Figure 1.

Histopathologic analysis of young adult liver-specific METTL3 knockout (M3LKO) mice demonstrates development of abnormal liver architecture and function. A: Representative liver pictures of 5-week–old wild-type (WT) and M3LKO mice. B: METTL3 depletion in M3LKO mice demonstrated by quantitative real-time RT-PCR (left panel) and immunoblotting of whole liver extracts (right panel). C: Immunohistochemical analysis demonstrates METTL3 depletion in the hepatocytes but not in nonparenchymal cells (NPCs). Yellow, red, and black arrows denote WT hepatocytes, NPCs, and M3LKO hepatocytes, respectively. D: Liquid chromatography–mass spectrometryanalysis of m⁶A residues in liver poly A⁺ RNA represented as m⁶A/A and m⁶A/G showed significant decrease in the WT and M3LKO mice. E: Representative microscopic pictures of formalin-fixed, paraffin-embedded liver sections of 5-week–old mice stained with hematoxylin and eosin (H&#). Yellow and red arrows denote ballooned (steatotic/apoptotic) and pleomorphic hepatocytes, respectively. F: Analysis of serum alanine phosphatase (ALP) and alanine aminotransferase (ALT) in 5-week–old mice. G: Representative images of H&E-stained liver sections of 10-week–old mice demonstrated apoptotic hepatocytes (yellow arrows), pleomorphic nuclei (red arrows), ductular reactions (white arrows), mitotic (yellow circle), and foci of altered hepatocytes (white circle). Data are expressed as relative METTL3 expression per sample (B). ∗∗P < 0.01 versus WT; ^†††P < 0.001 (t-test); ^‡P < 0.05, and ^‡‡‡P < 0.001 (Welch t-test). Scale bars = 5 mm (A); 200 μm (C and E); 100 μm (G).