Background & Aims: With the epidemic burden of obesity and metabolic diseases, nonalcoholic fatty liver disease (NAFLD) including steatohepatitis (NASH) has become the most common chronic liver disease in the western world. NASH may progress to cirrhosis and hepatocellular carcinoma. Currently, no treatment is available for NASH. Therefore, finding a therapy for NAFLD/NASH is in urgent need.Previously we have demonstrated that mice lacking CD47 or its ligand thrombos-pondin1 (TSP1) are protected from obesity-associated NALFD. This suggests that CD47 blockade might be a novel treatment for obesity-associated metabolic disease. Thus, in this study, the therapeutic potential of an anti-CD47 antibody in NAFLD progression was determined.Methods: Both diet-induced NASH mouse model and human NASH organoid model were utilized in this study. NASH was induced in mice by feeding with diet enriched with fat, fructose and cholesterol (AMLN diet) for 20 weeks and then treated with anti-CD47 antibody or control IgG for 4 weeks. Body weight, body composition and liver phenotype were analysed. Results:We found that anti-CD47 antibody treatment did not affect mice body weight, fat mass or liver steatosis. However, liver immune cell infiltration, inflammation and fibrosis were significantly reduced by anti-CD47 antibody treatment. In vitro data further showed that CD47 blockade prevented hepatic stellate cell activation and NASH progression in a human NASH organoid model. Conclusion:Collectively, these data suggest that anti-CD47 antibody might be a new therapeutic option for obesity-associated NASH and liver fibrosis.
Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.
Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.
Background: CD47 is a ubiquitously expressed cell membrane receptor implicated in self-recognition and immune function. Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function and energy homeostasis. Genetic deletion of CD47 has been shown to protect mice from diet-induced obesity and its-associated metabolic complications. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and metabolic disease was determined. Methods: Two obese mouse models (diet induced obese mice and leptin deficient ob/ob mice) were utilized. For diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet for 6 weeks to induce obesity and glucose intolerance. Then these mice were treated with CD47ASO or control ASO for 8 weeks with continuous HF diet feeding. For genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. Body weight was monitored weekly. By the end of study, glucose tolerance test, indirect calorimetry, body composition and cold exposure experiments were performed. Results: We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue, reduced hepatic lipogenic gene expression and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. CD47ASO treated mice displayed increased energy expenditure. Interestingly, these mice displayed increased voluntary wheel running distance in metabolic cage, which was associated with increased lean mass and expression of uncoupling proteins (UCP2 and UCP3) in skeletal muscle. Food intake or cold tolerance was comparable between control ASO and CD47 ASO treated mice. Conclusions: These findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.
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