{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:20:12Z","timestamp":1788931212384,"version":"build-2803163510"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,2,10]]},"abstract":"\n BACKGROUND:<\/jats:title>\n \n Apolipoprotein B (apoB) is essential for lipoprotein assembly and secretion and plays a central role in the development of cardiovascular disease and metabolic dysfunction\u2013associated steatotic liver disease. Although apoB protein degradation during very-low-density lipoprotein maturation has been extensively studied, the regulation of\n Apob<\/jats:italic>\n mRNA stability under physiological and pathological conditions remains unexplored.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n 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\n Helz2<\/jats:italic>\n upregulation. Biochemical assays were used to assess HELZ2 binding to\n Apob<\/jats:italic>\n mRNA and its role in\n Apob<\/jats:italic>\n mRNA degradation, and the effect of HELZ2 modulation on atherosclerosis was examined in\n Apoe<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n and\n Ldlr<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mouse models.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n We discovered a unique gain-of-function mutation in HELZ2 (L1833P, called\n Colby<\/jats:italic>\n ) that promotes hepatic lipid accumulation independently of changes in body weight on a standard chow diet. Mechanistically, HELZ2 binds\n Apob<\/jats:italic>\n mRNA and degrades it through its helicase activity, ensuring tight control of hepatic apoB levels. The\n Colby<\/jats:italic>\n mutation enhances HELZ2 helicase activity, resulting in marked reduction in\n Apob<\/jats:italic>\n expression and increased hepatic lipid accumulation. Conversely,\n Helz2<\/jats:italic>\n -deficient mice show increased\n Apob<\/jats:italic>\n mRNA levels and reduced hepatic triglycerides on a high-fat diet. Notably, modest liver-restricted induction of HELZ2 was sufficient to decrease hepatic\n Apob<\/jats:italic>\n mRNA and alter lipid handling, phenocopying the\n Helz2<\/jats:italic>\n \n Colby<\/jats:italic>\n <\/jats:sup>\n state and supporting the gain-of-function mechanism. A single copy of the\n Helz2<\/jats:italic>\n \n Colby<\/jats:italic>\n <\/jats:sup>\n mutation confers protection against atherosclerosis in\n Apoe<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n and\n Ldlr<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n \n HELZ2 is a key regulator of\n Apob<\/jats:italic>\n mRNA stability and lipid metabolism. Genetic or pharmacological modulation of HELZ2 activity represents a promising therapeutic strategy for cardiovascular disease and metabolic dysfunction\u2013associated steatotic liver disease.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circulationaha.125.076468","type":"journal-article","created":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T10:00:10Z","timestamp":1766656810000},"page":"415-434","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["HELZ2 Regulates\n Apob<\/i>\n mRNA Stability to Modulate Fatty Liver Disease and Atherosclerosis"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8236-4868","authenticated-orcid":true,"given":"Yiao","family":"Jiang","sequence":"first","affiliation":[{"name":"Center for the Genetics of Host Defense (Y.J., Z.Z.), University of Texas Southwestern Medical Center, Dallas."},{"name":"Division of Endocrinology, Department of Internal 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