Figure 6. Hepatocyte ketogenesis and tissue macrophage mitochondrial ketone metabolism independently and additively coordinate the hepatic fibrotic response in mice.

(A) XCMS online cloud plot of 1306 dysregulated chemical features when comparing antisense oligonucleotide (ASO)-treated control and Hmgcs2 ASO (ketogenesis insufficient) livers (n = 4/group) of mice maintained on HFD for 8 weeks. (B) Representative hematoxylin-eosin (scale bar, 50 μm) and (C) picrosirius red staining of liver sections from Hmgcs2 ASO-treated mice on the Oxct1^flox/flox control (Flox/Flox) and SCOT-Macrophage-KO backgrounds maintained on HFD for 8 weeks. CV, central vein; PV, portal vein. (D) Quantification of picrosirius red-positive area (% area/20× field) in ASO treated mice on Oxct1^flox/flox control (Flox/Flox) and SCOT-Macrophage-KO backgrounds (n>6/group). Quantification of picrosirius red-positive stain area (% area/20× field) in WT mice maintained on high fat fibrogenic diet and injected with (E) AcAc (n=7/group) or (F) D-βOHB (n=4/group) and their representative vehicles (ethanol for AcAc and NaCl for D-βOHB) twice a day with 10 μmol/g body weight each for 4 weeks. (G) Representative picosirius red stains of liver sections obtained from the AcAc and its vehicle groups. CV, central vein. PV, portal vein. Data expressed as mean ± SEM. Significant differences determined by Student’s t test, or ANOVA with multiple comparisons with Tukey post-hoc tests, as appropriate. * p < 0.05; **, p < 0.01; as indicated.