Abstract
Nonalcoholic steatohepatitis (NASH) has become a major concern that threatens human health worldwide. The underlying pathogenesis was crucial but remained poorly understood. Here, we found that the expression of hepatic farnesyl diphosphate synthase (FDPS) was increased in mice and patients with NASH. Elevated FDPS levels were positively correlated with NASH severity. Overexpression of FDPS in mice provoked increased lipid accumulation, inflammation, and fibrosis, while hepatic FDPS deficiency protected mice from NASH progression. Importantly, pharmacological inhibition of FDPS with clinically used alendronate remarkably attenuated NASH-associated phenotypes in mice. Mechanistically, we demonstrated that FDPS increased its downstream product farnesyl pyrophosphate levels, which could function as an aryl hydrocarbon receptor (AHR) agonist to upregulate the expression of fatty acid translocase CD36, to accelerate the development of NASH. Collectively, these findings suggest that FDPS exacerbates NASH via AHR-CD36 axis and identify FDPS as a promising target for NASH therapy.