Tirzepatide, a dual GIP/GLP-1 receptor agonist, alleviates metabolic dysfunction-associated steatotic liver disease by reducing the expression of CD36 and OBP2A
Yun Li, Wencong Sun, Hong Liu, Xiong Z. Ruan
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive lipid accumulation in the liver. This study aimed to investigate the therapeutic potential and underlying molecular mechanism of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in alleviating 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 the 8th week onward, a subset of these mice received weekly intraperitoneal injections of tirzepatide for four consecutive weeks. Our results demonstrated that tirzepatide significantly attenuated body weight gain, reduced liver weight, and alleviated macroscopic signs of hepatic lipid accumulation compared to untreated controls. Histological analysis confirmed a marked decrease in hepatic vacuolation and lipid deposition in the tirzepatide-treated groups. Tirzepatide effectively lowered serum glucose levels, as well as hepatic triglyceride and cholesterol contents, without inducing drug-related liver injury. Transcriptome sequencing revealed that tirzepatide treatment led to the down-regulation of mitochondrial oxidative phosphorylation pathways. Interestingly, tirzepatide reduced the hepatic expression of the fatty acid translocase CD36 and odorant-binding protein 2A, which are involved in lipid uptake and accumulation. Notably, tirzepatide did not significantly affect other major metabolic pathways in the liver. In extrahepatic tissues, tirzepatide reduced the expression of CD36 and odorant-binding protein 2A in adipose tissue and even up-regulated adipose triglyceride lipase, suggesting a potential role in promoting lipolysis. Tirzepatide does not affect CD36 levels in skeletal muscle. These findings suggest that tirzepatide may serve as an effective therapeutic agent for MASLD by reducing hepatic lipid accumulation and modulating extrahepatic metabolic pathways.