HELZ2 RegulatesmRNA Stability to Modulate Fatty Liver Disease and Atherosclerosis.

Abstract

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 ofmRNA 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 hepatocyteupregulation. Biochemical assays were used to assess HELZ2 binding tomRNA and its role inmRNA degradation, and the effect of HELZ2 modulation on atherosclerosis was examined inandmouse models. RESULTS: We discovered a unique gain-of-function mutation in HELZ2 (L1833P, called) that promotes hepatic lipid accumulation independently of changes in body weight on a standard chow diet. Mechanistically, HELZ2 bindsmRNA and degrades it through its helicase activity, ensuring tight control of hepatic apoB levels. Themutation enhances HELZ2 helicase activity, resulting in marked reduction inexpression and increased hepatic lipid accumulation. Conversely,-deficient mice show increasedmRNA levels and reduced hepatic triglycerides on a high-fat diet. Notably, modest liver-restricted induction of HELZ2 was sufficient to decrease hepaticmRNA and alter lipid handling, phenocopying thestate and supporting the gain-of-function mechanism. A single copy of themutation confers protection against atherosclerosis inandmice. CONCLUSIONS: HELZ2 is a key regulator ofmRNA 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.