Curcumin Corrects Hepatocyte Compartment‐Specific p300 Dysregulation in Mitigation of LPS/D‐Galactosamine‐Induced Liver Injury in Mice

ABSTRACT

Curcumin, a selective histone acetyltransferase p300 inhibitor, demonstrates to attenuate liver injury. However, the precise molecular mechanisms underlying its epigenetic regulation of metabolic‐inflammatory pathways in hepatocytes remain incompletely understood. Here, we demonstrated that curcumin alleviated LPS/

‐galactosamine‐induced liver injury characterized by serum ALT/AST hyperactivities, histopathological lesions, and intrahepatic lipid accumulation, in mice. Curcumin suppressed hepatic overphosphorylation of IRS1 at Ser ³⁰⁷ and IRS2 at Ser ⁷³¹ . It also attenuated mRNA overexpression of sterol regulatory element‐binding protein 1c and fatty acid synthase. Additionally, curcumin inhibited overphosphorylation of phosphoinositide 3‐kinase p85α at Tyr ⁶⁰⁷ , mammalian target of rapamycin at Ser ²⁴⁴⁸ , IκB kinase α/β at Ser ^176/180 , and nuclear factor κB at Ser ⁵³⁶ . Importantly, immunofluorescence, Western blot, and ELISA analyses demonstrated that curcumin reduced cytoplasmic p300 overaccumulation and hyperactivity while it restored nuclear p300 decrease and hypoactivity. These effects were validated in TNF‐α‐stimulated hepatocytes. Curcumin reestablished p300 homeostasis by normalizing nucleo‐cytoplasmic shuttling dynamics and prolonging nuclear retention. Colocalization analysis using Pearson's coefficient showed that curcumin reversed TNF‐α‐induced increase in colocalization ratio of cytoplasmic p300 to insulin receptor substrate (IRS) 1 and IRS2. Our findings suggest that curcumin corrects hepatocyte compartment‐specific p300 dysregulation to decouple insulin resistant‐lipogenic‐inflammatory crosstalk in mitigation of liver injury in mice.