Src-phosphorylation at the α1-Na/K-ATPase Modulates Liver Cell Senescence and Microbiota Communuty Changes on Diet Induced NASH in the Rodent

Abstract

Background: The global incidence of chronic liver disease and its sequels ESLD and HCC are increasing due to obesity and increase in life expectancy. We hypothesized Western diet accelerates aging cell processes inducing liver cell portfolio to senescence/apoptotic activity with altered metabolic cycles and disturbed gut-microbiota communities mainly though a Src pathway. Methods: Mice were exposed to NMC or HFD. Livers and plasma were collected at weeks 12, 24 and 48. Body compartments were determined by MRI spectroscopy. The terminal ileum (TI) and its microbiota were collected. Total DNA was extracted from contents of ileum and microbial community profiling was achieved by sequencing 16S rRNA v3-v4 hypervariable regions. Quantitative protein expression of Tp53, mTOR1, Src, SIRT7, FOX01, Grb2 were determined by Western Blots. Principal component analyses (PCA) was conducted. Results: TBW increases with aging manly due to an increase in the fat compartment with decreased lean mass and total body water (p< 005); changes that correlated with an increased proportion of liver cells in senescence/apoptosis (p< 0.05). Morphological changes correlated with Src peak gene expression. A significant increase in Verrucomicrobia was observed in the HFD group when compared to the NMC group (p< 0.05). Additionally, a significant decrease in Bacteroidetes was noted (p< 0.05). pNaKtide, a 33 amino-peptide that blocks the activation of Src at the α1-Na/K-ATPase subunit abrogated metabolic, genetic and morphologic changes establishing a wild phenotype. Conclusions: Blockage of the α1-Na/K-ATPase//Src amplification loop restored both physiological liver cell aging, and wild type gut-microbiota communities.