A1AT dysregulation of metabolically stressed hepatocytes by Kupffer cells drives MASH and fibrosis.

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with the activation of Kupffer cells (KCs) and hepatic stellate cells, at which point a metabolically stressed hepatocyte becomes integral to the progression of the disease. We observed a significant reduction in the level of alpha-1-antitrypsin (A1AT), a hepatocyte-derived secreted factor, in both patients with MASH and mice fed a fast-food diet (FFD). KC-mediated hepatic inflammation, most notably IL-1β, led to the transcriptional inhibition of A1AT by HNF4α. In quintuple Serpina1a-e knockout mice, ablation of A1AT worsened MASH through increased activity of proteinase 3 (PR3), a proinflammatory protease produced by F4/80^hi/CD11b^low/TIM4^-/CCR2⁺ monocyte-derived KCs (MoKCs). C

SUBMITTER: Park JS 

PROVIDER: S-EPMC11873038 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature