Non-alcoholic fatty liver disease (NAFLD) is a hepatic metabolic syndrome resulting from lipid metabolic imbalance. Interferon regulatory factor 8 (IRF8) is well known for its roles in immune cell differentiation and tumor pathogenesis; however, its role in regulating glucose homeostasis and lipid metabolism remains unclear.

This research, published in the Genes & Diseases journal by a team from Shanghai Jiao Tong University, Southern Medical University and Capital Medical University, elucidates the role of IRF8 in hepatic lipid metabolism using mouse models of gain and loss of function.

The initial investigation involving multiple murine models revealed an upregulation of IRF8 expression in the liver tissues of both humans and mice with NAFLD. The research findings also demonstrated that IRF8 exacerbates hepatic lipid accumulation and metabolic disturbance under both standard and high-fat dietary conditions. Additionally, IRF8 knockdown reduced hepatic lipid accumulation and alleviated metabolic disorders induced by a high-fat diet (HFD).

The researchers then employed adenovirus vectors expressing IRF8 (Ad-IRF8) or small interfering RNAs (si-IRF8) to respectively induce the overexpression or silencing of IRF8 in mouse primary hepatocytes (MPHs) and found that IRF8 positively regulates the expression of a core circadian rhythm gene, brain and muscle ARNT-like 1 (BMAL1), in hepatocytes. Furthermore, in vitro and in vivo studies collectively indicated that IRF8 modulates the expression of peroxisome proliferator-activated receptor γ (PPARγ) and related fatty acid uptake and synthesis genes mediated by BMAL1.

Notably, the application of a PPARγ inhibitor (GW9662) to IRF8-overexpressing MPHs effectively suppressed the cellular lipid deposition caused by IRF8 upregulation. This finding indicates that the IRF8/BMAL1/ PPARγ axis may play an important role in liver lipid metabolism. Furthermore, adeno-associated virus-mediated IRF8 knockdown in mouse liver markedly alleviated hepatic steatosis and obesity-related metabolic syndrome.

In conclusion, this study reveals a previously unknown and crucial factor modulating hepatic lipid homeostasis and the mechanism of hepatic steatosis in NAFLD models. Importantly, targeting the newly identified IRF8-BMAL1-PPARγ axis could offer promising therapeutic strategies for treating NAFLD and related metabolic disorders.

Reference

Title of Original Paper: IRF8 aggravates nonalcoholic fatty liver disease via BMAL1/PPARγ axis.

DOI: https://doi.org/10.1016/j.gendis.2024.101333

Journal Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

Funding Information:

National Science Foundation of China (No. 81974118, 82325010)
Shanghai Outstanding Academic Leaders (China) (No. 20XD1433300)
Shuguang Project of China (21SG11)
Innovative Research Team of High-level Local Universities in Shanghai, China (No. SHSMU-ZDCX20212700)
Major Natural Science Project of the Scientific Research and Innovation Plan of Shanghai Municipal Commission of Education (China) (No. 2023ZKZD17)
Shanghai Research Center for Endocrine and Metabolic Diseases (China) (No. 2022ZZ01002)
Shanghai Sixth People's Hospital Foundation (China) (No. ynqn202105)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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