Tirzepatide, a dual GIP/GLP-1 receptor agonist, alleviates metabolic dysfunction-associated steatotic liver disease by reducing the expression of CD36 and OBP2A.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by excessive hepatic lipid accumulation. This study evaluated the therapeutic effects and molecular mechanisms of tirzepatide, a dual GIP and GLP-1 receptor agonist, in treating hepatic steatosis. Eight-week-old C57BL/6J mice were fed either a high-fat diet or a high-fat, high-fructose, and high-cholesterol diet for 12 weeks to induce MASLD. From week 8, some mice received weekly intraperitoneal tirzepatide injections for four weeks. Tirzepatide significantly reduced body and liver weight gain. Histological analysis confirmed decreased hepatic vacuolation and lipid deposition. The drug also lowered serum glucose levels and reduced liver triglyceride and cholesterol content without causing liver injury. Transcriptome analysis showed that tirzepatide downregulated mitochondrial oxidative phosphorylation pathways. It also decreased hepatic expression of CD36 and odorant-binding protein 2A, both involved in lipid uptake. Importantly, tirzepatide did not significantly alter other major liver metabolic pathways. In adipose tissue, it reduced CD36 and odorant-binding protein 2A expression and upregulated adipose triglyceride lipase, suggesting enhanced lipolysis. However, it had no effect on CD36 levels in skeletal muscle. These results suggest that tirzepatide may be an effective treatment for MASLD by reducing liver fat accumulation and modulating lipid metabolism in extrahepatic tissues.