Higher pNRF2, SOCS3, IRF3, and RIG1 Tissue Protein Expression in NASH Patients versus NAFL Patients: pNRF2 Expression Is Concomitantly Associated with Elevated Fasting Glucose Levels

Abstract

Non-alcoholic fatty liver disease (NAFLD) embraces simple steatosis in non-alcoholic fatty liver (NAFL) to advanced non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and cirrhosis. NAFLD patients often have metabolic syndrome and high risks of cardiovascular and liver-related mortality. Our aim was to clarify which proteins play a role in the progression of NAFL to NASH. The study investigates paraffin-embedded samples of 22 NAFL and 33 NASH patients. To detect potential candidates, samples were analyzed by immunohistochemistry for the proteins involved in innate immune regulation, autophagy, apoptosis, and antioxidant defense: IRF3, RIG-1, SOCS3, pSTAT3, STX17, SGLT2, Ki67, M30, Caspase 3, and pNRF2. The expression of pNRF2 immunopositive nuclei and SOCS3 cytoplasmic staining were higher in NASH than in NAFL (p = 0.001); pNRF2 was associated with elevated fasting glucose levels. SOCS3 immunopositivity correlated positively with RIG1 (r = 0.765; p = 0.001). Further, in NASH bile ducts showed stronger IRF3 immunostaining than in NAFL (p = 0.002); immunopositive RIG1 tissue was higher in NASH than in NAFL (p = 0.01). Our results indicate that pNRF2, SOCS3, IRF3, and RIG1 are involved in hepatic lipid metabolism. We suggest that they may be suitable for further studies to assess their potential as therapeutics.

Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans

“…The elevated levels of LEPR and SOCS3 mRNA in both the OAT and liver associated with IR indicate a post-receptor mechanism with a predominance of negative feedback in peripheral tissue. Our data align with the differences between MASLD and MASH biopsies in the presence of SOCS3 [130], as well as with studies showing that SOCS3 inhibition prevents M1 polarization of Kupffer cells and steatotic progression to inflammation [131]. This demonstrates that comparable events occur in the liver and CNS [132,133].…”

Liver Diseases: Science, Fiction and the Foreseeable Future

“…Also, in this Special Issue, Schwertheim et al examined selected protein expressions in liver tissue from MASLD/NAFLD patients to clarify their potential alteration in the progression from simple steatosis to NASH. The expression of pNRF2, SOCS3, and RIG1 (hepatocytes), and (bile ducts) was significantly higher in NASH than in steatosis; thus, these proteins might be assessed as potential therapeutic targets [19].…”