image: (A–H) Western blots and quantitative PCR were performed to analyze IRF8 levels in the livers of C57BL/6J male mice fed with HFD or CD (A, B) (n = 5 biologically independent mice), lean or ob/ob male mice (C, D) (n = 5 biologically independent mice), C57BL/6J male mice fed with HFHC (40 kcal of fat, 20 kcal of fructose, and 2% cholesterol) or CD for 30 weeks (E, F) (n = 5 biologically independent mice), and lean or db/db male mice (G, H) (n = 5 biologically independent mice). (I, J) After culturing MPHs using DMEM plus 10% fetal bovine serum for 24 h, the relative protein and mRNA expression levels of IRF8 were measured. The remaining cells were further cultured in DMEM for another 24 h to detect the expression level of IRF8. Subsequently, the remaining cells were cultured in DMEM plus 10% fetal bovine serum for an additional 24 h to evaluate the relative protein and mRNA expression levels of IRF8. (K, L) MPHs were treated with 5% bovine serum albumin, 0.1 mM palmitic acid (PA), and 0.25 mM PA for 24 h, and then the mRNA (K) and protein (L) levels of IRF8 were examined. (M) IRF8 protein levels were analyzed in liver tissues from healthy or patients with NAFLD by western blots (n = 5 biologically independent individuals). Data are presented as mean ± standard error of the mean. p values were calculated using an unpaired two-tailed Student's t-test (B, D, F, H, J–L). IRF8, interferon regulatory factor 8; NAFLD, non-alcoholic fatty liver disease; HFD, high-fat diet; CD, chow diet.
Credit: Genes & Diseases
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
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