Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA1116573 | ENA |
REPOSITORIES: ENA
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Project description:Mutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MASLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition, Zmpste24 mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MASLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MASLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease.
2025-08-06 | GSE268361 | GEO
Project description:Mutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MAFLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition, Zmpste24 mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MAFLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MAFLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MAFLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease.
2025-08-06 | GSE268360 | GEO
Project description:Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MAFLD patients [RNA-seq]
| PRJNA1116574 | ENA
Project description:Although maternal obesity is an independent risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), the pathogenesis remains unclear. We aimed to evaluate the effect and mechanisms of multigenerational maternal western diet (WD) on MASLD progression, and test drug candidates in a preclinical model. Female mice were fed WD from 8 weeks before breeding initiation with a normal chow (NC)-fed male, throughout pregnancy and lactation. Male offspring were weaned onto NC or WD and assessed at the age of 16 weeks. Maternal WD feeding aggravated body weight gain, insulin resistance, steatosis and inflammation. Fibrosis was only observed in offspring exposed to maternal WD. Mechanistically, the latter exhibited reduced OXPHOS activity. Maternal WD aggravates MASLD in male offspring, with mitochondrial dysfunction contributing to disease severity.
2025-06-18 | GSE291363 | GEO
Project description:Zmpste24 is a metalloproteinase processing prelamin A into mature lamin A, a nuclear structure protein. Zmpste24-/- mice which accumulate prelamin A in cells recapitulate accelerated aging phenotypes observed in human premature aging disorder, Hutchinson Gilford progeria sydrome (HGPS). Zmpste24-/- mouse embryonic fibroblasts (MEFs) exhibited genomic instabiliy and accelerated aging at cellular level, which is premature senescence. We performed microarray analysis on Zmpste24-/- MEFs, compared to wild-type littermates' MEFs, at an early passage (P3), which is a pre-symptom stage before cellular senescence occurs in the mutant MEFs, in order to examine gene expression profile and figure out the underneath mechanism triggering the premature aging process.
2010-11-11 | GSE25257 | GEO
Project description:Metabolic dysfunction-associated fatty liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes (T2D), can progress to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. Ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms. Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target.
2025-08-07 | GSE294746 | GEO
Project description:Defining the aging-cancer relationship is a challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate many features of aging. However, their short lifespan and cell-intrinsic and -extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. To circumvent these limitations we have generated Zmpste24 mosaic mice. Interestingly, these mice develop normally - revealing cell-extrinsic mechanisms are preeminent in progeria- and display decreased incidence of infiltrating oral carcinomas. Moreover, ZMPSTE24 knock-down reduces human cancer cell invasiveness. Our results disclose the ZMPSTE24-prelamin A system as an example of antagonistic pleiotropy on cancer and aging, support the potential of cell-based and systemic therapies for progeria, and highlight ZMPSTE24 as a new anticancer target.
2014-06-01 | GSE41799 | GEO
Project description:Zmpste24 is a metalloproteinase processing prelamin A into mature lamin A, a nuclear structure protein. Zmpste24-/- mice which accumulate prelamin A in cells recapitulate accelerated aging phenotypes observed in human premature aging disorder, Hutchinson Gilford progeria sydrome (HGPS). Zmpste24-/- mouse embryonic fibroblasts (MEFs) exhibited genomic instabiliy and accelerated aging at cellular level, which is premature senescence. We performed microarray analysis on Zmpste24-/- MEFs, compared to wild-type littermates' MEFs, at an early passage (P3), which is a pre-symptom stage before cellular senescence occurs in the mutant MEFs, in order to examine gene expression profile and figure out the underneath mechanism triggering the premature aging process. Early passage wild-type and Zmpste24-/- MEFs were collected for RNA extraction, the quality of RNAs were determinded by Electrophoresis Assay (2100 Bioanalyzer, Agilent) and RNA extractions were used for hybridization on Affymetrix microarrays.
2010-11-11 | E-GEOD-25257 | biostudies-arrayexpress
Project description:Defining the aging-cancer relationship is a challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate many features of aging. However, their short lifespan and cell-intrinsic and -extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. To circumvent these limitations we have generated Zmpste24 mosaic mice. Interestingly, these mice develop normally - revealing cell-extrinsic mechanisms are preeminent in progeria- and display decreased incidence of infiltrating oral carcinomas. Moreover, ZMPSTE24 knock-down reduces human cancer cell invasiveness. Our results disclose the ZMPSTE24-prelamin A system as an example of antagonistic pleiotropy on cancer and aging, support the potential of cell-based and systemic therapies for progeria, and highlight ZMPSTE24 as a new anticancer target. We used siRNAs to silence ZMPSTE24 in different human cancer cell lines (SCC-40, SCC-2, A549 and MDA-MB-231), and compared their RNA expression profiles with those of mock treated cells. Each experimental condition (ZMPSTE24 or Scrambled siRNA) was performed in duplicate. Thus, a total of 16 array hybridizations were performed.
2014-06-01 | E-GEOD-41799 | biostudies-arrayexpress
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are still needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA stability post-transcriptionally. N-acetyltransferase 10 (NAT10), the sole enzyme catalyzing mRNA acetylation, has not been fully explored in human diseases, especially in MASLD and MASH. In the current study, abundant RNA acetylation was found in lipid metabolism-related genes in the livers of leptin receptor-deficient (db/db) mice. Besides, hepatic NAT10 expression is significantly increased in multiple mouse models of MASLD and MASH. NAT10 expression is also elevated in patients with MASLD and positively correlated with clinical characteristics. Genetic NAT10 knockdown protects against diet-induced hepatic steatosis and steatohepatitis in mice, while its overexpression exacerbates steatosis. Mechanistically, NAT10 could bind to Srebp-1c mRNA to promote its stability and expression, thereby upregulating lipogenic enzymes. In addition, the translational significance of our findings is that treatment of Remodelin, an NAT10 inhibitor, could improve liver steatosis and dyslipidemia in a preclinical mouse model. Together, these findings highlight the significance of ac4C modification and NAT10 in MASLD and MASH, offering a potential therapeutic target for disease treatment.
2024-09-22 | GSE275576 | GEO