Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity
Spencer Greatorex, … , Matthew J. Watt, Tony Tiganis
Spencer Greatorex, … , Matthew J. Watt, Tony Tiganis
Published December 7, 2023
Citation Information: J Clin Invest. 2024;134(3):e162533. https://doi.org/10.1172/JCI162533.
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Research Article Hepatology Metabolism

Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity

Abstract

Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2–related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signaling, and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high-fat diet–fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation, and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH and fibrosis in mice fed a NASH-promoting diet. Thus, mitochondria- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and progression to NASH and fibrosis in obesity.

Authors

Spencer Greatorex, Supreet Kaur, Chrysovalantou E. Xirouchaki, Pei K. Goh, Florian Wiede, Amanda J. Genders, Melanie Tran, YaoYao Jia, Arthe Raajendiran, Wendy A. Brown, Catriona A. McLean, Junichi Sadoshima, Matthew J. Watt, Tony Tiganis

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Figure 1

NOX4 and NFE2L2 antioxidant defense gene expression in NAFLD.

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NOX4 and NFE2L2 antioxidant defense gene expression in NAFLD. (A) RNA-Se...
(A) RNA-Seq analysis (GSE130970) of livers from patients without steatosis (n = 7), patients with NAFL (n = 13; NAS = 1–4, fibrosis score = 0), patients with NASH with mild fibrosis (n = 20; NAS = 3–6, fibrosis score = 1), and patients with NASH with advanced fibrosis (n = 22; NAS = 3–6, fibrosis score ≥2). (B) qPCR analysis of liver core biopsies from patients with obesity without steatosis (n = 7; NAS = 0), with NAFL (n = 8; NAS = 1–2), or with NASH and fibrosis (n = 8; NAS = 5–6, fibrosis score = 1–2). (C) C57BL/6 mice were fed a chow diet or a HFD for 12 weeks, and livers were processed for qPCR. (D–H) C57BL/6 mice were fed a chow diet or a HFD for 8–10 weeks, and hepatocytes were isolated and processed for (D and E) qPCR or (F and G) immunoblotting. (H) Quantification of protein levels for F and G. Representative and quantified results are shown as the mean ± SEM for the indicated number of mice. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (A and B) or Student’s t test (C–E and H); ##P <0.05, by Student’s t test (B).