F I G U R E 8 Working model of exercise effects in NASH model. In
this NASH mouse model, liver steatosis, liver injury, and fibrosis were
progressed. Exercise changed intrahepatic immune cell profile, and
suppressed liver steatosis, liver injury, and fibrosis, and that the
beneficial effects correlated with reductions in intrahepatic BMDMs
(F4/80intCD11bhi macrophage) and PD-1+ CD8+ T cells. Exercise
mice had increased IL-15 expression in muscle and fatty liver and liver
injury were exacerbated in IL-15 KO mice with NASH, suggesting that
IL-15 may be involved in the inhibitory effect of exercise on NASH
progression. Abbreviations: BMDMs, bone marrow-derived macrophage; KO, knockout; PD-1, programmed death receptor-1.
muscle-specific but systemic IL-15 KO mice, so further
investigation is needed to determine the extent to which
muscle-derived IL-15 contributes to the pathogenesis
of NASH.
In summary, the results of our study show that
exercise ameliorated hepatic steatosis, inflammation,
and fibrosis in a mouse model of NASH, and that the
beneficial effects correlated with reductions in intrahepatic BMDMs and PD-1+ CD8+ T cells. Therefore,
one of the many beneficial effects of exercise on NASH
pathogenesis may be an impact on the intrahepatic
immune cell profile. In addition, it is possible that IL-15
produced by exercise is involved in the inhibition of
NASH progression by exercise (Figure 8).
ACKNOWLEDGMENTS
The authors thank Chizu Tokoro, Hiromi Tanikawa,
Hiroko Nagai, and Tomomi Oishi for technical assistance. The authors thank Anne M. O’Rourke, PhD, from
Edanz (http://jp.edanz.com/ac) for editing a draft of this
manuscript.
F U N D I N G IN F O R M A T I O N
This research was supported by The Japan Agency
for Medical Research and Development (AMED,
21fk0210094) and a Grant-in-Aid for Research from
the National Center for Global Health and Medicine
(20A3001).
1. Parlati L, Régnier M, Guillou H, Postic C. New targets for NAFLD.
JHEP Rep. 2021;3:100346.
2. Rinella M, Charlton M. The globalization of nonalcoholic fatty
liver disease: prevalence and impact on world health. Hepatology. 2016;64:19–22.
3. Li J, Zou B, Yeo YH, Feng Y, Xie X, Lee DH, et al. Prevalence,
incidence, and outcome of non-alcoholic fatty liver disease in
Asia, 1999–2019: A systematic review and meta-analysis.
Lancet Gastroenterol Hepatol. 2019;4:389–98.
4. Guarino M, Kumar P, Felser A, Terracciano LM, Guixé-Muntet S,
Humar B, et al. Exercise attenuates the transition from fatty liver
to steatohepatitis and reduces tumor formation in mice. Cancers
(Basel). 2020;12:1407.
5. Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis
development in nonalcoholic steatohepatitis. Gastroenterology.
2020;158:1913–28.
6. Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y,
et al. Evidence-based clinical practice guidelines for nonalcoholic
fatty liver disease/nonalcoholic steatohepatitis 2020. Hepatol
Res. 2021;51:1013–25.
7. Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H, Nago
T, et al. Aerobic vs. resistance exercise in non-alcoholic fatty liver
disease: a systematic review. J Hepatol. 2017;66:142–52.
8. Lesnak JB, Fahrion A, Helton A, Rasmussen L, Andrew M,
Cunard S, et al. Resistance training protects against muscle pain
through activation of androgen receptors in male and female
mice. Pain. 2022;163:1879–91.
9. Koo BK, Kim D, Joo SK, Kim JH, Chang MS, Kim BG, et al.
Sarcopenia is an independent risk factor for nonalcoholic steatohepatitis and significant fibrosis. J Hepatol. 2017;
66:123–31.
10. Huber Y, Gehrke N, Biedenbach J, Helmig S, Simon P, Straub
BK, et al. Voluntary distance running prevents TNF-mediated
liver injury in mice through alterations of the intrahepatic immune
milieu. Cell Death Dis. 2017;8:e2893.
11. Yazdani HO, Kaltenmeier C, Morder K, Moon J, Traczek M,
Loughran P, et al. Exercise training decreases hepatic injury and
metastases through changes in immune response to liver
ischemia/reperfusion in mice. Hepatology. 2021;73:2494–509.
12. Peng H, Wang Q, Lou T, Qin J, Jung S, Shetty V, et al. Myokine
mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. Nat Commun. 2017;8:
1493.
13. Remmerie A, Martens L, Thoné T, Castoldi A, Seurinck R, Pavie
B, et al. Osteopontin expression identifies a subset of recruited
macrophages distinct from Kupffer cells in the fatty liver.
Immunity. 2020;53:641–57 e14.
14. Tran S, Baba I, Poupel L, Dussaud S, Moreau M, Gélineau A,
et al. Impaired Kupffer cell self-renewal alters the liver response
to lipid overload during non-alcoholic steatohepatitis. Immunity.
2020;53:627–40 e5.
15. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate
immunity and inflammation in NAFLD/NASH. Dig Dis Sci.
2016;61:1294–303.
16. Wang L, Sun P, Wu Y, Wang L. Metabolic tissue-resident CD8(+)
T cells: a key player in obesity-related diseases. Obes Rev. 2021;
22:e13133.
EXERCISE INHIBITS THE PROGRESSION OF NASH
Downloaded from http://journals.lww.com/hepcomm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX
1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/26/2023
17. Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A,
Laschinger M, et al. Auto-aggressive CXCR6(+) CD8 T cells
cause liver immune pathology in NASH. Nature. 2021;592:444–9.
18. Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M,
Szydlowska M, et al. NASH limits anti-tumour surveillance in
immunotherapy-treated HCC. Nature. 2021;592:450–6.
19. Tsuchida T, Lee YA, Fujiwara N, Ybanez M, Allen B, Martins S,
et al. A simple diet- and chemical-induced murine NASH model
with rapid progression of steatohepatitis, fibrosis and liver
cancer. J Hepatol. 2018;69:385–95.
20. Badmus OO, Hillhouse SA, Anderson CD, Hinds TD, Stec DE.
Molecular mechanisms of metabolic associated fatty liver
disease (MAFLD): Functional analysis of lipid metabolism
pathways. Clin Sci (Lond). 2022;136:1347–66.
21. Binas B, Danneberg H, McWhir J, Mullins L, Clark AJ. Requirement for the heart-type fatty acid binding protein in cardiac fatty
acid utilization. FASEB J. 1999;13:805–12.
22. Fang W, Deng Z, Benadjaoud F, Yang C, Shi GP. Cathepsin B
deficiency ameliorates liver lipid deposition, inflammatory cell
infiltration, and fibrosis after diet-induced nonalcoholic steatohepatitis. Transl Res. 2020;222:28–40.
23. Jiao J, Ooka K, Fey H, Fiel MI, Rahmman AH, Kojima K, et al.
Interleukin-15 receptor alpha on hepatic stellate cells regulates
hepatic fibrogenesis in mice. J Hepatol. 2016;65:344–53.
24. Ibrahim SH, Hirsova P, Gores GJ. Non-alcoholic steatohepatitis
pathogenesis: sublethal hepatocyte injury as a driver of liver
inflammation. Gut. 2018;67:963–72.
25. Kazankov K, Jørgensen SMD, Thomsen KL, Møller HJ, Vilstrup
H, George J, et al. The role of macrophages in nonalcoholic fatty
liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145–59.
26. Pan J, Ou Z, Cai C, Li P, Gong J, Ruan XZ, et al. Fatty acid
activates NLRP3 inflammasomes in mouse Kupffer cells through
mitochondrial DNA release. Cell Immunol. 2018;332:111–20.
27. Kim KH, Lee MS. Pathogenesis of nonalcoholic steatohepatitis
and hormone-based therapeutic approaches. Front Endocrinol
(Lausanne). 2018;9:485.
13
28. Yoo SZ, No MH, Heo JW, Park DH, Kang JH, Kim SH, et al. Role
of exercise in age-related sarcopenia. J Exerc Rehabil. 2018;14:
551–8.
29. Kawanishi N, Yano H, Mizokami T, Takahashi M, Oyanagi E,
Suzuki K. Exercise training attenuates hepatic inflammation,
fibrosis and macrophage infiltration during diet induced-obesity in
mice. Brain Behav Immun. 2012;26:931–41.
30. Fredrickson G, Barrow F, Dietsche K, Parthiban P, Khan S, Robert
S, et al. Exercise of high intensity ameliorates hepatic inflammation
and the progression of NASH. Mol Metab. 2021;53:101270.
31. Piccirillo R. Exercise-induced myokines with therapeutic potential for muscle wasting. Front Physiol. 2019;10:287.
32. Molanouri Shamsi M, Hassan ZM, Quinn LS, Gharakhanlou R,
Baghersad L, Mahdavi M. Time course of IL-15 expression
after acute resistance exercise in trained rats: Effect of
diabetes and skeletal muscle phenotype. Endocrine. 2015;49:
396–403.
33. Badolato R, Ponzi AN, Millesimo M, Notarangelo LD, Musso T.
Interleukin-15 (IL-15) induces IL-8 and monocyte chemotactic
protein 1 production in human monocytes. Blood. 1997;90:
2804–9.
34. Nandi M, Moyo MM, Orkhis S, Mobulakani JMF, Limoges MA,
Rexhepi F, et al. IL-15Ralpha-independent IL-15 signaling in
non-NK cell-derived IFNgamma driven control of Listeria monocytogenes. Front Immunol. 2021;12:793918.
How to cite this article: Tsutsui Y, Mori T,
Yoshio S, Sato M, Sakata T, Yoshida Y, et al.
Exercise changes the intrahepatic immune cell
profile and inhibits the progression of nonalcoholic
steatohepatitis in a mouse model. Hepatol Commun. 2023;7:e0236. https://doi.org/10.1097/
HC9.0000000000000236
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