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

Tetraspanins are transmembrane signaling and proin-flammatory proteins. Prior work demonstrates that the tet-raspanin, 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 de-marcates the nutritional and inflammatory status of hepato-cytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepa-tocyte 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, meta-bolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 dele-tion attenuated tumor necrosis factor alpha-induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in iso-lated murine hepatocytes. In vivo, CD53 deletion in nonal-coholic 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 inflamma-tory and metabolic signals in response to hepatocyte nutri-tional status and that CD53 blockade may provide a means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as nonalco-holic steatohepatitis and type 2 diabetes.

Automated summary

CD53 marks the nutritional and inflammatory status of hepatocytes, and its deletion can attenuate dyslipidemia and hepatic inflammatory activation. It also blocks peripheral adipose accumulation, adipose inflammation, and liver lipid accumulation. CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status and its blockade may be a potential therapeutic strategy for diseases involving overnutrition and inflammation.