274-LB: Complement Factor D Contributes to Metabolic Dysregulation by Hepatic CD9 Deficiency

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. Supplement_1; p. 1
• Main Author: ZHENG, YI
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2023
• Subjects: Adipocytes; Adipose tissue; AKT protein; CD9 antigen; Cell surface; Complement factor D; Diabetes; Diabetes mellitus; Energy expenditure; Fatty liver; Hepatocytes; Homeostasis; Lipogenesis; Liver; Metabolic disorders; Metabolism; Protein deficiency; Steatosis; Thermogenesis
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db23-274-LB

Diabetes-induced metabolic diseases involve functional integration among inter-organ communication, and the liver is central to this process. Here we show that deficiency of cell-surface protein tetraspanin CD9 in the liver of diabetic mice stimulates hepatocytes to synthesize and secrete complement factor D (CFD), which undermines whole-body metabolic homeostasis. Specifically, silencing liver CD9 exacerbated diet-induced obesity and fatty acid synthesis in white adipose tissue of mice with a markedly elevated CFD expression in both liver and plasma. Consistently, liver CFD-overexpressed mice exhibited severe hepatic steatosis, increased fat adipose deposition and decreased energy expenditure under HFD feeding. Mechanistically, CFD exerted its deleterious metabolic effects by activating its receptor C5aR-AKT dependent axis in the adipose tissues, and blockade of C5aR in adipocytes obviously abolished the CFD-induced lipogenesis and -suppressed thermogenesis in vitro and in vivo. Furthermore, we determined an increased CFD with the decreased CD9 expression in the fatty livers of human subjects, and also a negative correlation between CD9 and CFD was established in NAFLD patient samples. Together, these findings identify CFD inhibition as a potential pharmacological target for the management of diabetes and related metabolic disorders.