHA.125.076468
