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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)1904-1919
Number of pages16
JournalHepatology
Volume65
Issue number6
DOIs
StatePublished - Jun 2017
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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