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 7

IL-10 preserves hepatocellular viability/metabolic activity and restores stress-responsive STAT3/AKT/mTOR signaling.

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IL-10 preserves hepatocellular viability/metabolic activity and restores...
Phosphorylation ratios are shown under basal conditions in the lipotoxicity model (PA exposure) and interpreted as stress-responsive survival signaling; insulin stimulation was not performed. (A) In vivo hepatic STAT3/AKT/mTOR signaling. Immunoblot analysis of p-STAT3/STAT3, p-AKT/AKT, and p-mTOR/mTOR in liver tissues from ND, ND+IL-10, HFD, and HFD+IL-10 groups. Protein band intensities are quantified and expressed as phosphorylation ratios. β-Actin loading controls for AKT and mTOR were obtained from the same gel with STAT3. (B) Cells were incubated with PA at increasing concentrations or with DMEM alone (control) for 24 hours. Immunoblot analysis of p-STAT3/STAT3, p-AKT/AKT, and p-mTOR/mTOR. 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 = 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). Cells were then incubated with PA exposure in the presence of IL-10 (0 and 20 ng/mL) and/or (C) IL-10Rα, (D) cryptotanshinone, (E) LY294002, (F) rapamycin, or DMEM (control) for 24 hours. (B–E) For each inhibitor, immunoblot analysis was conducted to evaluate protein expression changes in p-STAT3/STAT3, p-AKT/AKT, and p-mTOR/mTOR ratios, except for the specific pathway targeted by each inhibitor. (G) Quantitative cell viability. For each inhibitor, relative fold-changes compared with the control (100%) were examined. 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); †P < 0.05 versus PA and IL-10 (20 ng/mL). HFD, high-fat diet; ND, normal diet; PA, palmitic acid.