Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients

Abstract

BackgroundNonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes. Our aim was to investigate the relationship between NAFLD and impaired glucose metabolism in terms of insulin receptor substrate 1 and 2 (IRS1 and IRS2) expression in the liver.MethodsLiver biopsy was performed at the University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD who were not being treated with any diabetes or dyslipidemia drugs. Among them, 63 underwent liver biopsy after an overnight fast, and 83 at 5 h after an oral glucose tolerance test (OGTT). Differences in messenger RNA (mRNA) levels of several glucose metabolism-related factors were determined and correlated with hepatic histological changes assessed by NAFLD activity score. We prospectively followed up with the patients until May 2017.ResultsHepatic necroinflammation was significantly correlated with serum insulin levels and inversely correlated with IRS1 mRNA levels. In specimens obtained after an OGTT, hepatic necroinflammation and IRS1 expression correlated significantly with both peripheral and hepatic insulin resistance. We also found that hepatic β-catenin and glucokinase mRNA levels were elevated in patients undergoing liver biopsy after an OGTT, especially in those with less hepatic necroinflammation and a lower degree of fibrosis. A prospective cohort study showed that ballooning is the most significant risk factor for developing diabetes.ConclusionsThe decreased hepatic expression of IRS1 and β-catenin in NAFLD is linked to histological progression such as ballooning, and might lead to diabetes as a result of impaired glucose metabolism.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1472-0) contains supplementary material, which is available to authorized users.

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].…”

Role of Insulin Resistance in MAFLD

“…Moreover, expression of Irs1 was upregulated in mouse primary hepatocytes stimulated with recombinant Wnt3a, which can activate canonical Wnt/β-catenin signaling [ 187 ]. In immunohistochemical staining of liver biopsies from NAFLD patients, the staining intensities of β-catenin and Irs1 seemed to be positively correlated [ 188 ]. While downregulation of Irs2 accompanied by decreased gluconeogenic gene expressions was observed in both patients with simple steatosis and NASH, expression of FAS , a lipogenic gene, was not decreased and was strongly correlated with Irs1 expression in NAFLD, suggesting that selective insulin resistance via downregulation of Irs2 is present in the early stages of NAFLD in humans [ 165 ].…”

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

“…Hence, IR and inflammation form a vicious circle, each condition promoting the other and accelerating the development of NAFLD and other metabolic disorders in the presence of lipotoxicity [107]. In both obese and lean subjects, high IR was found to be the most significant predictive factor for NAFLD [108], and research showed that serum insulin levels are firmly associated with ballooning and hepatic lobular inflammation [109]. The intricate relationship between IR, NAFLD, and T2DM is based on a vicious circle.…”