HELZ2 Regulates Apob mRNA Stability to Modulate Fatty Liver Disease and Atherosclerosis

BACKGROUND: Apolipoprotein B (apoB) is essential for lipoprotein assembly and secretion and plays a central role in the development of cardiovascular disease and metabolic dysfunction–associated steatotic liver disease. Although apoB protein degradation during very-low-density lipoprotein maturation has been extensively studied, the regulation of Apob mRNA stability under physiological and pathological conditions remains unexplored. METHODS: A forward genetic screen in randomly mutagenized mice identified HELZ2 (helicase with zinc finger 2) as a critical regulator of lipid metabolism. The metabolic effects of HELZ2 mutations or deficiency were evaluated in mice maintained on a chow diet or a high-fat diet. We also used a doxycycline-inducible, liver-specific HELZ2 overexpression model to test the sufficiency of hepatocyte Helz2 upregulation. Biochemical assays were used to assess HELZ2 binding to Apob mRNA and its role in Apob mRNA degradation, and the effect of HELZ2 modulation on atherosclerosis was examined in Apoe −/− and Ldlr −/− mouse models. RESULTS: We discovered a unique gain-of-function mutation in HELZ2 (L1833P, called Colby ) that promotes hepatic lipid accumulation independently of changes in body weight on a standard chow diet. Mechanistically, HELZ2 binds Apob mRNA and degrades it through its helicase activity, ensuring tight control of hepatic apoB levels. The Colby mutation enhances HELZ2 helicase activity, resulting in marked reduction in Apob expression and increased hepatic lipid accumulation. Conversely, Helz2 -deficient mice show increased Apob mRNA levels and reduced hepatic triglycerides on a high-fat diet. Notably, modest liver-restricted induction of HELZ2 was sufficient to decrease hepatic Apob mRNA and alter lipid handling, phenocopying the Helz2 Colby state and supporting the gain-of-function mechanism. A single copy of the Helz2 Colby mutation confers protection against atherosclerosis in Apoe −/− and Ldlr −/− mice. CONCLUSIONS: HELZ2 is a key regulator of Apob mRNA stability and lipid metabolism. Genetic or pharmacological modulation of HELZ2 activity represents a promising therapeutic strategy for cardiovascular disease and metabolic dysfunction–associated steatotic liver disease.