김건중 (University of Massachusetts Medical School)

한빛사논문

조회197

University of Massachusetts Medical School

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Nat. Commun., Jun 29 2024, 15 (1) | https://doi.org/10.1038/s41467-024-49633-y IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease

Randall H. Friedline¹, Hye Lim Noh¹, Sujin Suk^1,2, Mahaa Albusharif¹, Sezin Dagdeviren¹, Suchaorn Saengnipanthkul^1,3, Bukyung Kim^1,4, Allison M. Kim¹, Lauren H. Kim¹, Lauren A. Tauer¹, Natalie M. Baez Torres¹, Stephanie Choi¹, Bo-Yeon Kim^1,5, Suryateja D. Rao¹, Kaushal Kasina¹, Cheng Sun⁶, Benjamin J. Toles⁶, Chan Zhou⁷, Zixiu Li⁷, Vivian M. Benoit¹, Payal R. Patel¹, Doris X. T. Zheng¹, Kunikazu Inashima¹, Annika Beaverson¹, Xiaodi Hu¹, Duy A. Tran¹, Werner Muller⁸, Dale L. Greiner^1,9, Alan C. Mullen⁶, Ki Won Lee^2,10& Jason K. Kim^1,2,9,11

¹Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.

²WCU Biomodulation Major, Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.

³Division of Nutrition, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

⁴Division of Endocrinology and Metabolism, Department of Internal Medicine, Kosin University College of Medicine, Busan, Republic of Korea.

⁵Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea.

⁶Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.

⁷Division of Biostatistics and Health Services Research, Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA, USA.

⁸Division of Infection, Immunity & Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.

⁹Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA.

¹⁰XO Center, Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.

¹¹Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.

Corresponding author

Correspondence to Jason K. Kim.

Abstract

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2 ^-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2 ^-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-07-11)
연구진국외 연구진
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