Non‐alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle

Abstract

Molecular signaling events associated with the necroinflammatory changes in nonalcoholic steatohepatitis are not well understood. To understand the molecular basis of NASH, we evaluated reversible phosphorylation events in hepatic tissue derived from Class III obese subjects by phosphoproteomic means with the aim of highlighting key regulatory pathways that distinguish NASH from NAFLD. Class III obese subjects undergoing bariatric surgery underwent liver biopsy (8 NOR, 8 simple steatosis and 8 NASH). Our strategy was unbiased, comparing global differences in liver protein reversible phosphorylation events across the 24 subjects. Of the 3,078 phosphorylation sites assigned (2,465 phosphoserine, 445 phosphothreonine, 165 phosphotyrosine), 53 were altered by a factor of 2 among cohorts, and of those, 12 were significantly increased or decreased by ANOVA (P < 0.05). Statistical analyses of canonical signaling pathways identified carbohydrate metabolism and RNA post-transcriptional modification among the most over-represented networks. Collectively these results raise the possibility of abnormalities in carbohydrate metabolism as an important trigger for the development of NASH, in parallel with already established abnormalities in lipid metabolism.

Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease

“…Other causes of liver dysfunction, such as abnormal activation or inactivation of signalling pathways, might be overlooked. As an example, the GH-JAK2-STAT5 pathway strongly affects liver responses to metabolic and chemical insults in rodents 141 , yet the contributions of this and other signalling pathways to human NAFLD have not been directly tested using powerful approaches such as phosphoproteomics 142 . These knowledge gaps undoubtedly call for improved characterization of the animal models used in NASH research, the use of complementary techniques (such as integrative omics studies 143,144 ) and for careful translation of observations made therein to human pathology 145 .…”

Construction and Analysis of Protein-Protein Interaction Network of Non-Alcoholic Fatty Liver Disease

“…The findings of our literature survey confirmed the implication of the following: HSP90AB1 has been suggested as a possible biomarker in overweight and obese children with NAFLD [41]; HLA-B [42], CTNNB1 [43] and HSPA5 [44] are found to be abnormally expressed in NAFLD patients; CDKN1A polymorphism is associated with the development of human NAFLD [45]; TRAF1 has been also detected in NAFLD patients [46]; HSPB1 phosphorylation site has been differed between NAFLD cohorts [47]; SMAD4 was overexpresed in NASH patients [48]; SMAD2/3 phosphorylation and nuclear translocation documented in the liver of NASH patients[49]; RELA is well-known to cause inflammatory responses in NAFLD [50]; PIK3R3 has been proposed as an effective candidate target for the development of NAFLD [51]; GSK3B inhibition has been proposed as a possible therapeutic target to manipulate the NAFLD [52].…”

Identification of the Molecular Basis of Anti-fibrotic Effects of Soluble Guanylate Cyclase Activator Using the Human Lung Fibroblast

“…A total of 27 Ser/Thr phosphorylation events on SRRM2 were decreased upon sGC treatment (Table 6). Previously, two studies quantified changes in phosphorylation events of SRRM2 in the livers from simple steatosis, non-alcoholic steatohepatitis and cancer [32,33]. In these experiments, the phosphorylation events at Thr1003, Ser1083, Thr252, Ser395 and others were increased.…”