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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis

Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis

Published on: March 11, 2017

The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein

Minxuan Xu^1,2,3, Jun Tan^1,2, Liancai Zhu³

¹Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China.

Acta Pharmaceutica Sinica. B

|March 27, 2023

Abstract:

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

Insights

Ubiquitin-specific protease 13 (USP13) blocks inactive rhomboid protein 2 (IRHOM2) in hepatocytes. USP13 protects against nonalcoholic steatohepatitis (NASH) development and progression, offering a potential therapeutic target.

Area of Science:

Hepatology
Molecular Biology
Biochemistry

Background:

Nonalcoholic steatohepatitis (NASH) pathogenesis is complex and incompletely understood, leading to preclinical drug failures.
Inactive rhomboid protein 2 (IRHOM2) plays a role in deregulated hepatocyte metabolism and NASH progression.
The precise regulation of IRHOM2 remains unclear.

Purpose of the Study:

To identify novel endogenous regulators of IRHOM2.
To elucidate the molecular mechanism by which IRHOM2 is regulated.
To explore USP13 as a potential therapeutic target for NASH.

Main Methods:

Identification of IRHOM2-interacting proteins using biochemical assays.
Deubiquitination assays to determine USP13's enzymatic activity on IRHOM2.
Generation and analysis of hepatocyte-specific Usp13 knockout and transgenic mouse models.
Evaluation of therapeutic efficacy using lentivirus (LV) and adeno-associated virus (AAV) gene delivery in rodent NASH models.

Main Results:

Ubiquitin-specific protease 13 (USP13) was identified as a novel endogenous blocker of IRHOM2.
USP13 directly interacts with IRHOM2 and catalyzes its deubiquitination, specifically removing K63-linked ubiquitination induced by UBC13.
Hepatocyte-specific loss of Usp13 exacerbates NASH, while Usp13 overexpression or gene therapy mitigates NASH in multiple models.
USP13 functions by preventing IRHOM2 activation of downstream inflammatory and metabolic pathways.

Conclusions:

USP13 is a critical negative regulator of IRHOM2 in hepatocytes.
USP13 deficiency promotes NASH development and progression through IRHOM2.
USP13 represents a promising therapeutic target for NASH by modulating the IRHOM2 signaling pathway.

Read full analysis

Keywords:

Hepatosteatosis Irhom2 Liver inflammation NAFLD NASH Ubc13 Ubiquitination Usp13

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