Significant association of elevated serum galectin-9 levels with the development of non-alcoholic fatty liver disease in patients with rheumatoid arthritis

Po-Ku Chen; Wei-Fan Hsu; Cheng-Yuan Peng; Tsai-Ling Liao; Shih-Hsin Chang; Hsin-Hua Chen; Chu-Huang Chen; Der-Yuan Chen

doi:10.3389/fmed.2024.1347268

Significant association of elevated serum galectin-9 levels with the development of non-alcoholic fatty liver disease in patients with rheumatoid arthritis

Front Med (Lausanne). 2024 Feb 2:11:1347268. doi: 10.3389/fmed.2024.1347268. eCollection 2024.

Authors

Po-Ku Chen^{1

2}, Wei-Fan Hsu^{3

4}, Cheng-Yuan Peng^{3

4}, Tsai-Ling Liao^{5

6

7}, Shih-Hsin Chang^{1

3

5}, Hsin-Hua Chen^{5

7

8}, Chu-Huang Chen^{9

10}, Der-Yuan Chen^{1

2

3

5

7}

Affiliations

¹ Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan.
² Translational Medicine Laboratory, China Medical University Hospital, Taichung, Taiwan.
³ College of Medicine, China Medical University, Taichung, Taiwan.
⁴ Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
⁵ Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
⁶ Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
⁷ College of Medicine, National Chung Hsing University, Taichung, Taiwan.
⁸ Division of General Medicine, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁹ Vascular and Medicinal Research, Texas Heart Institute, Houston, TX, United States.
¹⁰ Institute for Biomedical Sciences, Shinshu University, Nagano, Japan.

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is prevalent among rheumatoid arthritis (RA) patients, but its pathogenesis has rarely been explored. Galectin-9 (Gal-9) interacts with T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3) expressed on hepatocytes and thus regulates T cell proliferation in a murine model of NAFLD. We aimed to examine the pathogenic role of the Gal-9/TIM-3 pathway in RA-NAFLD.

Methods: Serum levels of Gal-9, soluble TIM-3 (sTIM-3), fatty acid-binding proteins (FABP)1, and FABP4 were determined by ELISA in forty-five RA patients and eleven healthy participants. Using Oil-red O staining and immunoblotting, we examined the effects of Gal-9 and free fatty acid (FFA) on lipid accumulation in human hepatocytes and FABP1 expression.

Results: Serum Gal-9, sTIM-3 and FABP1 level were significantly higher in RA patients (median 5.02 ng/mL, 3.42 ng/mL, and 5.76 ng/mL, respectively) than in healthy participants (1.86 ng/mL, 0.99 ng/mL, and 0.129 ng/mL, all p < 0.001). They were also significantly higher in patients with moderate-to-severe NAFLD compared with none-to-mild NAFLD (p < 0.01; p < 0.05; and p < 0.01, respectively). Serum Gal-9 levels were positively correlated with sTIM-3, FABP1, FABP4 levels, and ultrasound-fatty liver score, respectively, in RA patients. Multivariate regression analysis revealed that Gal-9 (cut-off>3.30) was a significant predictor of NAFLD development, and Gal-9 and sTIM-3 were predictors of NAFLD severity (both p < 0.05). The cell-based assay showed that Gal-9 and FFA could upregulate FABP1 expression and enhance lipid droplet accumulation in hepatocytes.

Conclusion: Elevated levels of Gal-9 and sTIM3 in RA patients with NAFLD and their positive correlation with NAFLD severity suggest the pathogenic role of Gal-9 signaling in RA-related NAFLD.

Keywords: fatty acid-binding proteins; galectin-9; non-alcoholic fatty liver disease; rheumatoid arthritis; soluble T cell immunoglobulin and mucin-containing-molecule-3 (sTIM-3).

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a grant (MOST 111-2314-B-039-010) from the Ministry of Science and Technology, Taiwan and a grant (NSTC 112-2314-B-039-067) from the National Science and Technology Council, Taiwan.