Dysregulation of intercellular signaling by MOF deletion leads to liver injury

Abstract

Epigenetic mechanisms that alter heritable gene expression and chromatin structure play an essential role in many biological processes, including liver function. Human MOF (males absent on the first) is a histone acetyltransferase that is globally downregulated in human steatohepatitis. However, the function of MOF in the liver remains unclear. Here, we report that MOF plays an essential role in adult liver. Genetic deletion of Mof by Mx1-Cre in the liver leads to acute liver injury, with increase of lipid deposition and fibrosis akin to human steatohepatitis. Surprisingly, hepatocyte-specific Mof deletion had no overt liver abnormality. Using the in vitro coculturing experiment, we show that Mof deletion-induced liver injury requires coordinated changes and reciprocal signaling between hepatocytes and Kupffer cells, which enables feedforward regulation to augment inflammation and apoptotic responses. At the molecular level, Mof deletion induced characteristic changes in metabolic gene programs, which bore noticeable similarity to the molecular signature of human steatohepatitis. Simultaneous deletion of Mof in both hepatocytes and macrophages results in enhanced expression of inflammatory genes and NO signaling in vitro . These changes, in turn, lead to apoptosis of hepatocytes and lipotoxicity. Our work highlights the importance of histone acetyltransferase MOF in maintaining metabolic liver homeostasis and sheds light on the epigenetic dysregulation in liver pathogenesis.

Epigenetic Regulation of Hepatic Stellate Cell Activation and Macrophage in Chronic Liver Inflammation

“…Only the loss of MOF in macrophages and hepatocytes at the same time can lead to enhanced expression of inflammatory genes and nitric oxide (NO) signal transduction, which further leads to hepatocyte apoptosis and lipotoxicity. These results indicate that the expression of histone acetyltransferase MOF in macrophages plays an important role in maintaining normal liver metabolism (Lei et al, 2020 ). In addition, histone deacetylase 11 (HDAC11) is induced in Kupffer cells of alcoholic liver disease model mice, which reduces the expression of IL-10.…”

Lack of Mof reduces acute liver injury by enhancing transcriptional activation of Igf1

“…After the mouse is born, the messenger RNA expression level of Mof in the liver is relatively stable (Lu et al, 2012). A recent study by Lei et al (Lei et al, 2020) finds that genetic deletion of Mof by Mx1‐Cre lead to ALI. However, using Cre‐expressing adeno‐associated virus to specifically knockout Mof in liver would not affect liver function, which indicates that lack of MOF in Kupffer cells induce Mof ‐null hepatocytes apoptosis.…”

“…et al(Lei et al, 2020) finds that genetic deletion of Mof by Mx1-Cre lead to ALI. However, using Cre-expressing adeno-associated virus to specifically knockout Mof in liver would not affect liver function, which indicates that lack of MOF in Kupffer cells induce Mof-null hepatocytes apoptosis.…”

Mof plays distinct roles in hepatic lipid metabolism under healthy or non-alcoholic fatty liver conditions

“… 27 Additionally, there have been indications suggesting the involvement of Mof in hepatic lipid accumulation. 28 Nevertheless, the precise contribution of Mof to hepatic lipid metabolism remains undisclosed. Consequently, the present study aims to elucidate the impact of Mof on this metabolic process.…”