The tetraspanin transmembrane protein CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes

• Published in: The Journal of biological chemistry 2023-02, Vol.299 (2), p.102835, Article 102835
• Main Authors: Higgins, Cassandra B., Adams, Joshua A., Ward, Matthew H., Greenberg, Zev J., Milewska, Małgorzata, Sun, Jiameng, Zhang, Yiming, Chiquetto Paracatu, Luana, Dong, Qian, Ballentine, Samuel, Li, Weikai, Wandzik, Ilona, Schuettpelz, Laura G., DeBosch, Brian J.
• Format: Article
• Language: English
• Subjects: Animals; caloric restriction; CD53; Diet, High-Fat; energy metabolism; fasting; FGF21; glucose transport; GLUT; Hepatocytes - metabolism; Inflammation - genetics; Inflammation - metabolism; insulin resistance; lactotrehalose; Liver - metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - metabolism; nonalcoholic fatty liver disease; obesity; Obesity - metabolism; proteomics; tetraspanin; Tetraspanin 25 - metabolism; Tetraspanins - genetics; Tetraspanins - metabolism; thermogenesis; trehalose; Trehalose - metabolism
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2022.102835

Tetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction in fat- and fructose-exposed contexts. Furthermore, germline CD53 deletion in vivo blocked Western diet–induced dyslipidemia and hepatic inflammatory transcriptomic activation. Surprisingly, metabolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 deletion attenuated tumor necrosis factor alpha–induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in isolated murine hepatocytes. In vivo, CD53 deletion in nonalcoholic steatohepatitis diet-fed mice blocked peripheral adipose accumulation and adipose inflammation, insulin tolerance, and liver lipid accumulation. We then defined a stabilized and trehalase-resistant trehalose polymer that blocks hepatocyte CD53 expression in basal and over-fed contexts. The data suggest that CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status and that CD53 blockade may provide a means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as nonalcoholic steatohepatitis and type 2 diabetes.