IL-10 attenuates metabolic dysfunction–associated steatotic liver disease via modulation of hepatic responses to lipotoxicity
Akira Kado, Kazuya Okushin, Takeya Tsutsumi, Toshiyuki Kishida, Kazuhiko Ikeuchi, Hiroshi Yotsuyanagi, Kyoji Moriya, Kazuhiko Koike, Mitsuhiro Fujishiro
Akira Kado, Kazuya Okushin, Takeya Tsutsumi, Toshiyuki Kishida, Kazuhiko Ikeuchi, Hiroshi Yotsuyanagi, Kyoji Moriya, Kazuhiko Koike, Mitsuhiro Fujishiro
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Research Article Hepatology Immunology Metabolism

IL-10 attenuates metabolic dysfunction–associated steatotic liver disease via modulation of hepatic responses to lipotoxicity

Abstract

Lipotoxicity associated with metabolic dysfunction–associated steatotic liver disease (MASLD) causes dysregulated fatty acid (FA) and glucose metabolism, inducing cellular energy imbalance, oxidative stress (OS), and hepatocellular injury. IL-10 is altered in MASLD, including increased IL-10 transcripts in peripheral immune cells; however, its role in hepatic responses to lipotoxic stress remains unclear. We evaluated whether IL-10 treatment attenuates lipotoxic injury and MASLD-related phenotypes in vivo and in vitro to reveal MASLD treatment strategies. As MASLD models, mice fed a high-fat diet and in vitro normal human hepatocytes under palmitic acid exposure were treated with IL-10, along with confirmatory experiments in HepG2 cells. We assessed FA and glucose metabolism, OS, and apoptosis with histological changes and mechanisms related to hepatocellular viability/metabolic activity and stress-responsive survival signaling in vitro. IL-10 modulated FA synthesis and β-oxidation, reducing lipid accumulation, and IL-10 altered glucose metabolic pathways, consistent with improved glucose handling under lipotoxic stress. Furthermore, IL-10 reduced OS and cell death markers while enhancing antioxidant responses, consistent with hepatocellular protection. These data suggest that IL-10 attenuates lipotoxic injury by modulating hepatic response pathways, thereby improving MASLD-related phenotypes, and support the potential of IL-10 as a therapeutic target for MASLD.

Authors

Akira Kado, Kazuya Okushin, Takeya Tsutsumi, Toshiyuki Kishida, Kazuhiko Ikeuchi, Hiroshi Yotsuyanagi, Kyoji Moriya, Kazuhiko Koike, Mitsuhiro Fujishiro

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Figure 5

IL-10 suppresses hepatic oxidative stress in HFD-fed mice and normal human hepatocytes.

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IL-10 suppresses hepatic oxidative stress in HFD-fed mice and normal hum...
HFD-fed mice (A–D). (A) Mean fluorescence intensity (MFI) of the merged channel, a pseudo-colored overlay of images from the GFP (green, DCFDA) and DAPI (blue) channels, showing liver tissues from 4 experimental groups. ROS localization is shown with green fluorescence. Scale bar: 50 μm. Quantitative hepatic ROS levels and the ROS-positive area (percentage) in each view. The analysis was performed 4 times per group using different views. (B) MFI of the merged channel from the RFP (red, DHE) and DAPI (blue) channels, showing liver tissues from 4 experimental groups. Nuclear ROS localization is shown with red fluorescence. Scale bar: 50 μm. Quantitative evaluation of ROS is as described above. (C) Hepatic total SOD and catalase activities measured in liver homogenates (normalized to tissue/protein as indicated). Data are expressed as U/mg tissue. (D) Immunoblot analysis of SOD1, SOD2, CAT, and GPX. Protein band intensities are normalized to β-actin and expressed as ratios. Box-and-whisker plots show the median, IQR, and full data range. One-way ANOVA followed by Tukey’s multiple-comparison test; n = 4, *P < 0.05, **P < 0.01, ***P < 0.001. Normal human hepatocytes (NHHs) (E and F). (E) Quantitative intracellular ROS accumulation in NHHs and relative fold-changes compared with the control. (F) Immunoblot analysis of SOD1, SOD2, CAT, and GPX1 in NHHs. β-Actin loading controls for SOD2, CAT, and GPX1 were obtained from the same gel with SOD1. Box-and-whisker plots show the median, IQR, and full data range. One-way ANOVA followed by Tukey’s multiple-comparison test; n = 3, *P < 0.05 versus non-PA and IL-10 (0 ng/mL) (control); #P < 0.05 versus PA and IL-10 (0 ng/mL). CAT, catalase; GPX, glutathione peroxidase; HFD, high-fat diet; ND, normal diet; SOD, superoxide dismutase.