The histone methyltransferase Suv39h2 contributes to nonalcoholic steatohepatitis in mice

Zhiwen Fan, Luyang Li, Min Li, Xinjian Zhang, Chenzhi Hao, Liming Yu, Sheng Zeng, Huihui Xu, Mingming Fang, Aiguo Shen, Thomas Jenuwein, Yong Xu

Resultado de la investigación: Articlerevisión exhaustiva

35 Citas (Scopus)

Resumen

Uncontrolled inflammatory response highlights the central theme of nonalcoholic steatohepatitis (NASH), a growing global pandemic. Hepatocytes and macrophages represent two major sources of hepatic inflammation during NASH pathogenesis, contributing to excessive synthesis of proinflammatory mediators. The epigenetic mechanism that accounts for the activation of hepatocytes and macrophages in this process remains obscure. Here, we report that compared to wild-type littermates, mice with a deficiency in the histone H3K9 methyltransferase suppressor of variegation 39 homolog 2 (Suv39h2, knockout) exhibited a less severe form of NASH induced by feeding with a high-fat, high-carbohydrate diet. Pro-NASH stimuli increased Suv39h2 expression in cell culture, in mice, and in human livers. In hepatocytes, Suv39h2 bound to the Sirt1 gene promoter and repressed Sirt1 transcription. Suv39h2 deficiency normalized Sirt1 expression, allowing nuclear factor kappa B/p65 to become hypoacetylated and thus dampening nuclear factor kappa B–dependent transcription of proinflammatory mediators. In macrophages, Suv39h2-mediated repression of peroxisome proliferator–activated receptor gamma transcription favored a proinflammatory M1 phenotype over an anti-inflammatory M2 phenotype, thereby elevating hepatic inflammation. Conclusion: Suv39h2 plays a pivotal role in the regulation of inflammatory response in hepatocytes and macrophages, contributing to NASH pathogenesis. (Hepatology 2017;65:1904-1919).

Idioma originalEnglish (US)
Páginas (desde-hasta)1904-1919
Número de páginas16
PublicaciónHepatology
Volumen65
N.º6
DOI
EstadoPublished - jun. 2017
Publicado de forma externa

ASJC Scopus subject areas

  • Hepatology

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