Cold aerobic exercise mitigates NAFLD fibrosis through UBAP2L-regulated TGF-β/SMAD2 signaling

in Journal of Endocrinology
Authors:
Jianhong Zhang Sport Science School, Beijing Sport University, Beijing, China
Sports Medical Supervision Center, National Institute of Sports Medicine, Beijing, China

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Chaoyang Li Sport Science School, Beijing Sport University, Beijing, China

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https://orcid.org/0009-0009-0178-2183
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Zhijian Rao Exercise Biology Research Center, China Institute of Sport Science, Beijing, China
College of Physical Education, Shanghai Normal University, Shanghai, China

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Xue Geng Sport Science School, Beijing Sport University, Beijing, China
Exercise Biology Research Center, China Institute of Sport Science, Beijing, China

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Chen Liang Sports Medical Supervision Center, National Institute of Sports Medicine, Beijing, China

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Shijie Liu Exercise Biology Research Center, China Institute of Sport Science, Beijing, China

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Peng Huang Exercise Biology Research Center, China Institute of Sport Science, Beijing, China
School of Kinesiology, Shanghai University of Sport, Shanghai, China

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Dongzhe Wu Sport Science School, Beijing Sport University, Beijing, China

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Yiwei Feng School of Kinesiology, Shanghai University of Sport, Shanghai, China

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Jiexiu Zhao Exercise Biology Research Center, China Institute of Sport Science, Beijing, China

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Correspondence should be addressed to J Zhao: Zhaojiexiu@ciss.cn

(J Zhang and C Li contributed equally to this work)

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Non-alcoholic fatty liver disease (NAFLD) can progress to fibrosis and hepatocellular carcinoma, with TGF-β playing a key role. UBAP2L regulates TGF-β expression, but its role in NAFLD remains unclear. While exercise improves NAFLD and cold exposure enhances lipid metabolism, their combined effects on NAFLD-induced fibrosis are unknown. This study examines whether exercise with cold exposure attenuates NAFLD-induced fibrosis via the UBAP2L-mediated TGF-β/SMAD2/3 pathway. Fifty 5-week-old male C57BL/6N mice were assigned to five groups: normal control (C), high-fat diet (H), high-fat diet with cold exposure (HC), high-fat diet with exercise (HE), and high-fat diet with exercise and cold exposure (HCE). After 8 weeks of a high-fat diet, the HE and HCE groups underwent treadmill exercise (50 min/session, 5 days/week for 8 weeks). H&E, Oil Red O, Masson staining, biochemical analyses, proteomics, Western blot and RT-qPCR were used to assess fibrosis-related markers. We found that body weight, liver weight, hepatic TG, TC, LDL, Glu, CHO, AST and ALT were significantly elevated in the H group. In the HCE group, hepatic TG and BUN decreased, while HDL increased. Proteomics identified UBAP2L as the most upregulated protein in the H group, but it was downregulated in the HCE group. Western blot confirmed UBAP2L overexpression in the H group and its reduction in the HCE group, with decreased α-SMA. RT-qPCR showed elevated Tgf-β, α-Sma, Smad2, Smad3, Col1a2 and Ubap2l in the H group, which were downregulated by exercise with cold exposure. Exercise with cold exposure can reduce NAFLD-induced hepatic fibrosis, probably by downregulating UBAP2L and suppressing the TGF-β/SMAD2 pathway. These suggest exercise with cold exposure may be more effective than exercise at normal temperatures in mitigating NAFLD-related fibrosis.

 

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