Connectivity mapping of angiotensin-PPAR interactions involved in the amelioration of non-alcoholic steatohepatitis by Telmisartan

Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is associated with various metabolic disorders. Telmisartan is a potential treatment for NAFLD due to its ability to improve insulin sensitivity and decrease hepatic fat accumulation via modulation of PPARγ, and to suppress hepatic fibrosis by blocking angiotensin II receptors. However, the underlying mechanisms of action of telmisartan have yet to be fully elucidated. In the present study, diabetic nonalcoholic steatohepatitis (NASH) mice (STAM mice) received daily administrations of telmisartan for 6 weeks to assess the improvements in NASH. Hepatic transcriptome analyses revealed that the amelioration of NASH likely occurred through the regulation of inflammatory- and fibrosis-related gene responses. An integrated network analysis including transcriptional and non-transcriptional genes regulated by telmisartan showed that the NAFLD pathway is interconnected with the dysregulated RAS-PPAR-NFκB pathways. The downstream targets of PPARα, PPARδ, and RELA in this network significantly overlapped with telmisartan-induced differentially expressed genes (DEGs), which were verified in palmitate-treated Hepa1c1c7 cell line. This transcriptome approach accompanied with cell-based molecular analyses provided the opportunity to understand the fundamental molecular mechanisms underpinning the therapeutic effects of telmisartan, and will contribute to the establishment of a novel pharmacological treatment for NASH patients.