12421 Reduced ZMPSTE24 Expression Leads To Prelamin Accumulation And Development Of Steatosis In MASLD Patients

Abstract Disclosure: J. Schinderle: None. I. Bochkis: None. A. Wu: None. Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients. Joseph D. Schinderle1,2, Anqi Wu1,2, Irina M. Bochkis1,2* 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261 2 Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261 We have previously observed changes at the nuclear lamina in MASLD patients that led to redistribution of lamina-associated domains and reshaping of FOXA2 binding with progression of steatosis. Here we report that the changes at the nuclear envelope are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A, leading to accumulation of prelamin in MASLD patients. Mutations of LMNA and ZMPSTE24 have been associated with fatty liver. In addition, Zmpste24 mutant mice develop hepatic steatosis and Zmpste24 deficiency is linked to upregulation of p53 target genes. Ingenuity Pathway Analysis determined upregulated p53 activity in genes differentially expressed in both male and female MASLD patients. Furthermore, upstream analysis identified p53 as a regulator of genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 knockout animals. Additional regulator analysis of RNA-Seq determined that genes regulated by glucose and insulin to be downregulated in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data shows that MASLD patients with severe steatosis that have yet to progress to MASH are already suffering from severe metabolic consequences and underscores the need for treatment at this stage of the disease. Presentation: 6/2/2024