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Correspondence to editorial on “Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy”

Clinical and Molecular Hepatology 2024;30(4):1026-1027.
Published online: July 8, 2024

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Corresponding author : Qi Wang Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui, China Tel: +86-551-65908517, Fax: +86-551-65908424, E-mail: drqiwang@163.com

Editor: Sungsoon Fang, Yonsei University College of Medicine, Korea

• Received: June 24, 2024   • Accepted: July 5, 2024

Copyright © 2024 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,
We greatly appreciate it to receive the insightful comments from Professor Junjie Yu on our publication, providing an editorial [1] to summarize the major findings of our publication in the same issue [2]. Given that the body weight of macrophage Atg16l1 knockout mice is significantly increased with less energy expenditure after high fat and high cholesterol diet (HFHCD) feeding compared to the control group, and Lyz2-Cre is expressed in all macrophages, the contribution of macrophage ATG16L1 from other tissues, such as white adipose tissue (WAT) in metabolic dysfunction-associated steatohepatitis (MASH), may need more investigation. The authors would provide more discussion to refine this concern.
Previous studies have reported that global or brown adipocyte-specific deletion of pink1, a key molecular for mitophagy, could suppress the energy expenditure of mice [3], indicating autophagy might account for body weight. Our study found that macrophages Atg16l1 knockout increased the weight and liver weight of HFHCD-feeding mice. There were significant differences in energy expenditure between the different groups of mice with HFHCD provision, indicating that energy expenditure may account for the difference in body weight or liver weight for macrophages Atg16l1 knockout mice fed with HFHCD compared to the controls. Meanwhile, inflammation of visceral adipose tissues was decreased in macrophages of Atg16l1 knockout MASH mice as compared to floxed MASH mice. Moreover, we found that macrophage Atg16l1 depletion promoted lipid loading in hepatocytes by aggravating inflammatory response, which may also account for more body weight and liver weight gain in macrophage Atg16l1 knockout mice than that in macrophage Atg16l1 floxed mice fed with HFHCD.
As pointed out by Professor Yu, Lyz2-Cre-mediated conditional knockout affects all Lyz2+ cells. Therefore, macrophage ATG16L1 in other tissues, such as adipose tissue and the cardiovascular system, may regulate the progression of MASH through autophagy. A previous study has demonstrated that the role of autophagy in the differentiation of white adipose tissue was studied by deleting the autophagy-related 7 (atg7) gene from adipose tissue in mice. Atg7 deletion results in a striking phenotype at the cellular, tissue and whole-organism levels. For example, adipose tissue deposits in the mutant mice are much smaller in mass than those observed in their wild-type counterparts and the knockout mice are noticeably slimmer than their wild-type littermates. The mutant mice also exhibit higher basal physical activity levels and an array of metabolic changes. These findings establish a new function for autophagy and provide a new model system for use in the search for treatments for obesity and diabetes [4]. Moreover, another study by Liu et al. [5] demonstrates that macrophage-specific ATG5 deficiency exacerbates hepatic inflammation in MASH, while the level of inflammation in WAT shows no significant difference. This may be due to the unique histological and immunological characteristics of the liver. The study only used a 12-week HFD feeding protocol, so the role of macrophage ATG5 in WAT during the progression of MASH requires further investigation. Liao et al.’s study [6] indicates that macrophage-specific ATG5 deficiency exacerbates atherosclerosis, possibly due to defective autophagy in macrophages decreasing their phagocytic clearance capacity. Considering the differential roles of macrophage autophagy in tissues outside the liver, the tissue-specific role of macrophage ATG16L1 still requires further investigation.
To sum up, MASH might be tightly associated with other pathophysiological changes affected by HFHCD, such as adipose tissue deposition, atherosclerosis, obesity and diabetes. Autophagy-related proteins might play an important role in these diseases, which needs further investigation in the future.
This work was supported by grants from the National Natural Science Foundation of China (81971495, 82370668, 82071798), the CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-035) and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX24_2030).

Authors’ contribution

Qi Wang, Qingfa Bu, Haoming Zhou and Ling Lu are responsible for manuscript preparation, concept synthesis and finalization. All the authors have read and approved the final manuscript.

Conflicts of Interest

The authors have no conflicts to disclose.

HFHCD

high-fat and high-cholesterol diet

WAT

white adipose tissue

MASH

metabolic dysfunction-associated steatohepatitis

atg7

autophagy-related 7
  • 1. Yu J. Macrophage ATG16L1: Potential candidate for metabolic dysfunction-associated steatohepatitis treatment: Editorial on “Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy”. Clin Mol Hepatol 2024;30:721-723.
  • 2. Wang Q, Bu Q, Xu Z, Liang Y, Zhou J, Pan Y, et al. Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy. Clin Mol Hepatol 2024;30:515-538.
  • 3. Ko MS, Yun JY, Baek IJ, Jang JE, Hwang JJ, Lee SE, et al. Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice. Autophagy 2021;17:1205-1221.
  • 4. Goldman S, Zhang Y, Jin S. Autophagy and adipogenesis: implications in obesity and type II diabetes. Autophagy 2010;6:179-181.
  • 5. Liu K, Zhao E, Ilyas G, Lalazar G, Lin Y, Haseeb M, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy 2015;11:271-284.
  • 6. Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 2012;15:545-553.

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Correspondence to editorial on “Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy”
Clin Mol Hepatol. 2024;30(4):1026-1027.   Published online July 8, 2024
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Correspondence to editorial on “Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy”
Clin Mol Hepatol. 2024;30(4):1026-1027.   Published online July 8, 2024
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Correspondence to editorial on “Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy”
Correspondence to editorial on “Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy”