The imprinted geneZac1regulates steatosis in developmental cadmium-induced nonalcoholic fatty liver disease

• DOI: 10.1093/toxsci/kfac106
• Publication Date: 2022-10-06T13:54:38Z
• Authors: Sierra D Riegl; Cassie Starnes; Dereje D Jima; Marine Baptissart; Anna Mae Diehl; Scott M Belcher; Michael Cowley
• Keywords: Steatosis

Abstract Cadmium (Cd) exposure in adulthood is associated with nonalcoholic fatty liver disease (NAFLD), characterized by steatosis, inflammation, and fibrosis. The prevalence of NAFLD children increasing, suggesting a role for the developmental environment programming susceptibility. However, Cd underlying mechanisms remain unclear. We have proposed that imprinted genes are strong candidates connecting early life later disease. In support this, we previously identified roles Imprinted Gene Network (IGN) its regulator Zac1 response to maternal metabolic dysfunction. Here, test hypothesis sufficient program NAFLD, further, this process mediated IGN. Using mice, show cadmium chloride (CdCl2) leads histological, biochemical, molecular signatures steatosis fibrosis juveniles. Transcriptomic analyses comparing livers CdCl2-exposed control mice upregulation IGN coincident presentation. Increased hepatic expression independent promoter methylation imprinting statuses. Finally, over-expression cultured hepatocytes induce lipid accumulation Pparγ-dependent manner demonstrate direct binding Pparγ promoter. Our findings life, our previous work, establish as key regulators prosteatotic profibrotic pathways, two major pathological hallmarks NAFLD.