HELZ2 Regulates <i>Apob</i> mRNA Stability to Modulate Fatty Liver Disease and Atherosclerosis.

Abstract

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 <i>Apob</i> mRNA stability under physiological and pathological conditions remains unexplored. 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 <i>Helz2</i> upregulation. Biochemical assays were used to assess HELZ2 binding to <i>Apob</i> mRNA and its role in <i>Apob</i> mRNA degradation, and the effect of HELZ2 modulation on atherosclerosis was examined in <i>Apoe</i>^<i>-/-</i> and <i>Ldlr</i>^<i>-/-</i> mouse models. We discovered a unique gain-of-function mutation in HELZ2 (L1833P, called <i>Colby</i>) that promotes hepatic lipid accumulation independently of changes in body weight on a standard chow diet. Mechanistically, HELZ2 binds <i>Apob</i> mRNA and degrades it through its helicase activity, ensuring tight control of hepatic apoB levels. The <i>Colby</i> mutation enhances HELZ2 helicase activity, resulting in marked reduction in <i>Apob</i> expression and increased hepatic lipid accumulation. Conversely, <i>Helz2</i>-deficient mice show increased <i>Apob</i> mRNA levels and reduced hepatic triglycerides on a high-fat diet. Notably, modest liver-restricted induction of HELZ2 was sufficient to decrease hepatic <i>Apob</i> mRNA and alter lipid handling, phenocopying the <i>Helz2</i>^<i>Colby</i> state and supporting the gain-of-function mechanism. A single copy of the <i>Helz2</i>^<i>Colby</i> mutation confers protection against atherosclerosis in <i>Apoe</i>^<i>-/-</i> and <i>Ldlr</i>^<i>-/-</i> mice. HELZ2 is a key regulator of <i>Apob</i> 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.