USP7 mediates pathological hepatic de novo lipogenesis through promoting stabilization and transcription of ZNF638

Wenkai Ni,Mingbing Xiao,Lishuai Qu,Wenjie Zheng,Pinghong Zhou,Yihui Fan,Shengli Lin,Saiyan Bian,Cuihua Lu

doi:10.1038/s41419-020-03075-8

Abstract

Aberrant de novo lipogenesis (DNL) results in excessive hepatic lipid accumulation and liver steatosis, the causative factors of many liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). However, the underlying mechanism of DNL dysregulation remains largely unknown. Ubiquitination of proteins in hepatocytes has been shown to be widely involved in lipid metabolism of liver. Here, we revealed that Ubiquitin-specific peptidase 7 (USP7), a deubiquitinase (DUB), played key roles in DNL through regulation of zinc finger protein 638 (ZNF638) in hepatocytes. USP7 has been shown not only to interact with and deubiquitylate ZNF638, but also to facilitate the transcription of ZNF638 via the stabilization of cAMP responsive element binding protein (CREB). USP7/ZNF638 axis selectively increased the cleavage of sterol regulatory element binding protein (SREBP1C) through AKT/mTORC1/S6K signaling, and formed USP7/ZNF638/SREBP1C nuclear complex to regulate lipogenesis-associated enzymes, including acetyl-CoA carboxylase (ACACA), fatty acid synthase (FASN), and Stearoyl-CoA desaturase (SCD). In the mice liver steatosis model induced by fructose, USP7 or ZNF638 abrogation significantly ameliorated disease progression. Furthermore, USP7/ZNF638 axis participated in the progression of lipogenesis-associated HCC. Our results have uncovered a novel mechanism of hepatic DNL, which might be beneficial to the development of new therapeutic targets for hepatic lipogenesis-associated diseases.

Highlights

Lipid metabolism is controlled by a complicated network of signaling and enzymatic events in multiple cell types, by which it fulfils the requirements of energy storage and consumption of the body, membrane regeneration of the cell, as well as cellular homeostasis[1]
Overexpression of Ubiquitin-specific peptidase 7 (USP7) was able to upregulate the expression of zinc finger protein 638 (ZNF638) in SK-Hep[1] cells (Supplementary Fig. S1A). These results indicate that ZNF638 is a potential substrate that can be stabilized by USP7
We found that USP7 full length and TRAF domain but not catalytic domain (CD) and HUBL domain were able to pull down ZNF638, indicating TRAF domain mediates the association between USP7 and ZNF638 (Fig. 1L)

Summary

Introduction

Lipid metabolism is controlled by a complicated network of signaling and enzymatic events in multiple cell types, by which it fulfils the requirements of energy storage and consumption of the body, membrane regeneration of the cell, as well as cellular homeostasis[1]. De novo lipogenesis (DNL) that converts acetyl-CoA subunits to Official journal of the Cell Death Differentiation Association. Ni et al Cell Death and Disease (2020)11:843. Unveiling the mechanisms of abnormal DNL is critical for understanding the pathogenesis of DNL-associated diseases. DNL initiates from the conversion of citrate to acetyl-. CoA by ATP-citrate lyase (ACLY), which is further turned into malonyl-CoA with the assistance of acetyl-CoA carboxylase (ACACA). Condenses malonyl-CoA to produce palmitate, which is generated to monounsaturated fatty acids serving as the substrate of Stearoyl-CoA desaturase (SCD)[5]. The dynamic regulation of these synthases has been highlighted in the processes of DNL that may contribute to the pathogenesis of NAFLD, NASH, and HCC in conditions of abnormity. Mutations of AMP-activated protein kinase (AMPK) phosphorylation sites at ACACA1

Methods

Results

Conclusion