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<p>Metabolic-associated steatotic liver disease (MASLD) is highly prevalent in type 2 diabetes mellitus (T2D) and its incidence has increased with the obesity epidemic. Mutations of nuclear lamina-associated genes including <i>LMNA</i> have been associated with fatty liver. We previously described a mechanism relating changes at the nuclear lamina that lead to opening of previously repressed chromatin and upregulation of lipid synthesis and storage pathways to development of steatosis in MASLD. Here we report that the changes at the nuclear envelope in MASLD patients are caused by downregulation of zinc metalloproteinase Ste24 (ZMPSTE24), an enzyme that processes prelamin to mature lamin A, leading to accumulation of prelamin. In addition, <i>Zmpste24</i> mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. Functional analysis determined p53 as a regulator in genes differentially expressed and bound by FOXA2 in MASLD patients, corresponding to observations in <i>Zmpste24</i> knockout animals. ZMPSTE24 expression is repressed by mir-141-3p in male MASLD patients. Downregulation of ZMPSTE24 leads to the nuclear lamina changes responsible to development of MASLD we had previously reported. Hence, MASLD should be considered as a type of laminopathy and approaches to restore ZMPSTE24 expression and nuclear lamina function should be tested for treatment of the disease.</p>

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Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Joseph D. Schinderle,
  • Anqi Wu,
  • Irina M. Bochkis

摘要

Metabolic-associated steatotic liver disease (MASLD) is highly prevalent in type 2 diabetes mellitus (T2D) and its incidence has increased with the obesity epidemic. Mutations of nuclear lamina-associated genes including LMNA have been associated with fatty liver. We previously described a mechanism relating changes at the nuclear lamina that lead to opening of previously repressed chromatin and upregulation of lipid synthesis and storage pathways to development of steatosis in MASLD. Here we report that the changes at the nuclear envelope in MASLD patients are caused by downregulation of zinc metalloproteinase Ste24 (ZMPSTE24), an enzyme that processes prelamin to mature lamin A, leading to accumulation of prelamin. In addition, Zmpste24 mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. Functional analysis determined p53 as a regulator in genes differentially expressed and bound by FOXA2 in MASLD patients, corresponding to observations in Zmpste24 knockout animals. ZMPSTE24 expression is repressed by mir-141-3p in male MASLD patients. Downregulation of ZMPSTE24 leads to the nuclear lamina changes responsible to development of MASLD we had previously reported. Hence, MASLD should be considered as a type of laminopathy and approaches to restore ZMPSTE24 expression and nuclear lamina function should be tested for treatment of the disease.